Editing T cell

{{Short description|White blood cells of the immune system}}
{{Infobox cell
|Name = T cell
|Latin = lymphocytus T
|Image = Blausen 0625 Lymphocyte T cell (crop).png
|Caption = 3D illustration of a T cell
|Image2 = Red White Blood cells.jpg
|Caption2 = Scanning electron micrograph of a [[red blood cell]] (left), a [[platelet]] (center), and a T lymphocyte (right); colorized
|Precursor = 
|System = [[Immune system]]
}}

'''T cells''' are one of the important types of [[white blood cell]]s of the [[immune system]] and play a central role in the [[adaptive immune response]]. T cells can be distinguished from other [[lymphocytes]] by the presence of a [[T-cell receptor]] (TCR) on their [[cell surface receptor|cell surface]].

T cells are born from [[hematopoietic stem cells]],<ref>{{Cite web|title=5. Hematopoietic Stem Cells|url=https://stemcells.nih.gov/info/2001report/chapter5.htm|archive-url=https://web.archive.org/web/20161029020128/https://stemcells.nih.gov/info/2001report/chapter5.htm|archive-date=29 October 2016|url-status=dead|work=Stem Cell Information|location=Bethesda, MD|publisher=National Institutes of Health, U.S. Department of Health and Human Services|date=17 June 2001|access-date=21 December 2021}}</ref> found in the [[bone marrow]]. Developing T cells then migrate to the [[thymus]] gland to develop (or mature). T cells derive their name from the [[thymus]].<ref name = "Alberts_2002"/><ref>{{Cite book|vauthors = Alberts B, Johnson A, Lewis J, Raff M, Roberts K, Walter P|date=2002|chapter = Helper t Cells and Lymphocyte Activation|page = 1367|chapter-url=https://www.ncbi.nlm.nih.gov/bookshelf/br.fcgi?book=mboc4&part=A4422|title = Molecular Biology of the Cell|publisher=Garland Science|edition=4th|language=en|quote = T cells ... derive their [name] from the organs in which they develop. T cells develop [mature] in the thymus}}<!--N.B.: Contrary to this reference, B cells derive their name not from (human) bone marrow, but from the bursa (found in birds): {{cite journal|vauthors = Cooper MD|title = The early history of B cells|journal = Nature Reviews. Immunology|volume = 15|issue = 3|pages = 191–197|date = March 2015|pmid = 25656707|doi = 10.1038/nri3801|author-link = Max Dale Cooper|doi-access = free}}--></ref> After migration to the thymus, the precursor cells mature into several distinct types of T cells. T cell differentiation also continues after they have left the thymus. Groups of specific, differentiated T cell subtypes have a variety of important functions in controlling and shaping the [[immune response]].

One of these functions is immune-mediated cell death, and it is carried out by two major subtypes: [[Cytotoxic T cell|CD8<sup>+</sup> "killer"]] (cytotoxic) and [[T helper cell|CD4<sup>+</sup> "helper"]] T cells. (These are named for the presence of the cell surface proteins [[CD8]] or [[CD4]].) CD8<sup>+</sup> T cells, also known as "killer T cells", are [[Cytotoxicity|cytotoxic]] – this means that they are able to directly kill virus-infected cells, as well as cancer cells. CD8<sup>+</sup> T cells are also able to use small signalling proteins, known as [[cytokine]]s, to recruit other types of cells when mounting an immune response. A different population of T cells, the CD4<sup>+</sup> T cells, function as "helper cells". Unlike CD8<sup>+</sup> killer T cells, the CD4<sup>+</sup> helper T (T<sub>H</sub>) cells function by further activating [[memory B cell]]s and cytotoxic T cells, which leads to a larger immune response. The specific adaptive immune response regulated by the T<sub>H</sub> cell depends on its subtype (such as T-helper1, T-helper2, T-helper17, regulatory T-cell),<ref>{{cite journal|vauthors = Luckheeram RV, Zhou R, Verma AD, Xia B|title = CD4⁺T cells: differentiation and functions|journal = Clinical & Developmental Immunology|volume = 2012|pages = 925135|date = 2012|pmid = 22474485|pmc = 3312336|doi = 10.1155/2012/925135|doi-access = free}}</ref> which is distinguished by the types of cytokines they secrete.<ref name = "Alberts_2002">{{Cite book|vauthors = Alberts B, Johnson A, Lewis J, Raff M, Roberts K, Walter P|date=2002|chapter = Helper T Cells and Lymphocyte Activation|chapter-url= https://www.ncbi.nlm.nih.gov/books/NBK26827/|title = Molecular Biology of the Cell|publisher=Garland Science|edition=4th|language=en}}</ref>

[[Regulatory T cell]]s are yet another distinct population of T cells that provide the critical mechanism of [[Immune tolerance|tolerance]], whereby [[immune cells]] are able to distinguish invading cells from "self". This prevents immune cells from inappropriately reacting against one's own cells, known as an "[[Autoimmunity|autoimmune]]" response. For this reason, these regulatory T cells have also been called "suppressor" T cells. These same regulatory T cells can also be co-opted by cancer cells to prevent the recognition of, and an immune response against, tumor cells.

==Development==
===Origin, early development and migration to the thymus===
All T cells originate from c-kit<sup>+</sup>Sca1<sup>+</sup> [[haematopoietic stem cell]]s (HSC) which reside in the bone marrow. In some cases, the origin might be the foetal [[liver]] during [[embryonic development]]. The HSC then differentiate into multipotent progenitors (MPP) which retain the potential to become both [[Myeloid Cell|myeloid]] and [[lymphoid cells]]. The process of differentiation then proceeds to a common lymphoid progenitor (CLP), which can only differentiate into T, B or NK cells.<ref>{{cite journal|vauthors = Kondo M|title = One Niche to Rule Both Maintenance and Loss of Stemness in HSCs|journal = Immunity|volume = 45|issue = 6|pages = 1177–1179|date = December 2016|pmid = 28002722|doi = 10.1016/j.immuni.2016.12.003|doi-access = free}}</ref> These CLP cells then migrate via the blood to the thymus, where they [[wiktionary:engraft|engraft:]]. Henceforth they are known as [[thymocyte]]s, the immature stage of a T cell.

The earliest cells which arrived in the thymus are commonly termed ''double-negative'', as they express neither the [[CD4]] nor [[CD8]] co-receptor. The newly arrived CLP cells are CD4<sup>−</sup>CD8<sup>−</sup>CD44<sup>+</sup>CD25<sup>−</sup>ckit<sup>+</sup> cells, and are termed early thymic progenitor (ETP) cells.<ref>{{cite journal|vauthors = Osborne LC, Dhanji S, Snow JW, Priatel JJ, Ma MC, Miners MJ, Teh HS, Goldsmith MA, Abraham N|display-authors = 6|title = Impaired CD8 T cell memory and CD4 T cell primary responses in IL-7R alpha mutant mice|journal = The Journal of Experimental Medicine|volume = 204|issue = 3|pages = 619–631|date = March 2007|pmid = 17325202|pmc = 2137912|doi = 10.1084/jem.20061871}}</ref> These cells will then undergo a round of division and [[downregulate]] c-kit and are termed ''double-negative one'' (DN1) cells. To become T cells, the thymocytes must undergo multiple DN stages as well as positive selection and negative selection.

