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Contents

Introduction

This image shows a colored SEM T lymphocyte [1]

T lymphocytes are a special class of lymphocyte possessing T-cell receptor (TCR) on their cell surfaces, which is the defining characteristic of T cells, setting them apart from other lymphocytes like B lymphocytes or Natural Killer cells in terms of classification. T-cells earn their name from their main organ of maturation, the Thymus, which provides the means for their selection and differentiation, as shown in [2][3][4] and reviewed in [5]. Some T cells also mature within the human tonsil[6].

T cells are a diverse population of cells which enable the immune system to be modulated and regulated very precisely to fit the necessary host response. It is well known that T cells play a crucial role in the immune system, particularly pertaining to adaptive immune responses and cell-mediated immunity. As reviewed in [7], T-cells are able to determine the presence of immunogenic material by recognizing fragments of the target antigen displayed as part of the MHC cell surface receptors of target cells. Antibodies, one the other hand, as reviewed in [7], have binding specificity for intact antigen. As reviewed in [7], the majority of T cells, αβ T cells, as part of the host immune response, recognise antigen fragments, usually peptides incorporated into the class I or class II MHC molecules of the infected cell, in order to evoke an adaptive immune response. On the other hand, as reviewed in [8], γδ T cells, making up only a small fraction of total human T cells and functioning as part of the innate immune system with increased invariability, initiate more rapid immune responses. Nevertheless, as reviewed in [8], γδ T cells have some adaptive characteristics owing to their T cell receptors.

Since established acceptance of T-cells as a distinct type of lymphocyte in 1970[9], new classifications and characteristics of T cells have been discovered relevant to their structure, function, and roles in current research and clinical implications. This wiki will serve as a systematic overview of current information pertaining to T cells.

The following is a YouTube video by Handwritten Tutorials outlining the path by which T lymphocytes can develop from lymphoid progenitor cells:

Cells of the Immune System  

YouTube Link

History

Year Finding
1961 Found that the thymus plays a role in immune function, [2]
1964 Found that small lymphocytes continuously re-circulate through blood, lymphactics and secondary lymphoid tissue, [10]
1966 Found small lymphocytes have immunological memory potential, [11]
1967 Proposition of two major subsets of Lymphocytes, [12]
1970 Became widely accepted that Thymus derived (T cells) are distinct from antibody-forming (B cells), [9]
1972 T cells are found responsible for allogeneic cytotoxicity, [13]
1979 Generation of first monoclonal T cell, [14]
1983 Discovery of T cell antigen receptor (TCR) that consists of a disulfide linked heterodimer with both constant and variable regions, [15] , [16]
1984 Discovery of the TCR b locus and the basis for TCR diversity, [17], [18], [19]
1987 3D crystalline structure of class 1 MHC determined, [20]
1989 Discovery that CD8 glycoproteins expressed on cytotoxic T lymphocytes recognise antigens presented by class 1 MHC, [21]
1994 Demonstrated the CD8 T cell memory could be maintained in the absence of antigen [22]
1995 Regulatory T cells discovered [23]
1999 Found that memory CD4 T cells could persist long-term in the absence of MHC molecules[24]
2001 Discovery of FOXP3 gene and its involvement with T regulatory cell development [25]
2002 - 2003 Notion that T cells differentiate into memory T cells as a continuum [26]
2006 Role of Interleukins 7 and 15 in memory T cell maintenance and division through homeostatic proliferation [27]
2007 Discovery of the interplay between CD4 T cells and CD8 T cell in the development of memory CD8 T cells [28]

Commonalities between T cells subtypes

Functions

Model Figure of T Cell Migration 
Migratory challenges faced by T cells [29]


Two main T-cells are taken a part of the immune response. Especially dendrite cell takes huge part of T-cell activation[30], when they find the antigens, and they phagocyte antigens to process MHC on their surface, then it became APC (antigen presenting cell), before they bind with the APC we call them a naïve T-cell, this naïve T-cell never with antigen thus never activated. When CD4+ T cells also called helper T- cell has the CD4 co-receptor in their surface and them active when they bind with the APC with MHC class II[30]. Once they activate they become effector T-cell and memory T-cell and start to secret protein called cytokines to activate B-cells and cytotoxic T-cells. Helper T-cell differentiates into several subtypes such as Th1, Th2, Th3, Th17 and Th17 regulatory cells[31]. The second type of T-cell is CD8+ T cells, we call them as cytotoxic T-cell, they combine with the presenting MHC class I in APC, and also they become memory and effector cell[32]. The effector cytotoxic T-cell directly kills the infected cell and abnormal cancer cells.

z3465531 Grammar edit (awaiting approval):

CD4+ T cells and CD8+ T cells are the two main types of T-cells that take part in the immune response. Dendritic cells also play an especially huge part in T-cell activation[30], when they find and phagocyte the antigens to present them as part of the MHC on their surface. Subsequent to this process, the cell is referred to as an APC (antigen presenting cell). Before T cells bind with the APC, they are called naïve T-cells, which have never been in contact with antigen and thus never activated. CD4+ T cells, also called helper T-cells, have the CD4 co-receptor in their surface and TCRs with an affinity for the APC of MHC class II[30]. Once these CD4+ T cells activate they become effector T-cells and memory T-cells and start to secrete proteins called cytokines to activate B-cells and cytotoxic T-cells. Helper T-cells differentiate into several subtypes such as Th1, Th2, Th3, Th17 and Th17 regulatory cells[31]. The second type of T-cell is CD8+ T cells, called cytotoxic T-cells. Cytotoxic T-cells combine with the MHC class I presenting in APCs, and they also become memory and effector cells[32]. The effector cytotoxic T-cell directly kills the infected cell and abnormal cancer cells.


T Effector vs. T Regulatory Cells

However, regulatory T cell has different function from effector T cells. This regulatory T cell is more focusing on the suppress or down-regulate inducing and proliferation of effector T cells[33]. This is also subtype of T cell that prevent our body cell from the autoimmune disease and maintain tolerance to self-antigens[34]. This is very important because immune system destroys cells and tissues of the body when self/non-self discrimination fails, and this result in autoimmune diseases[35]. Tregs have the maker on the surface such as CD4, Foxp3 and CD25, and this maker that tells us Tregs derived from the same lineage as naïve CD4 cells[36]. Recent research has found that cytokine TGFβ is necessary to differentiate Tregs from the naïve CD4+ cells and important role in retaining Treg homeostasis[37].

z3465531 Grammar edit (awaiting approval):

However, regulatory T cells have different functions from effector T cells. The regulatory T cell is more focused on suppressing or inducing down-regulation, or proliferating effector T cells[33]. Regulatory T cells are also a subtype of T cell that prevents our body cell from autoimmune diseases and maintains tolerance to self-antigens[34]. Such functions are very important because the immune system destroys cells and tissues of the body when self/non-self discrimination fails, resulting autoimmune diseases[35]. Tregs have markers on their surface such as CD4, Foxp3 and CD25, and these markers indicate that Tregs are derived from the same lineage as naïve CD4 cells[36]. Recent research has found that cytokine TGFβ is necessary to differentiate Tregs from naïve CD4+ cells and plays an important role in retaining Treg homeostasis[37].


Migration and the Cytoskeleton

Lymphocyte rosettes [38]

The cytoskeleton of T cell is made of a dynamic filament meshwork that assemble the structure of the cell to maintain the its essential features. The cytoskeleton of the T cell gives the mobility that allows circulating within the blood stream, migrating through tissues, interacting with the APC[39]. To gives a mobility the physical structure of the T cell has to continuously remodeling. Circulating T cell in the blood stream can perform by short microvilli. This microvilli consists of bundles of highly dynamic actin filaments[40]. when the T cell interacts with soluble and endothelium-displayed chemokines induce microvillar and T cell is squeezing between endothelial junctions to enter the underlying tissues[41]. when the T-cell is inside the morphology of the cell changes to “hand mirror”. The motility of the T-cell in the tissue performs by F actin rich. The F actin filaments push the cell forward. The speed of the T-cell movement is much faster than most nonhematopoietic cells, average speed is 10 μm/min, and reaching rates of 25 μm/min10[42].For the last, T-cell forms a tight contact rich in branched actin filaments when T-cell recognise an APC. The contact between T-cell and APC forms immunological synapse (IS), and also making a scaffold for protein sequestration at the distal pole complex (DPC)[43].

z3465531 Grammar edit (awaiting approval):

The cytoskeleton of a T cell is made of a dynamic filament meshwork that forms the structure of the cell and maintains the cell's essential features. The cytoskeleton gives the T cell mobility that allows circulating within the blood stream, migrating through tissues, and interacting with the APC[44]. In order to achieve mobility, the physical structure of the T cell has to be continuously remodeled. Circulating T cells in the blood stream can perform movement by short microvilli. These microvilli consist of bundles of highly dynamic actin filaments[45]. When the T cell interacts with soluble and endothelium-displayed chemokines, (induce microvillar and?) the T cell is squeezing between endothelial junctions to enter the underlying tissues[46]. When the T-cell is inside, the morphology of the cell changes to “hand mirror”. The motility of the T-cell in the tissue is performed by F actin filaments which push the cell forward. The speed of the T-cell movement is much faster than most nonhematopoietic cells, averaging a speed of 10 μm/min, and reaching rates as high as 25 μm/min[47].For the last, the T-cell forms a tight contact rich in branched actin filaments when T-cell recognises an APC. The contact between T-cell and APC forms an immunological synapse (IS) and also makes a scaffold for protein sequestration at the distal pole complex (DPC)[48].

