2016 Group 6 Project
- 1 Introduction
- 2 History
- 3 Commonalities between T cell subtypes
- 3.1 Functions
- 3.2 Structure
- 3.3 Development
- 4 Types of T-Cells
- 4.1 T-Helper Cells
- 4.2 Cytotoxic T Cells
- 4.3 T Regulatory Cells
- 4.4 Natural Killer T-Cells
- 4.5 Memory T-Cells
- 5 Current Research and Future Directions
- 6 Final thoughts
- 7 Glossary
- 8 References
T lymphocytes are a special class of lymphocyte possessing T-cell receptor (TCR) on their cell surfaces. This is the defining characteristic of T cells, setting them apart from other lymphocytes like B lymphocytes or Natural Killer cells. 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  and reviewed in . Some T cells also mature within the human tonsil.
T cells are a diverse population of cells which enables 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 , 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 , have binding specificity for intact antigen.
As reviewed in , the majority of T cells, namely 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 , γδ T cells initiate more rapid immune responses but make up only a small fraction of total human T cells and function more invariably as part of the innate immune system. As reviewed in , γδ T cells nevertheless have some adaptive characteristics owing to their T cell receptors.
Since established acceptance of T-cells as a distinct type of lymphocyte in 1970, 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 the main types of 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|
|1961||Found that the thymus plays a role in immune function, |
|1964||Found that small lymphocytes continuously re-circulate through blood, lymphactics and secondary lymphoid tissue, |
|1966||Found small lymphocytes have immunological memory potential, |
|1967||Proposition of two major subsets of Lymphocytes, |
|1970||Became widely accepted that Thymus derived (T cells) are distinct from antibody-forming (B cells), |
|1972||T cells are found responsible for allogeneic cytotoxicity, |
|1979||Generation of first monoclonal T cell, |
|1983||Discovery of T cell antigen receptor (TCR) that consists of a disulfide linked heterodimer with both constant and variable regions,  , |
|1984||Discovery of the TCR b locus and the basis for TCR diversity, , , |
|1987||3D crystalline structure of class 1 MHC determined, |
|1989||Discovery that CD8 glycoproteins expressed on cytotoxic T lymphocytes recognise antigens presented by class 1 MHC, |
|1994||Demonstrated the CD8 T cell memory could be maintained in the absence of antigen |
|1995||Regulatory T cells discovered |
|1999||Found that memory CD4 T cells could persist long-term in the absence of MHC molecules|
|2001||Discovery of FOXP3 gene and its involvement with T regulatory cell development |
|2002 - 2003||Notion that T cells differentiate into memory T cells as a continuum |
|2006||Role of Interleukins 7 and 15 in memory T cell maintenance and division through homeostatic proliferation |
|2007||Discovery of the interplay between CD4 T cells and CD8 T cell in the development of memory CD8 T cells |
Commonalities between T cell subtypes
|Model Figure of T Cell Migration|
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(as reviewed in ), 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. As reviewed in, 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. 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(as reviewed in). 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(as reviewed in ). The effector cytotoxic T-cell directly kills the infected cell and abnormal cancer cells.
T Effector vs. T Regulatory Cells
The 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. Regulatory T cells are also a subtype of T cell that prevents our body from autoimmune diseases and maintains tolerance to self-antigens. Such functions are very important because the immune system destroys cells and tissues of the body when self/non-self discrimination fails, resulting in autoimmune diseases(as reviewed in). 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. Recent research has found that the cytokine TGFβ is necessary to differentiate Tregs from naïve CD4+ cells and plays an important role in retaining Treg homeostasis(as reviewed in).
Migration and the Cytoskeleton
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. 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. 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(as reviewed in). 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. For the last, the T-cell forms a tight contact rich in branched actin filaments when T-cell recognises an APC. As reviewed in, 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).