Double negative thymocytes can be identified by the surface expression of [[CD2]], [[CD5 (protein)|CD5]] and [[CD7]]. Still during the double negative stages, [[CD34]] expression stops and [[CD1]] is expressed. Expression of both CD4 and CD8 makes them ''double positive'', and matures into either CD4<sup>+</sup> or CD8<sup>+</sup> cells.

===TCR development===
{{Main articles|T-cell receptor}}
A critical step in T cell maturation is making a functional T cell receptor (TCR). Each mature T cell will ultimately contain a unique TCR that reacts to a random pattern, allowing the immune system to recognize many different types of [[pathogen]]s. This process is essential in developing immunity to threats that the immune system has not encountered before, since due to random variation there will always be at least one TCR to match any new pathogen.

A thymocyte can only become an active T cell when it survives the process of developing a functional TCR. The TCR consists of two major components, the alpha and beta chains. These both contain random elements designed to produce a wide variety of different TCRs, but due to this huge variety they must be tested to make sure they work at all. First, the thymocytes attempt to create a functional beta chain, testing it against a 'mock' alpha chain. Then they attempt to create a functional alpha chain. Once a working TCR has been produced, the cells then must test if their TCR will identify threats correctly, and to do this it is required to recognize the body’s [[major histocompatibility complex]] (MHC) in a process known as positive selection. The thymocyte must also ensure that it does not react adversely to "self" [[antigen]]s, called negative selection. If both positive and negative selection are successful, the TCR becomes fully operational and the thymocyte becomes a T cell.

====TCR β-chain selection====
At the DN2 stage (CD44<sup>+</sup>CD25<sup>+</sup>), cells upregulate the recombination genes RAG1 and RAG2 and re-arrange the [[Thyroid hormone receptor beta|TCRβ]] locus, combining [[V(D)J recombination|V-D-J recombination]] and constant region genes in an attempt to create a functional TCRβ chain. As the developing thymocyte progresses through to the DN3 stage (CD44<sup>−</sup>CD25<sup>+</sup>), the thymocyte expresses an invariant α-chain called pre-Tα alongside the TCRβ gene. If the rearranged β-chain successfully pairs with the invariant α-chain, signals are produced which cease rearrangement of the β-chain (and silence the alternate allele).<ref>{{Cite book|last=Murphy|first=Kenneth|title=Janeway's Immunobiology|publisher=Garland Science|year=2011|isbn=9780815342434|edition=8th|pages=301–305}}</ref> Although these signals require the pre-TCR at the cell surface, they are independent of ligand binding to the pre-TCR. If the chains successfully pair a pre-TCR forms, and the cell downregulates CD25 and is termed a DN4 cell (CD25<sup>−</sup>CD44<sup>−</sup>). These cells then undergo a round of proliferation, and begin to re-arrange the TCRα locus during the ''double-positive'' stage.

====Positive selection====
The process of positive selection takes 3 to 4 days and occurs in the thymic cortex.<ref>{{cite journal|vauthors = Ross JO, Melichar HJ, Au-Yeung BB, Herzmark P, Weiss A, Robey EA|title = Distinct phases in the positive selection of CD8+ T cells distinguished by intrathymic migration and T-cell receptor signaling patterns|journal = Proceedings of the National Academy of Sciences of the United States of America|volume = 111|issue = 25|pages = E2550–E2558|date = June 2014|pmid = 24927565|pmc = 4078834|doi = 10.1073/pnas.1408482111|doi-access = free|bibcode = 2014PNAS..111E2550R}}</ref> Double-positive thymocytes (CD4<sup>+</sup>/CD8<sup>+</sup>) migrate deep into the [[Thymus#Structure|thymic cortex]], where they are presented with self-[[antigen]]s. These self-antigens are expressed by [[Cortical thymic epithelial cells|thymic cortical epithelial cells]] on MHC molecules, which reside on the surface of cortical epithelial cells. Only thymocytes that interact well with MHC-I or MHC-II will receive a vital "survival signal", while those that cannot interact strongly enough will receive no signal and [[Apoptosis|die from neglect]]. This process ensures that the surviving thymocytes will have an 'MHC affinity' that means they will exhibit stronger binding affinity for specific MHC alleles in that organism.<ref>{{Cite journal |last1=Štefanov́a |first1=Irena |last2=Dorfman |first2=Jeffrey R. |last3=Tsukamoto |first3=Makoto |last4=Germain |first4=Ronald N. |date=February 2003 |title=On the role of self-recognition in T cell responses to foreign antigen |url=https://onlinelibrary.wiley.com/doi/10.1034/j.1600-065X.2003.00006.x |journal=Immunological Reviews |language=en |volume=191 |issue=1 |pages=97–106 |doi=10.1034/j.1600-065X.2003.00006.x |pmid=12614354 |issn=0105-2896|url-access=subscription }}</ref> The vast majority of developing thymocytes will not pass positive selection, and die during this process.<ref>{{cite journal|vauthors = Starr TK, Jameson SC, Hogquist KA|title = Positive and negative selection of T cells|journal = Annual Review of Immunology|volume = 21|issue = 1|pages = 139–176|date = 2003-01-01|pmid = 12414722|doi = 10.1146/annurev.immunol.21.120601.141107}}</ref>

A thymocyte's fate is determined during positive selection. Double-positive cells (CD4<sup>+</sup>/CD8<sup>+</sup>) that interact well with MHC ''class II'' molecules will eventually become CD4<sup>+</sup> "helper" cells, whereas thymocytes that interact well with MHC ''class I'' molecules mature into CD8<sup>+</sup> "killer" cells. A thymocyte becomes a CD4<sup>+</sup> cell by down-regulating expression of its CD8 cell surface receptors. If the cell does not lose its signal, it will continue downregulating CD8 and become a CD4<sup>+</sup>, both CD8<sup>+</sup> and CD4<sup>+</sup> cells are now ''single positive'' cells.<ref>{{cite journal|vauthors=Zerrahn J, Held W, Raulet DH|title=The MHC reactivity of the T cell repertoire prior to positive and negative selection|journal=Cell|volume=88|issue=5|pages=627–636|date=March 1997|pmid=9054502|doi=10.1016/S0092-8674(00)81905-4|s2cid=15983629|doi-access=free}}</ref>

This process does not filter for thymocytes that may cause [[autoimmunity]]. The potentially autoimmune cells are removed by the following process of negative selection, which occurs in the thymic medulla.