Structure

There are two main lymphocytes which are T-cells and B-cells, T-cell is about 70% and B-cell is about 20% of the lymphocyte in the blood. T-cell is located in different place as different functions, cytotoxic T-cell can find in the cytosol, and helper T1 cell can find in macrophage vesicles, and helper T2 cell can find in extracellular fluid. T-cell plays an important role such as activation of phagocytes, natural killer t cell and release cytokines to an antigen responsively. The reason why we call them as T-lymphocyte, because the stem cell from the bone marrow migrate to the thymus and the cell matures in the thymus.[49].


T Cell Morphology

B and T cell comparison [50]

The morphology of the T-cells is round shaped cell. There are many other round shaped cells such as red blood cells and B-lymphocyte. In the histological picture, B-lymphocyte has the most similar morphology, and these cells are not distinguishable before the cells are activated by antigen. It remains in the form of resting A or B cell as the figure shows. Moreover, T-cell has the similar organelle to other cells such as the nucleus, endoplasmic and so on[51], so how do we distinguish T-cell from other cell? The difference of the size is one of the factors to distinguish them from other lymphocytes. In the normal histological picture without the marker, it can not tell the difference between T-cells and B-cells. T-cell and B-cell are belonging to the small lymphocyte size in 7 to 10 µm, but as you can see from the figure comparing the size of T-cell to B-cell, B-cell is larger than the T-cell. Moreover, B-cells are filled with largely rough endoplasmic reticulum, but T-cells have very little endoplasmic reticulum[52]. This seems logical, as key feature of B Cells is production of high amounts of BCR and Antibodies, whereas T Cells are rather focused on cytokine action. For both B and T cells, the nucleus fills the majority of the cell and the ratio of nucleus to cell diameter is similar in both T-cell and B-cell with a ratio of 0.9 nucleus diameter divided by cell diameter[52].

Location

T Cells are found in the bloodstream as circulating T Cells and embedded in connective tissue, such as the lamina propria of the gut. However, the biggest density is found within secondary lymphoid organs, such as Tonsils, Spleen, Lymph nodes and peyer's patches in the gut, as reviewed by [53]. There is a specific tissue within the secondary lymphoid organs, surrounding the medullary sinus, that host mainly T cells. B cells and T cells are, thus, normally separated and cannot invade it's counterpart's specific tissue. This is important as B cells are most often, in fact, dependent on T cell activation. T cells must be specifically designed to invade this B cell specific tissues, an aspect with T Follicular Helper Cells will cover more in depth

Structure of TCR as its interacting with a MHCII receptor presenting an antigen on an antigen presenting gene. It is further presented, how the gene structure of the B locus of the TCR gene is comprised[54]


T Cell Receptor and Co-receptors

The markers on the surface are the factor of the differentiating T-cell from other cells. The markers are the T cell receptors. The common structure of the T cell is presenting of TCR and coreceptor on their surface of the cell. The TCR is analogous to a Fab fragment of BCR and Antibodies. Two protein chains, called heavy and light chains, are connected by disulfide bonds to form the TCR homo-dimer receptor. Equivalent to its Fab counterpart, TCR heavy and light chains are comprised of a constant (C) region and a variable region (V). The variable region contains, the so called CDR, complementary determining region. The CDR is the part of the TCR that actually interacts with an antigen. As such, they must be individual for each T Cell. This is achieved by VDJ-gene rearrangement, which is further elaborated in the development subsection. Due to its uniqueness, the variable region received its name. the C-Region, in contrast, does not display such heterogenity. Besides the CDR region, there is another source of heterogenity.

Two subtypes of TCR monomers exist, which will dimerize to form the TCR dimer. The alpha (α) and beta (β) monomers account for about 95% of the human TCRs, while 5% consist of gamma and delta (γ/δ) chains. Most of the γ/δ-TCR are found in the gut. No difference in function, however, has been described yet[55]. The concept of the T cell receptor is simple. The figure on the right side shows that T cell receptor is supported by CD3δ/ε, CD3γ/ε andCD247 ζ/ζ or ζ/η[56][57]. And other co-receptor helps that particular antigen can bind to the T cell receptor. There are three well-known co-receptors such as CD3, CD4, and CD8 with each different co-receptor defines the name and function of the T cell. T cell with co-receptor CD3 helps to activate the cytotoxic T cell, and co-receptor CD4+ which combines with MHC class II will become matured helper T cell[58] , and T cell with co-receptor CD8+ which combines with MHC class I will become cytotoxic T cell[59]. The CD3 consists of chains such as CD3γ, CD3δ, and CD3ε. The chains are highly connected to the surface of the T-cell. TCRα is related with CD3δε, and TCRβ with CD3γε, and then the ζζ module associated with TCRα[56]. The CD4 has 4 immunoglobulin-like domains which are called D1, D2, D3 and D4. D1 is used for contacting with the β2-domain of MHC class II molecules[60]. The CD8 forms a dimer, and it is commonly composed both CD8-α and CD8-β chain. These chains interact with the MHC Class I molecule.

Morphological Changes during Activation

The T Cell cytoskeleton is highly dynamic and drastically changes shape during activation. The TCR is directly linked to the actin cytoskeleton via the signaling adapters Nck (non-cytalytgtic region of tyrosin kinase), LAT (linker for activation of T Cells) and SLP76 (SH2 domain-containing leukocyte protein, 76kDA molecular weight) and others. They directly interfere with several actin polymerfisation regulatory proeins like cofilin, Arp2/3 an others. This will lead to polarization of the microtubuli organizing center (MTOC) towards the TCR in case of antigen activation [55]. This actin and microtubuli rearrangement eventually leads to generation of a structure called the immunological synapse, the MHC/TCR complex [56][57][58][59].

Development

Diagram of production site and lineage of lymphoid progenitor offspring. Lymphoid progenitor cells are created in t.he bone marrow and mature either in the thymus or bone marrow[60]
T Cell Development  

YouTube Link

Bone Marrow

Analogous to all blood cells, T Cell development begins with hematopoietic stem cells in the bone marrow (from greek, haime: blood, poenin: to create).

Bloodstream

T cells begin to differentiate making their way to the thymus through the bloodstream [61]. Settling of these lymphoid progenitor cells in the thymus is a continous regulated [62] and periodic process [63]. The mechanism these progenitor cells enter the thymus is mostly unknown, yet believed to be analogous to other leukocytes. The process, reviewed by von Adrian, UH et. al. in [64] begins with the loose adherence to blood vasculature via selectins and integrins which results in rolling, as the result of a chemokine gradient. This initial loose adherence is followed by tight adhesion and eventually entrance into the stroma across the endothelium.

Thymus

As soon as lymphoid progenitors enter the Thymus, they are termed thymocytes. Entering at the cortico-medullary junction of the thymus, the thymocytes travel through the cortex. The cortex is the outermost layer of connective tissue, into which lymphocytes are embedded. After traveling through the cortex they arrive at their final destination, the subcapsular zone of the thymus. There, the thymocytes subsequently run through several stages of differentiation T1 cell can find in macrophage vesicles, and helper T2 cell can find in extracellular fluid.

This image shows fluorescently labeled cell types in a lymph node, showing typical structure of a secondary lymphoid organ. More specifically, it is a Transverse mouse lymph node section depicting a ring of subcapsular sinus macrophages (CX3CR1-GFP, green) wrapped around numerous B cell follicles (anti-B220, blue) with the T cell zone (T cell-specific dsRed, red) located centrally.[65]

Double Negative stage

At first, the thymocytes do not possess CD4 and CD8 and are referred as double negative (DN, CD4-/CD8-). The expression of CD4/8 marks the point in T Cell development, where they are differentiable from B Cells. DN T Cells pass through four stages of selection, before they start to express all the corresponding receptors and surface proteins. The fourth stage of DN differentiation is where the αβ or γδ pre-TCR actually form. [66].

V(D)J Recombination

During those DN selection steps, the pre-TCR undergoes V(D)J recombination, a process that occurs both in B cells and T cells. V, D, and J are gene regions in the β locus of the TCR gene and make up the variable region of the TCR (see T Cell structure for TCR structure). There are various copies of each the V,D and J gene in the β locus. From every gene, only one gene copy gets selected, and the rest are spliced out by RAG1 and RAG1 (recombination activating genes) activity. This process is induced by signals from an already assembled receptor (reviewed in [67])[68]. This allows a great deal of different combinations, leading to highly unique receptors. Besides V(D)J rearrangement, somatic hypermutation, and mutations during the V(D)J rearrangement provide an incredible variety of TCR (reviewed in [69]). Following this tightly regulated process, T cells are generated with a single, specific TCR protein for each specific antigen [70].

Double Positive stage

Cells then move into the double positive (DP) stage, where CD8 and CD4 transmembrane proteins are expressed on the surface. This order of events is mandatory, as the TCR is required for double positive selection. During this stage 'positive' and 'negative selection' occurs (reviewed in [67]).