There are three main classes of lymphocytes, T cells, B cells and Natural Killer cells. T Cells comprise about 70% of all lymphocytes. T-cells are located in various places. Lymphoid organs often have a fairly structured morphology. T cells are generally concentrated in T cell specific areas of those Lymphoid organs, such as T cell dependent areas (TDA), which can be seen in the figure of a lymph node in the development subsection. T cells are also found patrolling through the blood and loosely accumulated in connective tissues of barrier organs such as the skin or gut lining. There even are T cells which are integrated into the epithelial linings of barrier organs, such as the intraepithelial leukocytes. They are called T cells since, in contrast to B cells, they mature in the Thymus after being created in the bone marrow. B cells, in contrast, not only develop in the bone marrow, but also fully develop there (reviewed in ).
T Cell Morphology
The morphology of the typical T-cell is a round shaped cell. There are many other round shaped cells such as red blood cells and B-lymphocyte. In the histological picture, the B-lymphocyte has the most similar morphology, and T-cells and B-cells are not distinguishable before the cells have been activated by antigen. It remains in the form of resting A or B cell as the figure shows. Moreover, the T-cell has similar organelles to B-cells, including the nucleus, endoplasmic reticulum, and others (as reviewed in)
There are, nevertheless, methods that remain for distinguishing T-cells from B-cells. Difference in size is one of the factors for distinguishing the lymphocytes. In the normal histological picture without the marker, one cannot 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 the figure comparing the size of the T-cell and B-cell depicts, B-cells are larger than the T-cells. Moreover, B-cells are filled with largely rough endoplasmic reticulum, but T-cells have very little endoplasmic reticulum. This seems logical, as key feature of B Cells is production of high amounts of BCR and antibodies, whereas T Cells are instead 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.
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 greatest density is found within secondary lymphoid organs, such as the tonsils, spleen, lymph nodes and Peyer's patches in the gut, as reviewed by . There is a specific tissue within the secondary lymphoid organs, surrounding the medullary sinus, that hosts mainly T cells. B cells and T cells are, thus, normally separated and unable to invade their 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 B cell specific tissues, an aspect involved with T Follicular Helper Cells to be covered in more depth later.
T Cell Receptor and Co-receptors
The markers on the surface are the crucial factor in differentiating T-cells from other cells. The markers are the T cell receptors. The common structure of the T cell involves the presentation of the TCR and co-receptor on the 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 heterogeneity. Besides the CDR region, there is another source of heterogeneity.
Two subtypes of TCR monomers exist, which 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.
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(as reviewed in ) . 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 whose presence or absence play are role in defining the name and function of the T cell. T cells with co-receptor CD3 help to activate the cytotoxic T cell, and co-receptor CD4+ which combines with MHC class II is a characteristic feature of the matured helper T cell(as reviewed in), and as reviewed in, T cells with co-receptor CD8+ which combines with MHC class I will become cytotoxic T cells. 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 is associated with TCRα(as reviewed in). 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. 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-catalytic region of tyrosine 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 polymerization regulatory proteins like cofilin, Arp2/3 an others. This will lead to polarization of the microtubule organizing center (MTOC) towards the TCR in case of antigen activation . This actin and microtubule rearrangement eventually leads to generation of a structure called the immunological synapse, the MHC/TCR complex.
|T Cell Development|
Analogous to all blood cells, T Cell development begins with hematopoietic stem cells in the bone marrow (from greek, haime: blood, poenin: to create).
T cells begin to differentiate making their way to the thymus through the bloodstream . Settling of these lymphoid progenitor cells in the thymus is a continous regulated  and periodic process . The mechanism by which these progenitor cells enter the thymus is mostly unknown, yet it is believed to be analogous to other leukocytes. The process, reviewed by von Adrian, UH et. al. in  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.
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 cells can be found in macrophage vesicles, and helper T2 cell can be found in extracellular fluid.
Double Negative stage
At first, the thymocytes do not possess CD4 and CD8 and are referred to as double negative (DN, CD4-/CD8-). The expression of CD4/8 marks the point in T Cell development, at which they are able to be differentiated 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. .