====Negative selection====
Negative selection removes thymocytes that are capable of strongly binding with "self" MHC molecules. Thymocytes that survive positive selection migrate towards the boundary of the cortex and medulla in the thymus. While in the medulla, they are again presented with a self-antigen presented on the MHC complex of [[medullary thymic epithelial cells]] (mTECs).<ref name="pmid20431619">{{cite journal|vauthors=Hinterberger M, Aichinger M, Prazeres da Costa O, Voehringer D, Hoffmann R, Klein L|title = Autonomous role of medullary thymic epithelial cells in central CD4(+) T cell tolerance|journal=Nature Immunology|volume=11|issue=6|pages=512–519|date=June 2010|pmid=20431619|doi=10.1038/ni.1874|s2cid = 33154019|url = https://hal.archives-ouvertes.fr/hal-00531148/file/PEER_stage2_10.1038%252Fni.1874.pdf}}</ref> mTECs must be [[Autoimmune regulator]] positive (AIRE<sup>+</sup>) to properly express tissue-specific antigens on their MHC ''class I'' peptides. Some mTECs are [[Phagocytosis|phagocytosed]] by [[Dendritic cell|thymic dendritic cells]]; this makes them AIRE<sup>−</sup> [[Antigen-presenting cell|antigen presenting cells]] (APCs), allowing for presentation of self-antigens on MHC ''class II'' molecules (positively selected CD4<sup>+</sup> cells must interact with these MHC class II molecules, thus APCs, which possess MHC class II, must be present for CD4<sup>+</sup> T-cell negative selection). Thymocytes that interact too strongly with the self-antigen receive an [[apoptosis|apoptotic]] signal that leads to cell death. However, some of these cells are selected to become [[Treg]] cells. The remaining cells exit the thymus as mature [[naive T cell]]s, also known as recent thymic emigrants.<ref>{{cite journal|vauthors=Pekalski ML, García AR, Ferreira RC, Rainbow DB, Smyth DJ, Mashar M, Brady J, Savinykh N, Dopico XC, Mahmood S, Duley S, Stevens HE, Walker NM, Cutler AJ, Waldron-Lynch F, Dunger DB, Shannon-Lowe C, Coles AJ, Jones JL, Wallace C, Todd JA, Wicker LS|title=Neonatal and adult recent thymic emigrants produce IL-8 and express complement receptors CR1 and CR2|journal=JCI Insight|volume=2|issue=16|date=August 2017|pmid=28814669|pmc=5621870|doi=10.1172/jci.insight.93739}}</ref> This process is an important component of [[central tolerance]] and serves to prevent the formation of self-reactive T cells that are capable of inducing autoimmune diseases in the host.

====TCR development summary====
β-selection is the first checkpoint, where thymocytes that are able to form a functional pre-TCR (with an invariant alpha chain and a functional beta chain) are allowed to continue development in the thymus. Next, positive selection checks that thymocytes have successfully rearranged their TCRα locus and are capable of recognizing MHC molecules with appropriate affinity. Negative selection in the medulla then eliminates thymocytes that bind too strongly to self-antigens expressed on MHC molecules. These selection processes allow for tolerance of self by the immune system. Typical naive T cells that leave the thymus (via the corticomedullary junction) are self-restricted, self-tolerant, and single positive.

===Thymic output===
About 98% of thymocytes die during the development processes in the thymus by failing either positive selection or negative selection, whereas the other 2% survive and leave the thymus to become mature immunocompetent T cells.<ref>{{Cite book|last=Murphy|first=Kenneth|title=Janeway's Immunobiology|publisher=Garland Science|year=2011|isbn=9780815342434|edition=8th|pages=297}} </ref>
The thymus contributes fewer cells as a person ages. As the thymus shrinks by about 3%<ref name="pmid10837068">{{cite journal|vauthors=Haynes BF, Markert ML, Sempowski GD, Patel DD, Hale LP|title=The role of the thymus in immune reconstitution in aging, bone marrow transplantation, and HIV-1 infection|journal=Annu. Rev. Immunol.|volume=18|pages=529–560|year=2000|pmid=10837068|doi=10.1146/annurev.immunol.18.1.529}}</ref> a year throughout middle age, a corresponding fall in the thymic production of naive T cells occurs, leaving peripheral T cell expansion and regeneration to play a greater role in protecting older people.

==Types of T cell==
T cells are grouped into a series of subsets based on their function. CD4 and CD8 T cells are selected in the thymus, but undergo further differentiation in the periphery to specialized cells which have different functions. T cell subsets were initially defined by function, but also have associated gene or protein expression patterns.

===Conventional adaptive T cells===
====Helper CD4<sup>+</sup> T cells====
{{Main|T helper cell}}
[[File:CD4+ T cell subsets.pdf|thumb|Depiction of the various key subsets of CD4-positive T cells with corresponding associated cytokines and transcription factors.]]

[[T helper cell]]s (T<sub>H</sub> cells) assist other lymphocytes, including the maturation of [[B cell]]s into [[plasma cell]]s and [[memory B cell]]s, and activation of [[cytotoxic T cells]] and [[macrophage]]s. These cells are also known as '''CD4<sup>+</sup> T cells''' as they express the [[CD4]] glycoprotein on their surfaces. Helper T cells become activated when they are presented with [[peptide]] [[antigen]]s by [[MHC class II]] molecules, which are expressed on the surface of [[antigen-presenting cell]]s (APCs). Once activated, they divide rapidly and secrete [[cytokine]]s that regulate or assist the immune response. These cells can differentiate into one of several subtypes, which have different roles. Cytokines direct T cells into particular subtypes.<ref name="pmid17476341">{{cite journal|vauthors=Gutcher I, Becher B|title = APC-derived cytokines and T cell polarization in autoimmune inflammation|journal = J. Clin. Invest.|volume = 117|issue = 5|pages = 1119–27|year = 2007|pmid = 17476341|pmc = 1857272|doi = 10.1172/JCI31720}}</ref>