Positive Selection

Positive selection allows survival only of cells that are able to trigger a viable, positive immune response. Key step for the initiation of an immune response is significant MHC/TCR binding. Cells that have TCRs that are not able to readily attach to an MHC undergo apoptosis. In fact, 90% of the thymocytes that pass through the DN selection stages have too weak binding and will undergo apoptosis [71] [72].

Negative Selection

Negative selection, the most critical step, purges cells that are self-reactive. Self-reactivity is tested in a highly orchestrated fashion: cortical epithelial cells of the thymus will present self-antigens, which should not trigger an immune response. Any T cell that will interact with the self-antigen undergoes apoptosis. This stage is essential: self-reactive cells are the hallmark of all autoimmune diseases, such as multiple sclerosis (reviewed in [73]). Approximately 5% of all cells are auto-reactive. Negative selection is a biological process is prone to errors. To counteract self-reactive T Cells, T regulatory cells are employed [71]. The many models in which negative selection occurs are reviewed in [67].

As reviewed in [74] the CD4/CD8 linage is determined through a multitude of complex signalling. The exact mechanisms are not fully understood yet with many models proposed. Ultimately T cells that bind to MHC-class-II-peptide complexes differentiate into CD4+ T cells, whilst DP cells that bind to MHC-class-I-peptide complex differentiate into CD8+ T cells.

Only 2-4% of of intrathymic lymphocytes that undergo V(D)J recombination get released as peripheral T lymphocytes [75].

Types of T-Cells

There is a plethora of different T Cell subtypes. Each of those subtype appears then again to have even more different subpopulations. Defining the different subtypes and distinguishing them from one another is one of the key achievements that are continuously made in T cell research. Before going into the different T Cell subtypes, one should become aware of a fact, that is ever-present in the immune system and only further highlighted by the extensive individuality of the mass of T cell subtypes: The immune system is incredibly adaptable. Each and every situation seems to have a tailor fit solution comprised of different types of T cells, forming subtypes and subpopulations dependent on the specific requirements of every individual case. Besides that, just like B Cells, T Cells posses this incredibly individual TCR createt by V(D)J recombination. The following subtypes should be taken as they are: a model to simulate and understand, and at some point in the future, possibly even exploit the complexity of the immune system. Most T cell subtypes are distinguished through surface markers and the majority seems to have one or a combination of transcription factors specific for that subset. It is, however, an ongoing discussion to what extent T cells may be subtyped and what a T cell needs to display to be considered a distinguished subtype. Just as any model, the accuracy of the different T cell subtypes are constrained and evolving and are by far not able to explain everything in the incredible interaction of T cell subtypes with each other and further other cells and systems.

The following table provides a quick summary of the following paragraphs. All information and their respective references are found in the corresponding subsections

Subtype Function Markers
T Helper Cells Helper cells may be imagined as the generals of the immune system commanding innate and adaptive immune cells . Their main task is secretion of cytokines and activation of B Cells to produce Antibodies CD4
Cytotoxic T Cells cytotoxic T cells patrol the ithe body to detect affected cellls. They are able to kill any nucleated infected cell of the body to interrupt with the pathogen proliferation. CD8
Regulatory T Cells cytotoxic T cells patrol the ithe body to detect affected cellls. They are able to kill any nucleated infected cell of the body to interrupt with the pathogen proliferation. CD4+,CD25+,FoxP3+
NKT Cells NKT cells are a diverse subset of T cells, but the typical NKT cell, known as the Type 1 NKT cell or iNKT cell, upon activation presents self or foreign lipid antigens to a variety of APCs expressing CD1d, including dendritic cells, B cells, neutophils, and macrophages. The NKT cell also releases cytokines to activate or regulate these cells as well as activate MHC-restricted T cells and NK cells. In this manner, NKT cells serve as an essential communicator between the innate and adaptive immune response. IL12R, CD40L
Memory T Cells Every T Cell subtype possesses it's own Memory Cell pool. Memory cells most often travel back to the bone marrow where they reside quiescent and provide immunity against antibodies that have already affected the body once. Dependent on the pathogen, Memory cells can get decades old CD45R


T-Helper Cells

This image shows a colored SEM T Helper Cell surface (blue) covered by HIV-1 (yellow)[76]
Helper T Cell Tutorial  

YouTube Link

Function

The main function of the helper T-cell is activating T-cell dependent B-cell to release antibody and also activating cytotoxic T-cell and macrophages. Simply put, T Helper cells are the cytokine factories ochestrating immune responses. The dendritic cell is taking a huge part in activation of T-cells. The dendritic cells present in mucosa when they find the antigen they eat the antigen and chop the protein of the antigen. Once they digest antigen, and they present the chopped protein in the MHC class II on their surface. Activation of T-cell happens when the naïve helper T interacts with the MHC class II of APC, CD4+ helper T cell actives[77], it differentiates to memory helper T-cell, effector helper T-cell and regulatory T cell. The effector helper T-cell produces cytokines to activate other leukocytes, including helper T-cell. The memory helper T-cell contains the antigen that actually activate T-cell, and this memory helper T-cell uses for the second immune response[78]. The regulatory helper T cell does not help immune response, but it regulates and decrease the response. These cells are supposed to play an important role in the self-limitation of the limitation of the immune system, and also, autoimmune diseases are prevented by the regulatory helper T cell. There are several T-cell subtypes such as Th1, Th2 and Th17. These subsets are namely different as they play a different role in the immune response. First, Th1 cell is trigged by IL-2, IL-12, and the effector T-cell secretes cytokine which is IFN-γ. This IFN-γ actives macrophages, CD8 T cell, IgG B cells and IFN-γ CD4 T cells[79]. The activated macrophages phagocytose the intracellular bacteria and virus. Second subtype Th2 is trigged by IL-4 and they secrete cytokine which are IL-4, IL-5, IL-9, IL-10 and IL-13[80][81]. The main effector cells are B cells and CD4 T cells, also eosinophils, basophils and mast cells. Th17 is protecting our body from pathogens at the site of mucosal surface. They called as Th17 because they secrete IL-17[82]. Th17 is related to T regulatory cells and also autoimmune and inflammatory disorders[83].

Further information on T-Helper Cells


Development

During the double positive stage, the thymocytes can interact with thymic cortical epithelial cells The double positive thymocyte interacting with MHC class II will develop into naïve CD4+ T-cells and migrate to peripheral lymphoid organs.

There are 4 stages of the activation of naïve helper T cells. First, recognition stage, in this stage This migrated naïve CD4+ T-cells are ready to interacts with APC, and they bind to the MHC class II. TCR are continuously phosphorylated and dephosphorylated by phosphatases (CD45). CD45 is common leukocyte antigen and the factor that helps interaction between naïve T-cell and APC[84]. When CD45 shortens, it is easier to interact and activate an effector helper t cell.

The second stage of T cell activation is verification(signal 2). Once the CD4+ T cell interacts with MHC class II, naïve T cell needs a second independent biochemical pathway. Without this second signal, T-cell assumes that it is auto-reactive. T cell will not a response to any antigen, this called anergic T cell. anergic T cell will die by apoptosis. the second signal is a relationship between CD28on the CD4+ T cell and the proteins CD80 or CD86 on the APC[85]. When the naïve T cell has both pathways activated, the only first signal is necessary for future activation. This is also known as memory T cell, which is the faster immune response because memory T cell has already gone biochemical changes and can produce effector cells much faster.

The third stage is proliferation. Once the two-signal activation is accomplished, the T cell proliferation occurs by releasing a potent T cell growth factor called IL-2. The Th0 cells forms after the helper T cell receiving both signals of activation and proliferation. This Th0 cell secretes IL-2, IL-4 and interferon gamma (IFN-γ), and Th0 differentiates to Th1 and Th2. IFN-γ leads Th2 cell production while IL-10 and IL-4 inhibit Th1 cell production. Unlikely, IL04 leads Th2 cell production and IFN-γ inhibits Th2 cells.

The last stage is maturation. After T-cell has gone through all of the processes, T-cell differentiates to an effector, memory and regulatory helper T cells.

Structure

CD4 and CD8 co-receptor [86] The structure of the helper T-cell can distinguish to the other T-cell. For example, comparing with the cytotoxic T-cell, helper T-cell has CD4 co-receptor on their surface unlikely cytotoxic T-cell has CD8[87]. Moreover, the functions of the helper T-cell are different from the other CD8 T-cell and B-cell. As you can see it from the name, the main function of the helper T-cell is helping immune response of other lymphocytes[31]. They activating the macrophages and cytotoxic CD8+ T cell, and also they active B-cell to produce antibodies. However, the cytotoxic T-cell and another macrophage act as the direct killer for the antigen, and the B-cell is producing the antigen.

Subsets

T Cell subtypes, functions and differentiation factors[88].

There are various T Helper Cell subsets. As an individual presentation would go over the scope of this page, one type was described in detail. The described type is key for one of the T cell main functions, activation of B cells, which is why this specific type is explained in detail. Other known T Helper Cell subtypes may be seen in the diagram on the right.