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 of the V,D and J genes 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 ). 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 ). Following this tightly regulated process, T cells are generated with a single, specific TCR protein for each specific antigen .
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 ).
Positive selection allows survival only of cells that are able to trigger a viable, positive immune response. The 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 excessively weak binding and then undergo apoptosis  .
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 present self-antigens, which should not trigger an immune response. Any T cell that interacts 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 ). Approximately 5% of all cells are auto-reactive. Negative selection is a biological process that is prone to errors. To counteract self-reactive T Cells, T regulatory cells are employed . The many models in which negative selection occurs are reviewed in .
As reviewed in  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 .
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 are some 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 many 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 possess an incredibly individual TCR created 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 to 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 is constrained and evolving and is by far not able to account for everything in the incredible interactions of T cell subtypes with each other as well as 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:
|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 cells. 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 cells. 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 upon activation uniquely present self or foreign lipid antigens to a variety of APCs expressing CD1d, including dendritic cells, B cells, neutrophils, 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.||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 quiescently and provide immunity against antibodies that have already affected the body once. Dependening on the pathogen and location, memory cells can become decades old.||CD45R|
|Helper T Cell Tutorial|
T helper cells play a critical role in the adaptive immune system. They assist in the activation of B cells, macrophages and cytotoxic T cells so they can perform their function in a coordinated manner . T helper cells are essentially a cytokine factory that release information to orchestrate an immune response. This chemically encoded information shapes the way the immune system responds to any pathogen (as reviewed in . ).
Cytotoxic T Cells
The role of cytotoxic T Cells (CTL) is to kill virally or bacterially infected or tumorigenic cells. As such, CTL must be able to do three things.
Firstly, they must be able to bind to any cell within the body. This is achieved by the CD8 co-receptor. The CD8 co-receptor allows CTLs 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 .
T Regulatory Cells
T Regulatory cells and their many subtypes differ from other T cell types in their function of only regulating other cells opposed to causing a direct effect. The inhomogeneity throughout subtypes present difficulties in finding adequate markers to clearly establish differentiating factors from effector T cells. It is important to distinguish Treg from Treg17, regulatory T Helper cells producing IL-17, also having immunomodulatory capacity . Treg are called 'regulatory' for their ability to suppress and hence regulate CD4+ T Helper, CD8+ T Killer, B Cells, Natural Killer Cells and dendritic Cells ( and reviewed in  ).
Treg cells work to balance out the errors that have been made during the T Cell development process. They recognize circulating, self-reactive T Cells and eliminate them with their negative effects to correct any erroneous development and build a second line of defence against autoimmunity . Gene defects involved with Treg development are correlated with susceptibility for autoimmune disorders, with complete inactivation resulting in fatal autoimmune diseases.
They are also unequivocally important for the preservation of tissues against immune-induced tissue damage. Tissue damage becomes very present in arthritis and other degenerative diseases which can cause catastrophic destruction of the motile system. Immune-induced tissue damage is achieved mostly through the NFkB pathway, activated through pro-inflammatory cytokines, and the anti-inflammatory TGFβ and IL10.
|Further information about T Regulatory Cells|
Tregs can stem from two different sources. Natural, thymic generated T regulatory cells, making up 70-90% of population and peripheral induced Treg cells (reviewed in  and ). Peripheral, induced Treg cells do not develop as Tregs, but start expressing Treg markers after differential events, with CD4+ T cells as progenitors.
IL-10 is the main anti-inflammatory cytokine acting in Treg cell development along with TGFbeta. High levels of TGFbeta secretions lead to or contribute to inducing Treg differentiation of normal FoxP3 negative CD4+ cells.
Tregs are found in both lymphoid and non-lymphoid tissues, with or without the presence of a current immune response. If inflammation occurs locally or systemically, Tregs are rapidly recruited to the site of inflammation, increasing their numbers dramatically. The amount of T regulatory cells within a particular organ correlates with its immunoactivity.