{|class="wikitable"
|+CD4<sup>+</sup> helper T cell subsets
!Cell type!!Cytokines Produced!!Key Transcription Factor!!Role in immune defense!!Related diseases
|-
|[[Th1 cell|Th1]]||[[IFNγ]], IL-2||[[TBX21|Tbet]]||Produce an inflammatory response, key for defense against intracellular bacteria, viruses and cancer.||MS, Type 1 diabetes
|-
|[[Th2]]||IL-4, IL-5, IL-13||GATA-3||Immunologically important against extracellular pathogens, such as worm infections||Asthma and other allergic diseases

|-
|[[Th17]]||IL-17F, IL-17A, IL-22||RORγt||Defense against gut pathogens and at mucosal barriers||MS, Rheumatoid Arthritis, Psoriasis
|-
|[[Th 9 cell|Th9]]<ref>{{cite journal|vauthors = Wang W, Sung N, Gilman-Sachs A, Kwak-Kim J|title = T Helper (Th) Cell Profiles in Pregnancy and Recurrent Pregnancy Losses: Th1/Th2/Th9/Th17/Th22/Tfh Cells|journal = Frontiers in Immunology|volume = 11|pages = 2025|date = 18 August 2020|pmid = 32973809|pmc = 7461801|doi = 10.3389/fimmu.2020.02025|doi-access = free}}</ref><ref name="Saravia 634–643">{{cite journal|vauthors = Saravia J, Chapman NM, Chi H|title = Helper T cell differentiation|journal = Cellular & Molecular Immunology|volume = 16|issue = 7|pages = 634–643|date = July 2019|pmid = 30867582|pmc = 6804569|doi = 10.1038/s41423-019-0220-6}}</ref>||IL-9||IRF4, PU.1||Defense against helminths (parasitic worms) and cell-dependent allergic inflammation||Multiple Sclerosis
|-

|[[Follicular B helper T cells|Tfh]]||IL-21, IL-4||Bcl-6||Help B cells produce antibodies||Asthma and other allergic diseases
|-
|Th22<ref>{{cite book|vauthors = Jia L, Wu C| title=T Helper Cell Differentiation and Their Function | chapter=The Biology and Functions of Th22 Cells | series=Advances in Experimental Medicine and Biology |volume = 841|pages = 209–230|year = 2014|pmid = 25261209|doi = 10.1007/978-94-017-9487-9_8|isbn = 978-94-017-9486-2}}</ref><ref name="Saravia 634–643"/>
|IL-22
|AHR
|Pathogenesis of allergic airway diseases and predominantly anti-inflammatory
|Crohn's Disease, Rheumatoid Arthritis, Tumors
|}

====Cytotoxic CD8+ T cells====
{{Main|Cytotoxic T cell}}
[[File:Killer T cells surround a cancer cell.png|thumb|Superresolution image of a group of cytotoxic T cells surrounding a cancer cell]]

[[Cytotoxic T cell]]s (T<sub>C</sub> cells, CTLs, T-killer cells, killer T cells) destroy virus-infected cells and tumor cells, and are also implicated in [[Organ transplant|transplant]] rejection. These cells are defined by the expression of the [[CD8]] protein on their cell surface. Cytotoxic T cells recognize their targets by binding to short peptides (8-11 [[amino acid]]s in length) associated with [[MHC class I]] molecules, present on the surface of all nucleated cells. Cytotoxic T cells also produce the key cytokines IL-2 and IFNγ. These cytokines influence the effector functions of other cells, in particular macrophages and NK cells.

====Memory T cells====
{{Main|Memory T cell}}
Antigen-naive T cells expand and differentiate into memory and [[effector T cells]] after they encounter their cognate antigen within the context of an MHC molecule on the surface of a professional antigen presenting cell (e.g. a dendritic cell). Appropriate co-stimulation must be present at the time of antigen encounter for this process to occur. Historically, memory T cells were thought to belong to either the effector or central memory subtypes, each with their own distinguishing set of cell surface markers (see below).<ref>{{cite journal|vauthors= Sallusto F, Lenig D, Förster R, Lipp M, Lanzavecchia A|title = Two subsets of memory T lymphocytes with distinct homing potentials and effector functions.|journal = Nature|volume = 401|issue = 6754|pages = 708–712|year = 1999|pmid = 10537110|doi = 10.1038/44385|bibcode = 1999Natur.401..708S|s2cid = 4378970}}</ref> Subsequently, numerous new populations of memory T cells were discovered including tissue-resident memory T (Trm) cells, stem memory TSCM cells, and virtual memory T cells. The single unifying theme for all [[memory T cell]] subtypes is that they are long-lived and can quickly expand to large numbers of effector T cells upon re-exposure to their cognate antigen. By this mechanism they provide the immune system with "memory" against previously encountered pathogens. Memory T cells may be either CD4<sup>+</sup> or CD8<sup>+</sup> and usually express [[CD45|CD45RO]].<ref name="pmid2965180">{{cite journal|vauthors=Akbar AN, Terry L, Timms A, Beverley PC, Janossy G|title = Loss of CD45R and gain of UCHL1 reactivity is a feature of primed T cells|journal = J. Immunol.|volume = 140|issue = 7|pages = 2171–8|date = April 1988|doi = 10.4049/jimmunol.140.7.2171|pmid = 2965180|s2cid = 22340282|doi-access = free}}</ref>

Memory T cell subtypes:
*Central memory T cells (T<sub>CM</sub> cells) express CD45RO, [[C-C chemokine receptor type 7]] (CCR7), and [[L-selectin]] (CD62L). Central memory T cells also have intermediate to high expression of [[CD44]]. This memory subpopulation is commonly found in the [[lymph node]]s and in the peripheral circulation. (Note- CD44 expression is usually used to distinguish murine naive from memory T cells).
*Effector memory T cells (T<sub>EM</sub> cells and T<sub>EMRA</sub> cells) express CD45RO but lack expression of CCR7 and [[L-selectin]]. They also have intermediate to high expression of [[CD44]]. These memory T cells lack lymph node-homing receptors and are thus found in the peripheral circulation and tissues.<ref>{{cite journal|vauthors=Willinger T, Freeman T, Hasegawa H, McMichael AJ, Callan MF|title = Molecular signatures distinguish human central memory from effector memory CD8 T cell subsets.|journal = Journal of Immunology|volume = 175|issue = 9|pages = 5895–903|year = 2005|pmid = 16237082|doi = 10.4049/jimmunol.175.9.5895|s2cid = 16412760|url = https://www.pure.ed.ac.uk/ws/files/13962949/Molecular_Signatures_Distinguish_Human_Central_Memory_from_Effector.pdf|doi-access = free}}</ref> T<sub>EMRA</sub> stands for terminally differentiated effector memory cells re-expressing CD45RA, which is a marker usually found on naive T cells.<ref>{{cite journal|vauthors= Koch S, Larbi A, Derhovanessian E, Özcelik D, Naumova E, Pawelec G|title = Multiparameter flow cytometric analysis of CD4 and CD8 T cell subsets in young and old people.|journal = Immunity & Ageing|volume = 5|issue = 6|pages = 6|year = 2008|pmid = 18657274|doi = 10.1186/1742-4933-5-6|pmc=2515281 | doi-access=free }}</ref>
*[[Tissue-resident memory T cells]] (T<sub>RM</sub>) occupy tissues (skin, lung, etc.) without recirculating. One cell surface marker that has been associated with T<sub>RM</sub> is the intern αeβ7, also known as CD103.<ref>{{cite journal|vauthors = Shin H, Iwasaki A|title = Tissue-resident memory T cells|journal = Immunological Reviews|volume = 255|issue = 1|pages = 165–81|date = September 2013|pmid = 23947354|pmc = 3748618|doi = 10.1111/imr.12087}}</ref>
*[[Virtual memory T cells]] (T<sub>VM</sub>) differ from the other memory subsets in that they do not originate following a strong clonal expansion event. Thus, although this population as a whole is abundant within the peripheral circulation, individual virtual memory T cell clones reside at relatively low frequencies. One theory is that homeostatic proliferation gives rise to this T cell population. Although CD8 virtual memory T cells were the first to be described,<ref>{{cite journal|vauthors=Lee YJ, Jameson SC, Hogquist KA|title = Alternative memory in the CD8 T cell lineage.|journal = Trends in Immunology|volume = 32|issue = 2|pages = 50–56|year = 2011|pmid = 21288770|doi = 10.1016/j.it.2010.12.004|pmc=3039080}}</ref> it is now known that CD4 virtual memory cells also exist.<ref>{{cite journal|vauthors= Marusina AI, Ono Y, Merleev AA, Shimoda M, Ogawa H, Wang EA, Kondo K, Olney L, Luxardi G, Miyamura Y, Yilma TD, Villalobos IB, Bergstrom JW, Kronenberg DG, Soulika AM, Adamopoulos IE, Maverakis E|title = CD4<sup>+</sup> virtual memory: Antigen-inexperienced T cells reside in the naïve, regulatory, and memory T cell compartments at similar frequencies, implications for autoimmunity.|journal = Journal of Autoimmunity|volume = 77|pages = 76–88|year = 2017|pmid = 27894837|pmc = 6066671|doi = 10.1016/j.jaut.2016.11.001}}</ref>