Follicular B helper T cells

[89][90] and [91] provide a thorough overview of Follicular B helper T Cells (Tfh). The importance of Tfh is obvious if one remembers the strong spatial separation between T and B Cells in secondary lymphoid organs. As secondary lymphoid organs provide by far the biggest defense structure and the major player in most immune responses, B and T cell interaction must be heavily coordinated. B cells most often require T cell activation before acquiring plasma B cell morphology and being able to retort any humoral immune attack. Follicular B helper T Cells, as their name would indicate, are able to enter the B cell follicle, a structure near the cortical epithelium of the lymphoid organ. Upon antigen contact, germinal centers form withing the follicle. Germinal centers are areas of activated B Cells, producing cytokines, and most importantly, producing antibodies. Germinal centers require Tfh, as they are able to invade and get into close enough contact with the B cells, to be able to bind the MHCII antigen presenting receptors on B cell surface with their TCR and CD4 co-receptor and thus start to activate follicular B Cells (FoB) through IL4 and IL21. IL21 is crucial in plasma cell differentiation and one of its key drivers. Responsible for the unique properties of Tfhs are certainly surface receptors which allow binding to B cells. Just as other T Helper Cell subsets, Tfh possess a master regulatory gene which will induce most of phenotype. This master regulatory gene is Bcl-6. Bcl-6 will affect microRNA expression, miRNA is a key driver of differentiation processes (reviewed [89][92]. Besides follicular B cells, also follicular Dendritic cells (fDC) are in stark contact with Fth. fDC form the antigen presenting entity within follicles, they are required for both T and B cell activation. Tfh cells are mainly characterized by expression of the CXCR5 surface receptor. CXCR5 is normally expressed on follicular B cells and allow to bind onto CXCL10. CXCL10, expressed by fibroblasts in follicular stroma, is found primarily within follicles and thus serves as signpost for follicular B cells[93]. Tfh thus are exclusively selected to enter follicular zones within secondary lymphoid organs by expression of CXCR5 Tfh also posses the CD40L, which allows binding to the CD40R on follicular B cells and make Tfh able to connect enough closely to B cells to activate them. Additionally, Follicular B Cell express ICOSL which will bind to ICOS expressed by Tfh. Also crucial is the Inducible T Cell Costimulator (ICOS). As MHCII interacting T Cells, Tfh must further posses a CD4 costimulatory receptor. As always in cell biology, adhesion does not only serve mechanical but also signaling properties. Hence, it is no surprise that CD40L/CD40R interaction will lead to bi-directional signaling, in both FoB and Tfh.

Clinical Implications and Disease

Autoimmune Demyelination

Myelin in the CNS contains proteins and lipids. This component could recognise as foreign by the immune system. Autoimmune demyelination is the term that our immune system attacks our myelin. This research found inhibition of sulfatides dependent navie T helper cells. The sulfatides are consisting major component of myelin glycolipids. The effect of sulfatides was not related to necrosis or apoptosis but they are upregulating two transcription factors in the early growth of T cell. This research found that Sulfatides inhibit navie T cell. Moreover, glycolipid 3-sulfate group was essential for the T cell suppression, and the T cell inhibition was galectin-4-dependent. The Th17 that is known as the major effect for autoimmune demyelination is inhibited by sulfatides. Therefore, following result shows that sulfatides can prevent autoimmune demyelination. It could be relevant for future treatment of the MS.[94]

autoimmune diseases  
here's a interesting discussion about th17 cells involved in Autoimmune demyelination such as MS. Look it up

HIV

Schematic model of HIV-1 replication and restrictions thereof in activated and resting CD4+ T lymphocytes[95]


Cytotoxic T Cells

Lattice Light-Sheet Microscopy Reveals Actin Dynamics in Conjugating T Cells as attacking a cancerous cell.[96]

Function

The role of cytotoxic T Cells (CTL) is to kill virally or bacterial infected or tumorigenic cells. As such, CTL must be able to do three things. Firstly, the differentiating factor of being able to bind to any cell within the body. This is achieved by the CD8 co-receptor. The CD8 co-receptor allows CTL to bind to MHCI, which is expressed on all nucleated cells. Secondly, CTL must be able to first recognise infected cells in order to destroy them. This is achieved by the presentation of proteins from the pathogen (viral/bacterial proteins) on MHCI receptors. CTL will, thus, only bind to infected and therefore death-sentenced cells. Lastly, they must be able to kill the infected cells. Cytolytic proteins contained in vesicles that get secreted by CTLs do this. The main killing mechanisms are perforins, granzymes, and FAS dependent death signalling [97].

Further Information on CTLs

Development

Dendritic cells directly stimulate naïve CD8 T cells by presenting antigen fragments in complex with MHC class 1 surface proteins. This antigen-MHC complex binds to the CD8 and TCR receptors that recognised the specific peptide fragment, and the cell becomes an antigen-specific CTL.

CD4+ helper T cells cell must also recognise the antigen-MHC class 2 complex on the same dendritic cell, this leads to generation of memory T cell and allow repetitive stimulation of cytotoxic T cells (reviewed in [98], [99]).

Inflammatory cytokines, in particular IFN-y, IL-12 and type I IFNs (IFN-a/b) play additional signalling roles in co-stimulating and determining T cell response [100].

Activation

MHCI molecules are found on the surface of all nucleated cells in the body. When a cell is infected with a virus or other pathogen rather than express ‘self house-keeping’ proteins of this pathogen are fragmented within the host cell, and these peptides become expressed through the MHCI [101].

CTLs are activated upon the binding of both their TCR and CD8 co-receptor to the same peptide-MHCI complex, as reviewed in [102]. The variable region of the TCR recognises the specific peptide antigens presented by the MHCI molecules on the surface of target cell [103], [101]. The CD8 stabilises the bond through contact with the non-polymorphic region of MHCI [103]. This CD8 - MHCI interaction serves as the first of two major signals in activation [104].

The second major signal is triggered by the association of B7-1 (CD80) or B7-2 (CD86) ligands on APC with the CD28 molecule expressed on the T cell [104]. CD28 signals promote production of cytokines, proliferation and survival of CTLs [reviewed in [105].

A CTL response may not always be elicited as many tumour cells will not express the B7-1 ligand, without full co-stimulation the T cell enters a state of hypo-responsiveness [106], leading to a less efficient immune response [107], [108].

Once the CTL is activated it secretes cytokines, with the major one being IL-2 that assist in clonal expansion, resulting in a larger population of cells that can detect specific antigenic somatic cells [109]. These signals also assist in the survival of the cell and memory T cell production [110].

Mechanisms of Action

CTL recognise and kill target cells through their characterised cytolitic activity that respond to APC by polarising and secreting cytotoxic granules leading to rapid lysis [97].

TCR recognition induces the rapid polarisation of the CTL secretory machinery at the point of contact with the target, forming the immunological synapse. Lytic granules are moved along the microtubule network and are secreted. It is at this secretory cleft, formed between the two cells that seal off the external environment, that the lytic granules are released [111].

There are two main contents in the lytic granules, perforin a pore-forming protein and granzymes that are a series of serine esterase. Perforin acts by incorporating itself into the lipid bilayer of the target cell through its unique lipid-recognition motif, a Calcium dependant C2 domain and then polymerises, creating pores in the membrane [112].

These pores then allow the enterance of the granzymes into the cytosol of the target cell (as reviewed in [113]). These granzymes act variously depending on type however, all secrete proteins that damage the cell during cytolysis [114]. There have been five granzymes identified in humans all with different specificites [115] and multiple potential substates [116].

In this process the CTL is protected from the toxic effects of its own proteins through the granule membrane, which is resistant to its contents action due to capthesin B [117]. In addition to this both perforin and granzymes are synthesised in an inactive pro-form with a short C-terminal amino acid pro-piece, that blocks the C2 chain ([118], reviewed in [113]). These amino acid pro-pieces are cleaved under acidic conditions once in the granule [119]

Within the lytic granules are also Fas ligands, a potential mediator of targeted cell death [120]. This initiates apoptosis by recruiting the Fas-associated death domain protein as a result of cross-linking to Fas transmembrane receptors on target cells surface. A cascade of caspase cleavage events results. Group II caspase proteins, notably caspase 3, play a role in cleaving structural components of the target cell (reviewed in [121]).

Interferon-IFN y is another essential cytokine that is produced in high levels upon TCR stimulation. IFN-y upregulates the expression of MHCI on cell, facilitating recognition by TCR and CD8 co-receptors [122].

Structure

Cytotoxic T Lymphocytes (CTLs), which are, also termed CD8+ T-cells, Killer T cells and Tc have the key structural features of T-cell Receptors (TCR) and surface CD8 glycoproteins that act as a co-receptors [103]. These receptors form what is known as the ‘immunological synapse’, with the MHC1 molecules of the infected peptide-presenting cell [123]. Through this they function to kill pathogen-infected, tumorigenic and other damaged cells [124], via secretion of cytotoxic mediators leading to apoptosis [111].

CD8

As reviewed in [125] the CD8 transmembrane glycoprotein on the T-cell surface can either be expressed as a αα-homodimer or αβ-heterodimer, with aB-heterodimers being the most prevalent within T cell populations. The B chain broadens the range of antigen recognition of the T cell, enhacing activation of CTLs [126]. The extracellular domain N-terminal exist on both a and B CD8 and has structural features to immunoglobulin-variable domains [127]. Th Ig-like ectodomain binds to MHCI in a similar mannr to antibody-antigen binding, This CD8-peptide-MHCI complex is assymentric with 75% binding to just one of the CD8 subunits [128]. This is linked to the transmebrane component through ‘stalk’ of roughly 48 amino acids long [103].

