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 target antigens. The fragments are displayed as part of the MHC cell surface receptors of antigen presenting cells (APCs). Antibodies, on the other hand, as reviewed in , have binding specificity for intact antigen.
As reviewed in , the majority (~95%) of T cells are αβ T cells, named after their T cell receptor subtype. As part of the host immune response, αβ T cells recognise antigen fragments, usually peptides incorporated into the class I or class II MHC molecules of the infected cell, and evoke an adaptive immune response. On the other hand, as reviewed in , γδ T cells seem to 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.
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 about 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|
As reviewed in and , there are three main T cell types that take part in the immune response: CD4+ T Helper Cells, CD8+ Cytotoxic T Cells and T Regulatory cells. The former two are often summarized as effector T cells, since they take effect against a pathogen. This terminology of effector versus regulatory T cells is widely used in the field and should be familiar when proceeding to subsequent paragraphs. Each subtype has very different functions. What all have in common, however, is their ability to regulate and orchestrate immune responses. Whereas Makrophages and B cells directly attack a pathogen, T cells always modulate other cells and indirectly combat pathogens. They can activate B cells, suppress general immunoactivity or lead to cell death of infected cells (reviewed in ). The latter eventually will cause phagocytosis by makrophages and thus presentation of the infecting pathogen to the immune system. So even despite the fact that T cells do not undertake actual pathogen killing (makrophages) or inhibiting (B cell antibodies), no immune response can take place without them.
Dendritic cells (DC) play the main part in T-cell activation. DCs find and internalize antigens to present them as part of the MHC receptor complex on their surface. They are the most important APCs (antigen presenting cell) and basically all adaptive immune responses are initially triggered by presentation of antigens by APC. Every T cell has a unique receptor (TCR), which allows binding of one exact amino acid sequence (with the exception of NKT, which are also able to bind lipids, as elaborated in a later section). This means, T cells, just as B cells, will only be activated if this exact sequence is present on the pathogen. With an extreme abundance of unique T cells, our body is able to detect nearly every possible antigen. Before T cells bind to their specific antigen presented by an APC, they are called naïve T-cells, and after the activation process they are referred to as active T cells. It is very important to emphasize that TCR (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, they squeeze between endothelial junctions to enter the underlying tissues(as reviewed in). When the T-cell is inside, the morphology of the cell changes to s “hand mirror” structure. The name originates from the fact that the nucleus will form a flat surface on one end of an elongated cell (mirror surface) while the other end is thin and elongated (the mirror handle), giving it the appearance of a 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
T cells typically have roundly shaped, fairly small (7 to 10µm) cells with typical lymphocyte morphology. Without markers, naive T cells cannot be distinguished from the other lymphocyte cell type (B cells) in histology slides. Approximately 10%, however, take the morphology of Large Granular Lymphocytes (LGL) with a size of 10-14µm. Granulocytes and monocytes are typically between 14-20µm. Small lymphocytes may thus be distinguished from granulocytes by size, yet LGL can have approximately the same size. Another difference between Granulo-/monocytes and lymphocytes is nucleus shape. Lymphocyte nuclei are generally evenly round, whereas granulo-/monocyte nuclei have more complicated shapes. The T cells with LGL morphology, in turn, cannot be distinguished from Natural Killer cells in unlabeled histology slides. Natural Killer cells comprise the bigger part of LGL morphology cells (reviewed in).
There are, nevertheless, methods that remain for distinguishing T cells from B cells. B-cells are filled with largely rough endoplasmic reticulum, but T cells have very little endoplasmic reticulum (as seen in the picture on the right) . This seems logical, as key feature of B Cells is production of high amounts of BCR/antibody proteins, 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 T cell receptor (TCR) structure (reviewed in ) is analogous to a Fab fragment, which is one of the extracellular oriented sides of the Y-shaped antibody/BCR. TCR are often accompanied by co-receptors which are necessary for activation. Two protein chains, called heavy and light chain, are connected by disulfide bonds to form the TCR hetero-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 variability, the variable region received its name. the C-Region, in contrast, does not display such heterogeneity, hence it is called Constant Region. Two subtypes of TCR monomers exist, which dimerize to form the TCR hetero-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 has been described yet, however γδ seem to lead to the faster production of less specific and variable IgM.
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 are closely connected to several actin polymerization regulatory proteins like cofilin, Arp2/3 and 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.
ThymusAs 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 means, T and B cells are the big exception of the central dogma that every cell in the body carries the same genome (not taking mutations into account). Every single B and T cell has different genetic information after VDJ rearrangement. Thus, in contrast to all other somatic cells, they are not just different in gene transcription. The VDJ gene rearrangement 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||N Natural Killer T Cells are extremely unique in two features. Firstly, their TCR recognizes lipids which makes them the only T cell type able to recognize non-protein antigens. Secondly, their TCR can bind to a non-MHC receptor, CD1d, on APCs which present the lipid antigen.||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
NKT (reviewed in  and ) are true T cells (CD3+, CD56-) and are thus fundamentally different from NK cells, despite a very similar name. They do, however, share certain functions (reviewed in ). NKT cells are extremely unique. Normal T cells are only able to recognize protein antigens. NKT cells, however, can recognize lipid antigens. The MHC receptor is only able to present protein fragments, hence NKT cells must able to bind to a different receptor on APCs, to which normal T cells cannot bind. This receptor is called CD1d. NKT cells also releases cytokines to activate or regulate these cells as well as activate MHC-restricted T cells and NK cells (as reviewed in ). The ability to bind to CD1d is owed to the presence of a special, semi-invariant αβ TCR, as reviewed in . The term "semi-invariant" indicates a reduced variance within the TCR. As the variance in TCR is mainly due to the great variance in antigen-proteins, lipid-recognizing TCRs do not need to posses this degree of variance. CD1d presents both self, foreign (e.g. isoglobotrihexosylceramide) and glycolipids,(e.g. α-glycuronylceramides, within cell walls of Gram negative bacteria) (reviewed in ). As reviewed in , 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.
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.
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
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 . It is often forgotten that most commercialized products are originally based on academic basic research, such as the one performed by Phillip Greenberg, working at the Fred Hutchinson Cancer Research Center (FHCRC).  He has recently founded Juno Therapeutics Last Accessed 19/05/16. 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.