====Regulatory CD4<sup>+</sup> T cells====
{{Main|Regulatory T cell}}

[[Regulatory T cell]]s are crucial for the maintenance of [[immunological tolerance]]. Their major role is to shut down T cell–mediated immunity toward the end of an immune reaction and to suppress [[autoreactive T cell]]s that escaped the process of negative selection in the thymus.

Two major classes of CD4<sup>+</sup> T<sub>reg</sub> cells have been described—FOXP3<sup>+</sup> T<sub>reg</sub> cells and FOXP3<sup>−</sup> T<sub>reg</sub> cells.

Regulatory T cells can develop either during normal development in the thymus, and are then known as thymic Treg cells, or can be induced peripherally and are called peripherally derived Treg cells. These two subsets were previously called "naturally occurring" and "adaptive" (or "induced"), respectively.<ref name="pmid23507634">{{cite journal|vauthors=Abbas AK, Benoist C, Bluestone JA, Campbell DJ, Ghosh S, Hori S, Jiang S, Kuchroo VK, Mathis D, Roncarolo MG, Rudensky A, Sakaguchi S, Shevach EM, Vignali DA, Ziegler SF|title=Regulatory T cells: recommendations to simplify the nomenclature|journal=Nat. Immunol.|volume=14|issue=4|pages=307–8|year=2013|pmid=23507634|doi=10.1038/ni.2554|s2cid=11294516|url=http://www.escholarship.org/uc/item/75m8c11s|doi-access=free}}</ref> Both subsets require the expression of the [[transcription factor]] [[FOXP3]] which can be used to identify the cells. Mutations of the ''FOXP3'' gene can prevent regulatory T cell development, causing the fatal [[autoimmune disease]] [[IPEX (syndrome)|IPEX]].

Several other types of T cells have suppressive activity, but do not express FOXP3 constitutively. These include [[Type 1 regulatory T cell|Tr1]] and [[T helper 3 cell|Th3]] cells, which are thought to originate during an immune response and act by producing suppressive molecules. Tr1 cells are associated with IL-10, and Th3 cells are associated with [[TGF-beta]]. Recently, [[Th17 cells]] have been added to this list.<ref name="pmid24434314">{{cite journal|vauthors=Singh B, Schwartz JA, Sandrock C, Bellemore SM, Nikoopour E|title=Modulation of autoimmune diseases by interleukin (IL)-17 producing regulatory T helper (Th17) cells|journal=Indian J. Med. Res.|volume=138|issue=5|pages=591–4|year=2013|pmid=24434314|pmc=3928692}}</ref>

===Innate-like T cells===
'''Innate-like T cells''' or '''unconventional T cells''' represent some subsets of T cells that behave differently in immunity. They trigger rapid immune responses, regardless of the major histocompatibility complex (MHC) expression, unlike their conventional counterparts (CD4 T helper cells and CD8 cytotoxic T cells), which are dependent on the recognition of peptide antigens in the context of the MHC molecule. Overall, there are three large populations of unconventional T cells: NKT cells, MAIT cells, and gammadelta T cells. Now, their functional roles are already being well established in the context of infections and cancer.<ref>{{cite journal|vauthors = Godfrey DI, Uldrich AP, McCluskey J, Rossjohn J, Moody DB|title = The burgeoning family of unconventional T cells|journal = Nature Immunology|volume = 16|issue = 11|pages = 1114–1123|date = November 2015|pmid = 26482978|doi = 10.1038/ni.3298|s2cid = 30992456}}</ref> Furthermore, these T cell subsets are being translated into many therapies against malignancies such as leukemia, for example.<ref>{{cite journal|vauthors = de Araújo ND, Gama FM, de Souza Barros M, Ribeiro TL, Alves FS, Xabregas LA, Tarragô AM, Malheiro A, Costa AG|display-authors = 6|title = Translating Unconventional T Cells and Their Roles in Leukemia Antitumor Immunity|journal = Journal of Immunology Research|volume = 2021|pages = 6633824|date = 2021|pmid = 33506055|pmc = 7808823|doi = 10.1155/2021/6633824|doi-access = free}}</ref>

====Natural killer T cell====
{{Main|Natural killer T cell}}
[[Natural killer T cell]]s (NKT cells – not to be confused with [[natural killer cell]]s of the innate immune system) bridge the [[adaptive immune system]] with the [[innate immune system]]. Unlike conventional T cells that recognize protein peptide antigens presented by [[major histocompatibility complex]] (MHC) molecules, NKT cells recognize glycolipid antigens presented by [[CD1d]]. Once activated, these cells can perform functions ascribed to both helper and cytotoxic T cells: cytokine production and release of cytolytic/cell killing molecules. They are also able to recognize and eliminate some tumor cells and cells infected with herpes viruses.<ref>{{cite journal|vauthors = Mallevaey T, Fontaine J, Breuilh L, Paget C, Castro-Keller A, Vendeville C, Capron M, Leite-de-Moraes M, Trottein F, Faveeuw C|title = Invariant and noninvariant natural killer T cells exert opposite regulatory functions on the immune response during murine schistosomiasis|journal = Infection and Immunity|volume = 75|issue = 5|pages = 2171–80|date = May 2007|pmid = 17353286|pmc = 1865739|doi = 10.1128/IAI.01178-06}}</ref>