CD28

CD28 is a covalent homodimer, it has a pair of immunoglobulin superfamily-like variable domains attached to a transmembrane and cytoplasmic domains posessing signalling motifs that a tyrosine dependant [129]. The MYPPPY loop present on the variable domain is the site of cross linking with the B7-1 or -2 ligand [130].

Clinical Implications and Disease

Hepatitis B virus

Contributors to T cell exhaustion in HBV [131]

Hepatitis B is an infectious disease of the liver that results from the exposure to blood or body fluids containing blood that is infected with the hepatitis B virus. Infection with HBV can be acute resulting in nausea, vomiting, mild fever, and dark urine, and development of jaundice. Most adults clear the virus and chronic infection developing in only 5 – 10% cases. In chronic stages there are minimal symptoms however, cirrhosis and liver cancer often develop in later stages. Infection during early childhood is often asymptomatic as a result up to 90% of cases persist as chronic HBV [132].

HBV-specific CTLs play a crucial role in the clearance of the virus however, these CTLs become exhausted through a variety of mechanisms. These include Treg cells inhibiting CTLs, loss of CD4+ T-cell help, and high viral load, all contributing to the progression of chronic HBV [133]. The resulting uncontrolled HBV leads to liver damage by lysis of hepatocytes. This lysis is carried out by both the CTLs and their recruitment of non-virus specific T cells. The balance between viral replication and the immune defenses independently determine the severity of liver damage (reviewed in [134]).

Multiple sclerosis

MS is a relatively poorly understood neurodegenerative autoimmune disease. The progressive and multifocal demyelination is the result of invasion of inflammatory cells across the blood-brain barrier (BBB). It is also suspected there is some degree of genetics involved in the susceptibility of one developing the disease (reviewed in [135]).

The lesions that are associated with demyelination exhibited clonal expanded CTLs and yd T cells, where normally there is few T cells in the BBB. These CTLs have the potential to damage and destroy all CNS cell subtypes including astrocytes, microglia and neurons (reviewed in [136]).

T Regulatory Cells

Function

T Regulatory cells (Tregs) are another subtype of T Cells. There exists a plethora of subtypes which causes difficulties to find adequate markers. The general model is that T regulatory cells are inherently different from other T cells. Other T cells are summarized as T effector cells, as they will all cause a direct effect. T regulatory cells, in contrast, do only regulate other cell types and not cause any effect themselves. The inhomogenity of subtypes provided difficulties to clearly establish what Treg distinguishes from T effector cells. It is further important to distinguish Treg from Treg17, regulatory T Helper cells producing IL-17, also having immunomodulatory capacity[137].

Treg are called 'regulatory' for their ability to suppress CD4+ T Helper, CD8+ T Killer, B Cells, Natural Killer Cells and dendritic Cells as shown in [138] and reviewed in [139][140][141] and [142].

As explained in the development section, there is a common key step during T Cell development in the bone marrow and maturation in the thymus, established by the body to ensure that our immune system will not attack itself. This negative control, as every natural process, is not perfect. Hence, the body has established a type of cell that will try to balance out the errors that have been made during T Cell development.

The Treg cells will recognize circulating, self-reactive T Cells and counteracts with their negative effects to correct any erroneous development and build a second line of defense against autoimmunity[143][144].

Further information about T Regulatory Cells  
If Tregs are inactivated, both mice and humans will develop fatal autoimmune diseases, and genes responsible for Treg development are correlated with susceptibility for autoimmune disorders. They are equally important for the preservation of tissues against immune-induced tissue damage.

Immune-induced tissue damage is achieved mostly through matrix-metalloproteases, which are triggered by the NFkB pathway. The NFkB Pathway is mainly activated through pro-inflammatory cytokines, and the anti-inflammatory TGFβ and IL10. Tissue damage becomes very present in arthritis and other degenerative diseases which can cause catastrophic destruction of the motile system[145].

Origin

Tregs are found both in lymphoid and non-lymphoid tissues, with or without the presence of a current immune response. This is a rare condition in the immune systems and show how important the ability is to quickly respond in the case of inflammation. If, however, inflammation occurs locally or systemically, Tregs are even further rapidly recruited to the site of inflammation and their number increases dramatically. Commonly, the amount of T regulatory cells within a particular organ is correlating with its immunoactivity.

Non-surprisingly, the intestine hosts an abundance of Tregs, and Treg deficiency is highly associated with intestine inflammation in particular in both humans and mice. As most T Cells, adult tissue specific Treg cells are not particularly motile and will not circulate in an extensive manner[146]. These intestine specific Treg cells are somewhat different from other Treg cells and will display other phenotypical properties.

Alongside with their abundance in the intestine, Tregs are also expected to be majorly present in the skin due to the skin's barrier function. And they are in fact. The skin Treg cells, just like intestinal Treg, seem to be fairly resident, as an abundance of them is present even in absence of obvious inflammation. skin associated Treg are found predominantely in the vicinity of the invaginations of hair follicles [147].

Mechanism of Action

Mechanisms of action include immunosuppressive cytokines, such as IL-10 from Treg Memory cells, parakrine signaling via cell-cell interaction or modulation of antigen presenting cells.Disruption is involved in all autoimmune or chronic inflammation involving diseases. Underactivity is related with the former, overactivity with the latter.

Several Pathways are important for Treg regulation. A good review is provided by [141] and [148].

TGFbeta and IL10

These two anti-inflammatory cytokines, have been postulated as main suppressive forces. TGFbeta and IL10 will lead to decreased CD4/8+ cell proliferation. Simplified, they will make activation T effector cells impossible.

Cytolytic Activity

Another possible mechanism of suppression is cytolytic activity. CD4+ 25+ FoxP T Cells can under certain circumstances, express perforin and granzyme. Granzyme is a serine protease which leads to apoptosis, however, cannot independently enter the cell. First, the cell wall has to be perforated by perforins, a perforin monomer will bind to the cell surface and polymerize with other monomers to form a perforating pore. Through these pores, granzymes may enter the cell. [149][118]. These killing mechanisms are normally only observed in CD8+ cells, such as CTL, NK Cells, NK T Cells and Intraepithelial T-Lymphocytes. Tregs are hence the big exception among CD4+ cells. Killing of effector cells such as CD4+ and CD8+ T Helper cells certainly is an effective measure to confine immune responses.

Galectin-1 mediated mechanism

Also suggested was function through cell cycle arrest of effector cells through Galectin-1. Galectin-1 will bind to various glycoproteins expressed on effector cells, such as CD45/43/7. Binding will simply lead to an arrest of the cell cycle, which essentially will lead to apoptose. Galectin-1 bound Teff cells will not be able to produce inflammatory cytokines as well, further combating inflammatory state.

Mechanistic interaction between Tregs and affected cells

The suppression of CD4/8+ cell proliferation requires direct contact of Tregs and its affected cells. This proximity is partially achieved by TCR/CD3-Ligand interaction. [141]

Regulation of Treg supression

If APC (antigen presenting cells, such as DC, NK and Makrophages) are activated through lipopolysaccharide (LPS, found in the outer bacterial membrane of gram negative bacteria) binding to the APC's TLR receptors, the APC will suppress Tregs, which reasonably leads to a declined immunosuppression in the presence of pathogens. Further, if APC are present, activated T effector cells will increase their expression of IL6R and GITR, two cytokine receptors, which makes them insusceptible against Treg suppression.

Activation

The activation of Tregs is concisely reviewed in [150] and holds several exceptions from normal T Cell activation. Whereas normal CD4+ T Cells need MHCII APC activation to proliferate, by either dendritic cells, makrophages, natural killers or B-Cells, Treg do not. In fact, Tregs seem to be anergic, that is, they will not proliferate, even if confronted with their specific TCR antigen[141].

Typical T Cell activation factors, as the Th2 secreted main T Cell regulatory factor, IL2 are, however still involved an will lead to altered gene expression within the cell. Main player of Treg activation seems to be IRF4, interferon regulatory factor 4, a transcription factor[151].

Clonal amplification and memory

Just as T Cell Effector populations, T Regulatory Cells may be activated by antigen presenting cells and consequently amplify clonally. Just as in other T Cell populations, a memory T reg subpopulation is formed[143]. Most research, however, focusses on long term Treg activity rather than acute, since immunomodulatory function naturally is more interesting in the context of chronic inflammation conditions such as HIV, MS and cancer.

Nontheless, Treg cells also provide acute effects. Treg cells expand upon acute viral infections, after successful dealing with the disease, decrease (to 5-10% of peak concentration) in concentration again to form a memory pool. Subsequently, in a secondary immune response, Treg will expand more rapidly as seen with other Lymphocytes, and secrete large quantities of IL-10. The function of this Treg guided secondary immune response is to suppress and overreaction of T Effector cell driven secondary immune response. Treg concentrations, hence, seem to fluctuate equal to those of effector T Cells, further underlining their importance as immune reaction gate keepers.