Tregs are in higher concentrations within the skin predominantly in the vicinity of the invaginations of hair follicles. Here they serve as a protection barrier, with an abundant presence even in absence of obvious inflammation. .
The transcription factor, Interferon regulatory factor 4 (IRF4) is crucial to Treg activation. Additionally, more typical T cell activation factors, such as IL-2, are still involved in altering gene expression within the cell. .
Mechanism of Action
Several Pathways are important for Treg regulation. Mechanisms of action include immunosuppressive cytokines, such as IL-10 from Treg Memory cells, paracrine signaling via cell-cell interaction or modulation of antigen presenting cells. Disruption as hypoactivity can lead to autoimmune conditions and hyperactivity resulting in chronic inflammation involving diseases (reviewed in  and ).
TGFbeta and IL10
These two anti-inflammatory cytokines have been postulated as main immunosuppressive forces. TGFbeta and IL10 result in a decrease in CD4/8+ cell proliferation, making activation of T effector cells impossible.
Suppression through cytolytic activity occurs under certain circumstances using killing mechanisms are normally only observed in CD8+ cells. CD4+ 25+ FoxP T Cells express perforin and granzymes, which leads to apoptosis (process discussed in CTLs) . This control in the population of effector cells, such as CD4+ and CD8+ T Helper cells serves to confine immune responses.
Galectin-1 mediated mechanism
Galectin-1 acts to arrest the effector cells cycle by binding to various glycoproteins such as CD45/43/7, expressed on effector cells. This binding and arresting of the cell cycle will result in apoptosis. Galectin-1 bound Teff cells will also not be able to produce inflammatory cytokines, further combating inflammatory state.
Mechanistic interaction between Tregs and target cells
The suppression of CD4/8+ cell proliferation requires direct contact of Tregs and its target cells. This is partially achieved by TCR/CD3-Ligand interaction. 
Regulation of Treg supression
When Tregs are suppressed there is a decline in immunosuppression. This occurs when APC activated through lipopolysaccharide (LPS, found in the outer bacterial membrane of gram negative bacteria) binding to their TLR receptors. In addition to this, activated T effector cells will increase their expression of IL6R and GITR, two cytokine receptors, making them insusceptible to Treg suppression.
Clonal amplification and memory
Treg cells activated by APC have the potential to clonally amplify and for a memory T reg subpopulation .
Treg cells expand after successfully overcoming acute viral infections, to form a memory pool by decreasing in concentration (to 5-10% of peak). Subsequently, in a secondary immune response Tregs will expand more rapidly and secrete large quantities of IL-10. The function of Treg in the secondary immune response is to suppress the overreaction of T effector cells. Hence, Treg concentrations fluctuate with the effector T Cells, further underlining their importance as immune reaction gatekeepers.
Most research however, focuses on long term Treg activity rather than acute, since immunomodulatory function is more relevant in the context of chronic inflammation conditions such as HIV, MS and cancer.
There is a big inhomogenity in definitions of what characterizes a Treg in humans. They are commonly defined by expression of the surface markers CD3, CD4, CD25 and the transcription factor FoxP3. Also used is negative expression of CD127 and less often, CD45RA. These six markers are generally considered to be the "backbone" markers to define Treg Cells.
CD25 is a component of the high-affinity IL-2 receptor complex .
CD4+ CD25+ Tregs normally represent about 2-4% of the CD4+ T Cell population.
Clinical Implications and Disease
The role of T Regulatory Cells in cancer is twofold, either boosting or halting tumour development and growth (reviewed in).
Generally, in the main growth phase of cancers, hyperplasia and dysplasia, tumours are supported by inflammation. Metastases result from this inflammation due to better perfusion and destruction and invasion of surrounding connective tissue including the basal lamina (reviewed in ). Conversely, once a tumour has formed, the immune system will attempt to destroy it. As Treg have a predominant immunosuppressive function, it is desirable to have overactive Tregs during initial tumour growth, but hypoactive or depleted during solid tumour state .