====Mucosal associated invariant T cells====
{{main|Mucosal associated invariant T cell}}
Mucosal associated invariant T (MAIT) cells display [[Innate immune system|innate]], effector-like qualities.<ref name=":02">{{cite journal|vauthors = Napier RJ, Adams EJ, Gold MC, Lewinsohn DM|title = The Role of Mucosal Associated Invariant T Cells in Antimicrobial Immunity|journal = Frontiers in Immunology|volume = 6|pages = 344|date = 2015-07-06|pmid = 26217338|pmc = 4492155|doi = 10.3389/fimmu.2015.00344|doi-access = free}}</ref><ref>{{cite journal|vauthors = Gold MC, Lewinsohn DM|title = Mucosal associated invariant T cells and the immune response to infection|journal = Microbes and Infection|volume = 13|issue = 8–9|pages = 742–8|date = August 2011|pmid = 21458588|pmc = 3130845|doi = 10.1016/j.micinf.2011.03.007}}</ref> In humans, MAIT cells are found in the blood, liver, lungs, and [[Mucous membrane|mucosa]], defending against microbial activity and infection.<ref name=":02"/> The [[MHC class I]]-like protein, [[MR1 (gene)|MR1]], is responsible for presenting bacterially-produced [[B vitamins|vitamin B]] metabolites to MAIT cells.<ref name=":4">{{cite journal|vauthors = Eckle SB, Corbett AJ, Keller AN, Chen Z, Godfrey DI, Liu L, Mak JY, Fairlie DP, Rossjohn J, McCluskey J|title = Recognition of Vitamin B Precursors and Byproducts by Mucosal Associated Invariant T Cells|journal = The Journal of Biological Chemistry|volume = 290|issue = 51|pages = 30204–11|date = December 2015|pmid = 26468291|pmc = 4683245|doi = 10.1074/jbc.R115.685990|doi-access = free}}</ref><ref name=":6">{{cite journal|vauthors = Ussher JE, Klenerman P, Willberg CB|title = Mucosal-associated invariant T-cells: new players in anti-bacterial immunity|journal = Frontiers in Immunology|volume = 5|pages = 450|date = 2014-10-08|pmid = 25339949|pmc = 4189401|doi = 10.3389/fimmu.2014.00450|doi-access = free}}</ref><ref name=":12">{{cite journal|vauthors = Howson LJ, Salio M, Cerundolo V|title = MR1-Restricted Mucosal-Associated Invariant T Cells and Their Activation during Infectious Diseases|journal = Frontiers in Immunology|volume = 6|pages = 303|date = 2015-06-16|pmid = 26136743|pmc = 4468870|doi = 10.3389/fimmu.2015.00303|doi-access = free}}</ref> After the presentation of foreign antigen by MR1, MAIT cells secrete pro-inflammatory [[cytokine]]s and are capable of [[Lysis|lysing]] bacterially-infected cells.<ref name=":02"/><ref name=":12"/> MAIT cells can also be activated through MR1-independent signaling.<ref name=":12"/> In addition to possessing innate-like functions, this T cell subset supports the [[Adaptive immune system|adaptive]] immune response and has a memory-like phenotype.<ref name=":02"/> Furthermore, MAIT cells are thought to play a role in [[autoimmune disease]]s, such as [[multiple sclerosis]], arthritis and [[inflammatory bowel disease]],<ref name=":5">{{cite journal|vauthors = Hinks TS|title = Mucosal-associated invariant T cells in autoimmunity, immune-mediated diseases and airways disease|journal = Immunology|volume = 148|issue = 1|pages = 1–12|date = May 2016|pmid = 26778581|pmc = 4819138|doi = 10.1111/imm.12582}}</ref><ref name=":9">{{cite journal|vauthors = Bianchini E, De Biasi S, Simone AM, Ferraro D, Sola P, Cossarizza A, Pinti M|title = Invariant natural killer T cells and mucosal-associated invariant T cells in multiple sclerosis|journal = Immunology Letters|volume = 183|pages = 1–7|date = March 2017|pmid = 28119072|doi = 10.1016/j.imlet.2017.01.009}}</ref> although definitive evidence is yet to be published.<ref>{{cite journal|vauthors = Serriari NE, Eoche M, Lamotte L, Lion J, Fumery M, Marcelo P, Chatelain D, Barre A, Nguyen-Khac E, Lantz O, Dupas JL, Treiner E|title = Innate mucosal-associated invariant T (MAIT) cells are activated in inflammatory bowel diseases|journal = Clinical and Experimental Immunology|volume = 176|issue = 2|pages = 266–74|date = May 2014|pmid = 24450998|pmc = 3992039|doi = 10.1111/cei.12277}}</ref><ref>{{cite journal|vauthors = Huang S, Martin E, Kim S, Yu L, Soudais C, Fremont DH, Lantz O, Hansen TH|title = MR1 antigen presentation to mucosal-associated invariant T cells was highly conserved in evolution|journal = Proceedings of the National Academy of Sciences of the United States of America|volume = 106|issue = 20|pages = 8290–5|date = May 2009|pmid = 19416870|pmc = 2688861|doi = 10.1073/pnas.0903196106|bibcode = 2009PNAS..106.8290H|doi-access = free}}</ref><ref>{{cite journal|vauthors = Chua WJ, Hansen TH|title = Bacteria, mucosal-associated invariant T cells and MR1|journal = Immunology and Cell Biology|volume = 88|issue = 8|pages = 767–9|date = November 2010|pmid = 20733595|doi = 10.1038/icb.2010.104|s2cid = 27717815|doi-access = free}}</ref><ref>{{cite journal|vauthors = Kjer-Nielsen L, Patel O, Corbett AJ, Le Nours J, Meehan B, Liu L, Bhati M, Chen Z, Kostenko L, Reantragoon R, Williamson NA, Purcell AW, Dudek NL, McConville MJ, O'Hair RA, Khairallah GN, Godfrey DI, Fairlie DP, Rossjohn J, McCluskey J|title = MR1 presents microbial vitamin B metabolites to MAIT cells|journal = Nature|volume = 491|issue = 7426|pages = 717–23|date = November 2012|pmid = 23051753|doi = 10.1038/nature11605|bibcode = 2012Natur.491..717K|s2cid = 4419703|url = https://espace.library.uq.edu.au/view/UQ:284808/UQ284808_OA.pdf}}</ref>

====Gamma delta T cells====
{{Main|Gamma delta T cell}}
[[Gamma delta T cell]]s (γδ T cells) represent a small subset of T cells which possess a γδ TCR rather than the αβ TCR on the cell surface. The majority of T cells express αβ TCR chains. This group of T cells is much less common in humans and mice (about 2% of total T cells) and are found mostly in the gut [[mucosa]], within a population of [[intraepithelial lymphocyte]]s. In rabbits, sheep, and chickens, the number of γδ T cells can be as high as 60% of total T cells. The antigenic molecules that activate γδ T cells are still mostly unknown. However, γδ T cells are not MHC-restricted and seem to be able to recognize whole proteins rather than requiring peptides to be presented by MHC molecules on [[antigen presenting cells|APCs]]. Some [[murinae|murine]] γδ T cells recognize MHC class IB molecules. Human γδ T cells that use the Vγ9 and Vδ2 gene fragments constitute the major γδ T cell population in peripheral blood. These cells are unique in that they specifically and rapidly respond to a set of nonpeptidic phosphorylated [[isoprenoid]] precursors, collectively named [[phosphoantigen]]s, which are produced by virtually all living cells. The most common phosphoantigens from animal and human cells (including cancer cells) are [[isopentenyl pyrophosphate]] (IPP) and its isomer [[dimethylallyl pyrophosphate]] (DMPP). Many microbes produce the active compound hydroxy-DMAPP ([[HMB-PP]]) and corresponding mononucleotide conjugates, in addition to IPP and DMAPP. Plant cells produce both types of phosphoantigens. Drugs activating human Vγ9/Vδ2 T cells comprise synthetic phosphoantigens and [[bisphosphonates|aminobisphosphonates]], which upregulate endogenous IPP/DMAPP.