Development

Tregs can stem from two different sources. Natural, thymic generated T regulatory cells, and peripheral induced Treg cells. peripheral, induced Treg cells did not initially develop as Tregs, but started expressin Treg markers after differential events. 70-90% of all Tregs seem to be thymus generated, reviewed in [150][152] and </ref>[153], Treg that have been induced have normal CD4+ T cells as progenitors. An important factor in normal Treg cell development is TGFbeta, besides IL10 the main anti-inflammatory cytokine. If normal FoxP3 negative CD4+ cells are heavily confronted with high TGFbeta secretion, this may lead or contribute to induced Treg differentiation. Helios seems to be an important marker to differentiate between induced and natural Treg cells, the latter lacking in Helios expression. induced Tregs have a considerable heterogeneity compared to natural Tregs, emphasizing they adaptive and highly regulated homeostasis. APC interaction during development may be another point of difference, induced Treg seem to be more strongly influenced by APC, whereas thymic, natural Tregs are less geared towards APC activation [154]

Structure

CD4+ CD25+ Tregs normally represent about 2-4% of the CD4+ T Cell population[155]. Treg cells are commonly defined by expression of the surface markers CD3, CD4, CD25 and the transcription factor FoxP3[156]. CD25 is a componet of the high-affinity IL-2 receptor complex [23]. However, there is a big inhomogenity in definitions of what makes a Treg a Treg. Also often used is negative expression of CD127 and, more rarely but still fairly prevalent, CD45RA. These six markers are generally considered to be the "backbone" markers to define Treg Cells. [157][158]. This inhomogenity provides significant difficulties to asses Treg functions in humans. Conversely, Treg in mice have established very useful and genuinely accurate markers.

Clinical Implications and Disease

Cancer

Inflammation and Cancer

The role of T Regulatory Cells in cancer is twofold. As comprehensively reviewed in[159], T Regulatory Cells can either boost or halt tumour development and growth. This stems from the complex interaction of tumours with the immune system. The interaction between inflammation and cancer is an own extensive research area. A short version of the findings is concisely reviewed in many articles, such as [160].

Generally, in the main growth phase of cancers, called hyper- and dysplasia, tumours are supported by inflammation. Inflammation can help the tumour to grow in providing better perfusion and destroying connective tissue surrounding the tumour, invade into connective tissue, such as the basal lamina, and thus metastasize.

Conversely, as soon as the solid tumour has formed, the immune system will try to shut down the tumour. As Treg mainly have an immunosuppressive function, it is desirable to have overactive Tregs during tumour growth, and inactivated or depleted during solid tumour state[159].

T Regulatory Cells and Cancer

T Regulatory Cells often are in fact increased in cancer patients and this increase is correlated with a inferior clinical outcome[161][162][163][164]. However, there are also contradicting results to this assertion[165]. This lead to the targeting of Treg cells in through chemotherapy.

Manipulation of T Regulatory Cell function in cancer

T Regulatory Cells are more susceptible for chemotherapy for an increased proliferative potential can be observed in Treg [164][166]. Majorly, however, this approach hasn't been too fruitfull, as most agents are not specific enough [167]. Other approaches have tried to inhibit Treg proliferative signaling more specifically. The problem herewith is, T regulatory cells and T effector cells share many signaling pathways.

A promising target for manipulation may be the IL-2 induced STAT5 pathway which increases the FoxP3 levels and thus repressive potential[159], a transcription factor important in Treg signaling[156]. Another important signaling pathway that is targeted, is the PI3k/Akt pathway, activation of PI3K/Akt will lead to delocalization of FoxO1 and FoxO3, which are crucial for Treg induction. PTEN, in turn, supresses PI3K/Akt, which will lead to less Treg induction and fewer total Treg cells. Suppression of PTEN or activation of PI3K/Akt thus may be a suitable therapy strategy against Treg overpopulation in cancer[159]. Conclusively it may be said that Treg modulation is a promising area of cancer research and its proceedings should be further attentively observed.

HIV/AIDS

The implications of Treg function in HIV/AIDS is of equally big interest. A review is found in [168], [169] and [170]. HIV is generally characterized with a lymphopenia, i.e. decreased concentration, of CD4+ and Treg cell concentration. Again as in cancer, this may pose merit or detrimental consequences. Generalized T-Cell activation in a hallmark of AIDS, which may be fought by Treg action. However, it may also diminish anti-HIV specific lymphocyte action, which would lead to HIV persistence. Further, Treg cells may obviously not be examined isolatedly. Treg and Th17 balance seems to serve a delicate function in HIV progression. Much about our perception on Treg and HIV is based on analogies between cancer and Tregs. Both diseases are accompanied chronic inflammation, thus Treg might have similar functions in both conditions. Particularly CD39+ Tregs seem to play a major role in both conditions[171]. It is hard to define a simple strategy involving Treg activity manipulation against either of the two diseases, as simple deactivation may lead to autoimmune episodes, the defence from which is one of the key roles of Treg.

Transplantations

The immunomodulatory properties of Treg cells can be harnessed for allograft transplant tolerance, important e.g. in the replacement of skin after severe burns[145].


Natural Killer T-Cells

NKT cells, by which is meant specifically iNKT cells, interact with a variety of innate and adaptive immune cells to regulate the immune response. NKT cells interact with macrophages, neutrophils, B cells, NK cells, dentritic cells, and other T cells.[172]

As reviewed in [173] and [174], NKT cells are a small specialized subset of true T cells, rather than NK cells. As reviewed in [175], NKT cells are comprised of type 1 NKT cells, which are CD1d restricted and also known as invariant NKT cells, and type 2 NKT cells, which display a diversity of TCRs. As reviewed in [176], a third group of NKT-like cells not CD1d restricted and possessing a diversity of TCRs has also been classified. As reviewed in [175], typically unqualified statements of NKT cells are understood to refer to type 1 NKT cells, i.e. iNKT cells, but this has been a source of early inadvertent ambiguity in the study of NKT cells.

Function

As reviewed in [173] and [174], NKT cells crucially regulate immune responses regarding microbial infection, autoimmunity, and cancer by connecting the innate and adaptive immune systems. As reviewed in [174], when the MHC I complex presents lipid antigens of CD1d molecules of bacteria, fungi, and parasites, T cell receptors of NKT cells can be activated in order to evoke an immune response. However, as reviewed in [174], NKT cells are also capable of activation by self-recognition of lipids and/or proinflammatory cytokines generated by one another during an infection.

As reviewed in [173], NKT cells, much like cells of the innate immune system, are some of the first cells to play a role in infectious and inflammatory responses, all the while assisting in the preparation of the adaptive immune response to follow. As reviewed in [173], they have been found to play an important role in autoimmune disease, regulating transplantation tolerance, inflammatory responses, asthma and allergic disease, and a variety of infectious diseases due to bacteria, viruses, fungi, and parasites.

Even as NKT cells were first being discovered as a separate classification of T cells, there were indications of their potential regulatory role within the immune system. For instance, a collection of suppressor T cell hybridomas were discovered to have a common Vα chain (Vα14), and common Jα segment (Jα18, at the time known as Jα281), and common glycine residue in the N-region.[177][178]

Further Information on Natural Killer T Cells

Natural killer T (NKT) cells are a diverse class of T lymphocytes which have characteristics in common with both T cells as well as natural killer cells. Importantly, NKT cells are not natural killer cells and are instead classified as T cells, owing to the presence of their semi-invariant αβ T-cell receptors (TCRs), as reviewed in [179]. Importantly, many NKT cells possess TCRs that bind CD1d, which is an antigen binding both self and foreign lipids, such as isoglobotrihexosylceramide, as well as glycolipids, such as microbial α-glycuronylceramides, within the cell walls of lipopolysaccharide, Gram negative bacteria, as reviewed in [179]. As reviewed in [176], NKT cells are now broadly accepted as Cd1-restricted T cells which typically express both a semi-invariant T-cell receptor as well as many NK cell markers.

Structure

As reviewed in [179], the best understood NKT cells, known as ‘type 1’ NKT cells or ‘invariant’ NKT cells, are a subclass of T cells that possess a very invariant TCR, but they are capable of recognition of lipids and glycolipids in the antigen presenting molecule CD1d, as opposed to recognition of peptide-major histocompatibility complexes (MHCs) typical of other T-cells. As reviewed in [179], ‘type 2’ NKT cells also bind and detect lipids and glycolipids presented by the molecule CD1d.

Since NKT cells possess this crucial characteristic of being able to recognize glycolipids, they have been found to be a very useful area of study in addressing pathogens such as mycobacterium, the bacterial agent responsible for tuberculosis. Specifically, incorporation of specific glycolipid activators, such as α-galactosylceramide (αGalCer), into an attenuated strain of mycobacterium causes a more robust recruitment NKT cells and therefore a more effective vaccination[180].

NKT cells can be positive or negative for NK1.1, CD4, CD8, CD25, CD56, and CD161, as found in [181] and reviewed in [182]. As reviewed in [173], NKT cells possess cytokine mRNA, enabling them to generate cytokines rapidly after being activated, and these cytokines play a crucial role in determining the T cell response by the host. NKT cells have an antigen-specific TCRs in the manner of true T cells, and these receptors enable the cell to detect self-antigens as well as foreign antigens. Additionally, the TCRs of NKTs provide the immune system with the ability to detect lipid antigens otherwise undetected by conventional T cells.