T Regulatory Cells are often increased in cancer patients and correlates with an inferior clinical outcome . Treg cells therefore, became a target of chemotherapy due to their increased susceptibility, seen through increased proliferative potential . However, as most agents are not specific enough this approach hasn't been successful. Attempts to inhibit Treg prolifertive signaling more specifically incurred problems as Tregs and T effector cells share many signaling pathways .
Another signaling pathway targeted is the PI3k/Akt pathway. Activation of PI3K/Akt leads to delocalization of FoxO1 and FoxO3, which are crucial for Treg induction. PTEN, in turn, suppresses 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 .
It is evident that Treg modulation is a promising area of cancer research with many potential pathways to be explored.
HIV is generally characterized with a decreased number of lymphocytes, i.e. lymphopenia. As in cancer, this may present positive or detrimental consequences.
Regulation of effector T cells by Tregs in HIV infection can result in the destruction of anti-HIV specific lymphocytes causing persistence of infection. The balance between Treg and Th17 serves a function in HIV progression.
The roles Tregs play in HIV are somewhat analogous to the role they play in cancer, with both diseases exhibiting chronic inflammation. Particularly CD39+ Tregs play a major role in both conditions .
Difficulties arise in developing strategies with regard to manipulating Treg activity against either of the two diseases, as simple deactivation may lead to autoimmune episodes.
Natural Killer T-Cells
As reviewed in  and , NKT cells are a small specialized subset of true T cells, rather than NK cells. NKT cells upon activation uniquely present self or foreign lipid antigens to a variety of APCs expressing CD1d, including dendritic cells, B cells, neutrophils, and macrophages (as reviewed in ). The NKT cell also releases cytokines to activate or regulate these cells as well as activate MHC-restricted T cells and NK cells (as reviewed in ). As reviewed in , 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 are also CD1d restricted and display a diversity of TCRs. As reviewed in , a third group of NKT-like cells not CD1d restricted and possessing a diversity of TCRs has also been classified. As reviewed in , 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.
As reviewed in  and , NKT cells crucially regulate immune responses regarding microbial infection, autoimmunity, and cancer by connecting the innate and adaptive immune systems. As reviewed in , 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 , 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 , 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 , 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, giving evidence for the existence of an NKT cell subset of immune cells as well as suggesting potential regulatory role.
As reviewed in , 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 , 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 , 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.
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 having competing research labs, Parker has formed a massive 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. 
The CAR Race
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), are extremely promising and several companies, including Juno Therapeutics, Kite Pharma and Novartis are competing to provide the first marketable solution. This competition has reached extents, that it is sometimes called the CAR T-Cell Race. 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. 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 . Based is this commercial fencing on academic research, such as the one of Phillip Greenberg, working at the Fred Hutchinson Cancer Research Center (FHCRC).  He has recently founded Juno Therapeutics. Most therapies CAR focus on CD19 , but Greenberg, or more precisely the FHCRC has recently filed a patent for CARs against WT-1 . 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 .
CARs, reviewed in  and , 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. The T Cell signaling domain ensures proper signaling within the host T Cell, normally a zeta-chain is used. 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 .
The process of CAR therapy, reviewed in , 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.
T Cells and Space
The scope of T cell research has broadened remarkable, even to space and the effects of micro-gravity. The Hughes-Fulford Laboratory is currently researching T Cells on the ISS as part of their research of ageing 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. According to NASA, APOLLO astronauts have shown several unusual immunological phenomena, including the occurrence of a disease that normally only occurs under immune suppression. 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.
Research at the UNSW and Active Labs
T Cells have an incredible variety of subtypes, many of which are 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 are unable to be gauged yet. Research, particularly in conjunction with genetic engineering, thus holds unprecedented promises. Whether the boundary to the immortal superhuman actually may be crossed, seems unclear, and beside 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.