==Activation==
{{see also|T-cell receptor#Signaling pathway}}
[[Image:T cell activation.svg|thumb|328px|right|The T lymphocyte activation pathway: T cells contribute to immune defenses in two major ways; some direct and regulate immune responses; others directly attack infected or cancerous cells.<ref name=NIAID>The [[NIAID]] resource booklet [https://www.niaid.nih.gov/publications/immune/the_immune_system.pdf "Understanding the Immune System (pdf)"].</ref>]]
Activation of CD4<sup>+</sup> T cells occurs through the simultaneous engagement of the [[T-cell receptor]] and a co-stimulatory molecule (like [[CD28]], or [[CD278|ICOS]]) on the T cell by the major histocompatibility complex (MHCII) [[peptide]] and co-stimulatory molecules on the [[Antigen-presenting cell|APC]]. Both are required for production of an effective immune response; in the absence of [[co-stimulation]], T cell receptor signalling alone results in [[anergy]]. The signalling pathways downstream from co-stimulatory molecules usually engages the [[phosphoinositide 3-kinase|PI3K]] pathway generating [[PIP3]] at the plasma membrane and recruiting [[pleckstrin homology domain|PH domain]] containing signaling molecules like [[Phosphoinositide-dependent kinase-1|PDK1]] that are essential for the activation of [[PRKCQ|PKC-θ]], and eventual [[Interleukin 2|IL-2]] production. Optimal CD8<sup>+</sup> T cell response relies on CD4<sup>+</sup> signalling.<ref>{{cite journal|vauthors = Williams MA, Bevan MJ|title = Effector and memory CTL differentiation|journal = Annual Review of Immunology|volume = 25|issue = 1|pages = 171–92|date = 2007-01-01|pmid = 17129182|doi = 10.1146/annurev.immunol.25.022106.141548}}</ref> CD4<sup>+</sup> cells are useful in the initial antigenic activation of naive CD8 T cells, and sustaining memory CD8<sup>+</sup> T cells in the aftermath of an acute infection. Therefore, activation of CD4<sup>+</sup> T cells can be beneficial to the action of CD8<sup>+</sup> T cells.<ref>{{cite journal|vauthors = Janssen EM, Lemmens EE, Wolfe T, Christen U, von Herrath MG, Schoenberger SP|title = CD4<sup>+</sup> T cells are required for secondary expansion and memory in CD8+ T lymphocytes|journal = Nature|volume = 421|issue = 6925|pages = 852–6|date = February 2003|pmid = 12594515|doi = 10.1038/nature01441|bibcode = 2003Natur.421..852J|s2cid = 574770}}</ref><ref>{{cite journal|vauthors = Shedlock DJ, Shen H|title = Requirement for CD4 T cell help in generating functional CD8 T cell memory|journal = Science|volume = 300|issue = 5617|pages = 337–9|date = April 2003|pmid = 12690201|doi = 10.1126/science.1082305|bibcode = 2003Sci...300..337S|s2cid = 38040377}}</ref><ref>{{cite journal|vauthors = Sun JC, Williams MA, Bevan MJ|title = CD4<sup>+</sup>T cells are required for the maintenance, not programming, of memory CD8+ T cells after acute infection|journal = Nature Immunology|volume = 5|issue = 9|pages = 927–33|date = September 2004|pmid = 15300249|pmc = 2776074|doi = 10.1038/ni1105}}</ref>

The first signal is provided by binding of the T cell receptor to its cognate peptide presented on MHCII on an APC. MHCII is restricted to so-called professional [[antigen-presenting cell]]s, like dendritic cells, B cells, and macrophages, to name a few. The peptides presented to CD8<sup>+</sup> T cells by MHC class I molecules are 8–13 amino acids in length; the peptides presented to CD4<sup>+</sup> cells by MHC class II molecules are longer, usually 12–25 amino acids in length,<ref>Jennifer Rolland and Robyn O'Hehir, "Turning off the T cells: Peptides for treatment of allergic Diseases," Today's life science publishing, 1999, Page 32</ref> as the ends of the binding cleft of the MHC class II molecule are open.

The second signal comes from co-stimulation, in which surface receptors on the APC are induced by a relatively small number of stimuli, usually products of pathogens, but sometimes breakdown products of cells, such as [[necrosis|necrotic]]-bodies or [[heat shock proteins]]. The only co-stimulatory receptor expressed constitutively by naive T cells is CD28, so co-stimulation for these cells comes from the [[CD80]] and [[CD86]] proteins, which together constitute the [[B7 (protein)|B7]] protein, (B7.1 and B7.2, respectively) on the APC. Other receptors are expressed upon activation of the T cell, such as [[OX40]] and ICOS, but these largely depend upon CD28 for their expression. The second signal licenses the T cell to respond to an antigen. Without it, the T cell becomes [[anergy|anergic]], and it becomes more difficult for it to activate in future. This mechanism prevents inappropriate responses to self, as self-peptides will not usually be presented with suitable co-stimulation. Once a T cell has been appropriately activated (i.e. has received signal one and signal two) it alters its cell surface expression of a variety of proteins. Markers of T cell activation include CD69, CD71 and CD25 (also a marker for Treg cells), and HLA-DR (a marker of human T cell activation). CTLA-4 expression is also up-regulated on activated T cells, which in turn outcompetes CD28 for binding to the B7 proteins. This is a checkpoint mechanism to prevent over activation of the T cell. Activated T cells also change their cell surface glycosylation profile.<ref>{{cite journal|vauthors=Maverakis E, Kim K, Shimoda M, Gershwin M, Patel F, Wilken R, Raychaudhuri S, Ruhaak LR, Lebrilla CB|title = Glycans in the immune system and The Altered Glycan Theory of Autoimmunity|journal = J Autoimmun|volume = 57|issue = 6|pages = 1–13|year = 2015|pmid = 25578468|doi = 10.1016/j.jaut.2014.12.002|pmc=4340844}}</ref>

The [[T cell receptor]] exists as a complex of several proteins. The actual T cell receptor is composed of two separate peptide chains, which are produced from the independent T cell receptor alpha and beta (''TCRα'' and ''TCRβ'') genes. The other proteins in the complex are the [[CD3 (immunology)|CD3]] proteins: CD3εγ and CD3εδ heterodimers and, most important, a CD3ζ homodimer, which has a total of six [[immunoreceptor tyrosine-based activation motif|ITAM]] motifs. The ITAM motifs on the CD3ζ can be phosphorylated by [[Lck]] and in turn recruit [[ZAP70|ZAP-70]]. Lck and/or ZAP-70 can also phosphorylate the [[tyrosines]] on many other molecules, not least CD28, [[Linker of activated T cells|LAT]] and [[Lymphocyte cytosolic protein 2|SLP-76]], which allows the aggregation of signalling complexes around these proteins.