Invariant natural killer T (iNKT) cells require[183] and express greatly the transcriptional factor promyelocytic leukemia zinc finger (PLZF) for their development, and PLZF appears to regulate the differentiation developing within the thymus into cells with seemingly innate effector characteristics[184].

Development

Tissue dependent NKT cell homing[185]

As reviewed in [185] with the adjacent diagram, NKT cells are developed in the thymus, but a mere fraction of NKT cells actually frequent the lymph nodes during typical conditions as opposed to other T cells. As reviewed in [185], the most significant proportions of NKT cell populations are found in the liver, lungs, spleen, and bone marrow, and this localisation is thought to be a consequence of differing chemokine receptor expression among the separate localising populations.

Clinical Implications and Disease

Immune System Diseases

There is evidence to show that microbial exposure at a young age is critical to the function of NKT cells, crucial to addressing diseases relating to the immune system such inflammatory bowel disease (IBD) and asthma. Germ-free (GF) mice tend to accumulate invariant natural killer T (iNKT) cells in the lungs and in the lamina propria of colon, increasing morbidity as compared with specific pathogen-free mice. Also, the GF mice have increased intestinal and pulmonary expression of CXCL16, a chemokine ligand associated with increased iNKT cells of the mucosa.[186]

Neonatal GF mice colonized with conventional microbiota, the mice tend to be protected from iNKT accumulation within the mucosa and associated pathogenicity. Contact with commensal microbes by a critical early age is crucial to developing a healthy levels of mucosal iNKT. Additionally, iNKT cells are valuable in providing resistance to environmental exposures, but failure of these cells to further mature by interaction with any conventional microbiota during the early stages of life results in the natural killer T-cells themselves to be a potential source of pathogenicity.[186]

Cancer

Originally, NKT cells were discovered to play a protective role against cancer, but recent studies have shown that NKT cells are able to inhibit tumor immunosurveillance are well as promote it. There paradoxical results have been determined to be a consequence of different classes of NKT cells governing different roles.[173] Importantly, NKT cells with an invariant TCR (Type 1) and also NKT cells with variable TCRs (Type 2) have been discovered to play a regulatory role for one another enabling the modulation of the following immune responses. Additionally, NKT cells are capable of regulating other cells involved in host innate immunity, including cells such as myeloid-derived suppressor cells, NK cells, and dendritic cells.[173]

Asthma

As reviewed in [187], it is likely that Th2 cells and iNKT cells complement one another to result in asthma and that different forms of asthma can result from varying routes of pathogenesis by which the two types of cells interact.

Memory T-Cells

Function

This image shows the effect of antigen exposure on memory T cells[188]

As reviewed in [189], Memory T cells, also known as Memory T lymphocytes, are a special subset of T cells that have previously experienced a particular antigen, from sources such as infection and cancer, and have developed specific recognition and a prepared response for a second encounter with the antigen in question. As reviewed in [189], Previous pathogen exposure, but importantly also vaccination, increase the number of pathogen-specific memory T cells in circulation and also affect their migratory patterns. As reviewed in [189], A second encounter with the antigen produces a secondary immune response, characterized by a faster and stronger showing of immune cells in response to the antigen than generated in the primary exposure.

Further Information on Memory T cells

Structure

Memory T cells are able to be CD4+, as reviewed in [190], or CD8+, as reviewed in [191], and memory T cells tend to express CD45R antibodies, which is then lost while UCHL1 reactivity is gained in the priming of the T cells [192].

Sub-populations

Memory T cells are commonly split into at least three subtypes, as reviewed in [193]:

• central memory T cells (TCM cells),

• effector memory T cells (TEM cells and TEMRA cells) [194] and

• resident memory T cells (TRM)

Other new sub populations of memory T cells are being analysed through the use of co stimulatory molecular markers such as CCR7, CD27, CD28, and CD45RA[195].

Development

Generation and maintenance of resident memory T-cell subsets.[196]

As reviewed in [193], the memory T cell population in circulation is commonly broken up into two main subsets, namely central memory T cells (TCM) and effector memory T cells (TEM). As reviewed in [193], each of these populations are specific to a particular localization within the body, namely TCM within the secondary lymphoid organs and TEM circulating throughout non-lymphoid tissues.

However, as reviewed in [193], a recently classified third subset, known as tissue-resident memory (TRM) cells has been discovered to migrate within peripheral tissues demanding particular chemoattractants and T cell recruitment, including the skin and genital tract.

As reviewed in [197], Naive T cells are developed in the thymus but remain relatively inactive as they circulate sparsely through secondary lymphoid tissues. As reviewed in [198], once a T cell binds to antigen by means of the major histocompatibility complex (MHC) and peptide associate, the T cell is then primed (activated). These primed naive T cells begin the expansion phase by dividing and differentiating into a diverse set of effector T cells. As reviewed in [198], following this expansion phase, a contraction phase is initiated in which only select number (only about 5-10%) of this effector T-cell population following this expansion phase are differentiated into diverse memory T cells. The rest of the activated T-cells are eliminated. As reviewed in [199], this functional model of memory T cells, however, is most accurate when considering acute infections, as chronic infections can amount to T cell dysfunction and rampant pathogen due to abnormal development of memory T cells and strain on the remaining T cells.

Maintenance of population

One of the major limiting factors to memory CD8(+) T cell populations is the stability of the cell lysosomes. The genes IL-15 and IL-7 contribute to the production of serine protease inhibitor (Spi) 2A, which inhibits cytosolic cathepsin and thus inhibits apoptosis. In animal models, Spi2A inhibition results in less CD8+ T lymphocyte maturation and less homeostatic proliferation as well. Spi2A is required in order for the memory CD8(+) T lymphocytes to maintain population numbers after viral infection and that one specific mechanism of action is protection from lysosomal breakdown via cathepsin B inhibition. Furthermore, T cells deficient in Spi2A can have their homeostatis restored by concurrently blocking cathepsin B, which strongly suggests that the physiological target of Spi2A is indeed cathepsin B.[200]

Clinical Implications and Disease

HIV

More than 80% of total HIV-1 DNA has been found to be in non-gut-homing CD45RO+ memory T lymphocytes, while less than 10% found in regulatory T cells and CD38+ activated memory cells, and most of the HIV-1 DNA is present in non-gut homing resting CD(+) T cells.[201]

Autoimmune Diseases

Current Research and Future Directions

T Cells and Cancer

Sean Parker, founder of Napser and Co-founder of Facebook, has invested 250M USD in a project he calls the "cancer dreamteam", which will heavily focus on immunotherapy of cancer. Instead of competing having research labs, Parker formed a big group of scientists from the Memorial Sloan Kettering Cancer Center, Stanford University, UCLA, UCSF, the University of Texas MD Anderson Cancer Center, and the University of Pennsylvania to work synergistically. The different labs focus on different approaches, the Sean N. Parker Autoimmune Research Laboratory at UCSF for example, works on an approach to boost T Regulatory Cells in order to fight cancer. [202]

The CAR Race

Flowchart of CAR generation procedure. Generation of scFV by through mAb, genetic Engineering of CAR sequence, introduction into viral vector and transfection of T. Own creation.

Besides philanthropic and governmental efforts to cure cancer with the use of T Cells, the interest in economic leverage of such uses is high. Genetically engineered T Cell Receptors specific against cancer specific antigens, called Chimeric Antigen Receptors (CARs)[203], are extremely promising and several companies, including Juno Therapeutics, Kite Pharma and Novartis are competing to provide the first marketable solution[204]. This competition has reached extents, that it is sometimes called the CAR T-Cell Race[205]. The promise is huge, as immunotherapy often is the last rescue if all current therapies have failed. The FDA recognized this, and awarded the first 'breakthrough therapy' designation to the new drug approval (NDA) filling for CTL019, the anti-CD19 chimeric antigen receptor T-cell therapy developed at the University of Pennsylvania on July 1, 2014[206]. CARs will reprogram the human immune system to specifically recognize cancer cell surface markers and launch an immune response against the tumor cells. In most cases, CD8+ Killer T Cells are equipped with the CARs, but current clinical trails are exploring further options for carriers, such as CD4+ T-Helper cells [207]. Based is this commercial fencing on academic research, such as the one of Phillip Greenberg, working at the Fred Hutchinson Cancer Research Center (FHCRC). [208] He has recently founded Juno Therapeutics. Most therapies CAR focus on CD19 [209][210][211], but Greenberg, or more precisely the FHCRC has recently filed a patent for CARs against WT-1 [212]. As patents become obsolete as soon as the underlining research has been published, it is to be expected that the according research will be published soon, most likely together with Juno Therapeutics Phase I/II trial results in 2016/17 [213].

CARs, reviewed in [206] and [214], are basically comprised of an extracellular tumor binding domain, the signaling domain of a T Cell and co-stimulatory domains, designed to improve the function. Oddly, despite being called chimeric t cell receptors, often only the signaling domain is actually of TCR origin. The tumor binding domain normally is a single-chain variable fragment (scFV), which combines the two variable regions of heavy and light chain immunoglobulin fragments with a linker protein[215]. The T Cell signaling domain ensures proper signaling within the host T Cell, normally a zeta-chain is used[216]. The Zeta-Chain forms a complex with CD3 and the TCR alpha/beta subunit and is crucial for TCR signaling. Lastly, the co-stimulatory domains often are isolated from other receptors, such as CD27, a TNFalpha-superfamily receptor [217].

The process of CAR therapy, reviewed in [218], is a patient individual, genetic engineering approach. First, patient T Cells are isolated from the blood. A viral vector containing the CAR sequence is introduced into the T Cell, which is subsequently reintroduced into the organism. The genetically altered T Cells will start to transcribe and express the CAR, the CAR will recognize its cancer specific epitope. Consequently, this will lead to clonal proliferation of the CAR engineered T Cell, creating a massive immune reaction against the targeted cancer. In theory, no regrowth of the cancer can occur, as T Memory Cells will have formed and thus provide immunity against the cancer.

Crispr/Cas9 and T Cells

The poster child of gene editing, Crispr/Cas9 has now arrived at human T cells, with first experiments modifiying PD-1, which is involved in T Cell cancer defence[219].

T Cells and Space

The popularity of T Cells has risen unarguably. In fact, it has risen to space. The Hughes-Fulford Laboratory is currently researching the effect of micro-gravity on T Cells on the ISS[220]. This apparently is part of their research of aging and T Cells. Interestingly, this will be the first NIH, i.e. governmental, funded research project in space that is carried out by a commercial space travel company, SpaceX, founded by Elon Musk, the founder of paypal, Tesla and SolarCity[221]. According to NASA, this is particularly interesting, since APOLLO astronauts have shown several unusual immunological phenomena, including the occurrence of an disease that normally only occurs under immune supression. Hence, the reasoning is that space must have had an influence on the T Cells. The Experiment ran from 2014-2015, the results are pending.[222]


Research at the UNSW and Active Labs

Here is an incomplete list of Research at the UNSW and Labs currently performing research about T Cells for further interest
  • UNSW, Dr Cindy Ma, Garvan Institute of Medical Research: Using human primary immunodeficiencies to investigate CD4+ T cell differentiation
  • UNSW, Prof Pageon and Dr Gaus Singular Molecule Science: Investigating the dynamics of T cell signalling during immune recognition
  • UNSW, Kirby Institute, Dr. Turtville: HIV and T Cells
  • Monash University, Melbourne: Professor Frank Alderuccio, tried to exploit Treg cells against Multiple Sclerosis, with little success so far. His research continues.
  • The University of Melbourne, Mackay Lab: Tissue-Resident Memory T cells; Lymphocyte Differentiation; Peripheral Immunity
  • Stanford, The Goronzy Lab: T cell homeostasis, T cell receptor calibration with age, T cell receptor calibration in autoimmunity, metabolism and others
  • Ragon Institute of MGH, MIT and Harvard, Walker Lab: HIV and CD8+ Cells
  • Yale, Hafler Lab: Autoreactive CD4+ T Cells in Multiple Sclerosis, Th1 Tregs, Cancer, and T-Cell co-stimulatory pathways
  • McMaster University, McMaster T-cell Epitope Centre (MTEC): Allergen Specific Immunotherapy (SIT)
  • La Trobe University, Chen Lab: Influenza and T Cells
  • Peripheral Immunity University of California, San Francisco, Ansel Lab: T Cell genetics, especially allergy and asthma

Final thoughts

T Cells have an incredible variety of subtypes, many of which yet to be classified. The complexity of each individual and distinctively functioning type and their interaction is mind boggling. The most serious and challenging diseases our society faces nowadays, such as HIV, MS and Cancer, are all caused or arise in close relation with T Cells. Fundamental phenomena, such as aging, are equally related to T cells. As seen with CARs, T Cells can be hijacked and turned into effective patrolling and immunizing soldiers against cancer and possibly a huge amount other types of diseases. The boundaries of this technology no one can gauge yet. Research, particularly in conjunction with genetic engineering, thus holds unprecedented promises. When the boundary to the immortal superhuman actually may be crossed, seems unclear and besides science's child-like curiosity, caution and ethical questioning will have to be science's companion in the future. With all that in mind, T Cells certainly are and will be one of the most interesting fields of research, and many great discoveries are yet to come.


Glossary

A Glossary in chronological order. References are found within the respective paragraphs
Term Meaning
antigen Polymer that triggers an adaptive immune response. Can be nucleic acid, carbohydrate, lipid or protein
TCR T Cell Receptor, is found on T Cell surface
MHC Major Histocompatibility Complex, Receptor found on all nucleated cells to present antigens
αβ Subunits of the TCR heterodimer. TCR is either αβ or γδ. No functional implication known
γδ Subunits of the TCR heterodimer. TCR is either αβ or γδ. No functional implication known
Heterodimer Aggregate of two unequal protein chains
Lymphoid Tissue tissue with primary immunological function and high leukocyte count. Connected to lymphoid ducts and nodes
CD Cluster of Differentiation. Surface glycoproteins, display cell identity to the outside of the cell and used as markers to determine cell type.
CD8 Surface protein on T Cells and Natural Killer Cells, acts as a co-receptor for TCR/MHCI
B locus Locus: unique position within genetic code. B locus is the position on the genome carrying T Cell receptor genes
FOXP3 Forkhead box Protein 3. Transcription factor from the FOX family
disulfie bond covalent chemical bond created by oxidation of two cystein amino acid residues. Post translational modification.
CD4 Surface protein on helper T cells and T regulatory cells. Co-receptor for TCR/MHCII
Cytokine Cytos: Cell. Kinesis: Movement. Cell signaling molecule
Interleukin Inter: between, leukos: white. Chemical signaling molecule to signal between leukocytes
APC Antigen presenting cell. Present internalized portions of pathogens on MHCII molecules and activate adaptive immune system
Th1 T Helper Cell subtype. Mainly against intracellular pathogens (bacteria, virus)
Th2 T Helper Cell subtype. Mainly against extracellular pathogens (Helminths, bacteria)
Th17 T Helper Cell subtype. Secretes IL17 ( Th17 specific). Mainly extracellular pathogens and involved in autoimmunity
TGFβ Transforming Growth Factor, cytokine. One of the two major anti-inflammatory cytokines (besides IL10)
IL10 Interleukin10, One of the two major anti-inflammatory cytokines (besides TGFβ)
BCR Locus: unique position within genetic code. B locus is the position on the genome carrying T Cell receptor genes
B locus B Cell receptor. Same structure as antibody/immunoglobuline molecules
Primary lymphoid organs where leukocytes originate and maturate, i.e. Thymus and Bone Marrow
secondary lymphoid organ where the majority of leukocytes reside after maturation
CDR Complementary Determining Region. Contains antigen binding sites and is withing variable region
VDJ Variable Diverse Joining gene clusters within B locus and BCR/Antibody locus that determine TCR/BCR/Antibody diversity
Cortex latin for bark. Outermost layer of connective tissue of an organ
Medulla latin for pulp. Inner layer of connective tissue of an organ
DN Double Negative. Stage within T Cell development. Neither CD8 nor CD4 expressed, hence double negative for both
DP Double Positive. Stage within T Cell development. Both CD8 and CD4 expressed
Dendritic Cell Protein tyrosine phosphatase, a surface protein on the surface of T Cells
CD45 Protein tyrosine phosphatase, a surface protein on the surface of T Cells
CD28 TCR co-receptor, specific marker just for T Cells
CD80 Found on activated B Cells, specific for B cells
CD86 Found on antigen presenting cells
IFN Interferon, a cytokine
Tfh' Follicular T Helper Cells, T cells able to migrate into secondary lymphoid organ follicles
FoB Follicular B Cells, B cells residing in secondary lymphoid organ follicles
CXCR Chemokine Receptors
CD40L on follicular T Helper cells, allows binding to CD40
CD40 on antigen presenting cells and follicular B cells, acts as costimulatory receptor
fDC fDC follicular dendritic cells. Special population of DC within secondary lymhpoid organ follicles
C2 Domain A protein domain contained in various receptors involved in cell membrane targeting
MYPPPY loop A Met-Tyr-Pro-Pro-Pro-Tyr loop domain, found in CD28 molecules
HBV Hepatitis B Virus
Tregs T Regulatory cells
NKT Natural Killer T Cells
Hybridoma Hybris was a creature in ancient greek mythology with two heads. Hybridoma cells are cell lines that are immortalized through fusion with cancer cell lines
CD1 Expressed on the surface of antigen presenting cells. Related to MHC molecule, involved in presentation of lipid-antigens
PLZF Promyelocytic leukemia zinc finger. Zinc finger are DNA binding protein domains that are comprised of a helix-turn-helix motive complexed with a zinc ion in the middle. they bind to the major groove of DNA
IBD Inflammatory Bowel Disease. Chronic inflammation of the bowel, with various subtypes such as Crohn's Disease and others
CXCL16 Cytokine, binds do CXCR6. Produced by dendritic cells in follicular T cell region of secondary lymphoid organs
iNKT invariant Natural Killer T Cells, subtypes of NKT found in mice
CAR chimeric antigen receptor. Genetically engineered T Cell receptor. Chimera, a beast in ancient greek mythology, is a fire-breathing hybrid between a lion, snake and a goat.

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