Phosphorylated [[linker of activated T cells|LAT]] recruits SLP-76 to the membrane, where it can then bring in [[Phosphoinositide phospholipase C|PLC-γ]], [[VAV1]], [[ITK (gene)|Itk]] and potentially [[phosphoinositide 3-kinase|PI3K]]. PLC-γ cleaves PI(4,5)P2 on the inner leaflet of the membrane to create the active intermediaries diacylglycerol ([[Diglyceride|DAG]]), inositol-1,4,5-trisphosphate ([[inositol trisphosphate|IP3]]); PI3K also acts on PIP2, phosphorylating it to produce phosphatidlyinositol-3,4,5-trisphosphate (PIP3). DAG binds and activates some PKCs. Most important in T cells is PKC-θ, critical for activating the transcription factors [[NF-κB]] and AP-1. [[Inositol triphosphate|IP3]] is released from the membrane by PLC-γ and diffuses rapidly to activate calcium channel receptors on the [[endoplasmic reticulum|ER]], which induces the release of [[calcium in biology|calcium]] into the cytosol. Low calcium in the endoplasmic reticulum causes STIM1 clustering on the ER membrane and leads to activation of cell membrane CRAC channels that allows additional calcium to flow into the cytosol from the extracellular space. This aggregated cytosolic calcium binds calmodulin, which can then activate [[calcineurin]]. Calcineurin, in turn, activates [[NFAT]], which then translocates to the nucleus. NFAT is a [[transcription factor]] that activates the transcription of a pleiotropic set of genes, most notable, IL-2, a cytokine that promotes long-term proliferation of activated T cells.

PLC-γ can also initiate the [[NF-κB pathway]]. DAG activates PKC-θ, which then phosphorylates CARMA1, causing it to unfold and function as a scaffold. The cytosolic domains bind an adapter [[BCL10]] via [[CARD domain|CARD]] (Caspase activation and recruitment domains) domains; that then binds TRAF6, which is ubiquitinated at K63.{{rp|513–523}}<ref name="isbn0-12-289632-7"/> This form of ubiquitination does not lead to degradation of target proteins. Rather, it serves to recruit NEMO, IKKα and -β, and TAB1-2/ TAK1.<ref name="pmid14579250">{{cite journal|vauthors=Wu H, Arron JR|title = TRAF6, a molecular bridge spanning adaptive immunity, innate immunity and osteoimmunology|journal = BioEssays|volume = 25|issue = 11|pages = 1096–105|date = November 2003|pmid = 14579250|doi = 10.1002/bies.10352|s2cid = 28521713}}</ref> TAK 1 phosphorylates IKK-β, which then phosphorylates IκB allowing for K48 ubiquitination: leads to proteasomal degradation. Rel A and p50 can then enter the nucleus and bind the NF-κB response element. This coupled with NFAT signaling allows for complete activation of the IL-2 gene.<ref name="isbn0-12-289632-7">{{cite book|vauthors=Tatham P, Gomperts BD, Kramer IM|title = Signal transduction|publisher = Elsevier Academic Press|location = Amsterdam|year = 2003|isbn = 978-0-12-289632-3}}</ref>

While in most cases activation is dependent on TCR recognition of antigen, alternative pathways for activation have been described. For example, cytotoxic T cells have been shown to become activated when targeted by other CD8 T cells leading to tolerization of the latter.<ref name="pmid21045195">{{cite journal|vauthors=Milstein O, Hagin D, Lask A, Reich-Zeliger S, Shezen E, Ophir E, Eidelstein Y, Afik R, Antebi YE, Dustin ML, Reisner Y|title = CTLs respond with activation and granule secretion when serving as targets for T cell recognition|journal = Blood|volume = 117|issue = 3|pages = 1042–52|date = January 2011|pmid = 21045195|pmc = 3035066|doi = 10.1182/blood-2010-05-283770}}</ref>

In spring 2014, the [[T-Cell Activation in Space]] (TCAS) experiment was launched to the [[International Space Station]] on the [[SpaceX CRS-3]] mission to study how "deficiencies in the human immune system are affected by a microgravity environment".<ref name=nsf20140414prelaunchArticle>{{cite news|vauthors = Graham W|title=SpaceX ready for CRS-3 Dragon launch and new milestones|url=http://www.nasaspaceflight.com/2014/04/spacex-crs-3-dragon-new-milestones/|access-date=2014-04-14|newspaper=NASAspaceflight.com|date=2014-04-14}}</ref>

T cell activation is modulated by [[reactive oxygen species]].<ref>{{cite journal|vauthors = Belikov AV, Schraven B, Simeoni L|title = T cells and reactive oxygen species|journal = Journal of Biomedical Science|volume = 22|pages = 85|date = October 2015|pmid = 26471060|pmc = 4608155|doi = 10.1186/s12929-015-0194-3 | doi-access=free }}</ref>

===Antigen discrimination===
A unique feature of T cells is their ability to discriminate between healthy and abnormal (e.g. infected or cancerous) cells in the body.<ref name="Feinerman_2008">{{cite journal|vauthors=Feinerman O, Germain RN, Altan-Bonnet G|title = Quantitative challenges in understanding ligand discrimination by alphabeta T cells|journal = Mol. Immunol.|volume = 45|issue = 3|pages = 619–31|year = 2008|pmid = 17825415|pmc = 2131735|doi = 10.1016/j.molimm.2007.03.028}}</ref> Healthy cells typically express a large number of self derived [[T-cell receptor#Antigen discrimination|pMHC]] on their cell surface and although the T cell antigen receptor can interact with at least a subset of these self pMHC, the T cell generally ignores these healthy cells. However, when these very same cells contain even minute quantities of pathogen derived pMHC, T cells are able to become activated and initiate immune responses. The ability of T cells to ignore healthy cells but respond when these same cells contain pathogen (or cancer) derived pMHC is known as antigen discrimination. The molecular mechanisms that underlie this process are controversial.<ref name="Feinerman_2008"/><ref name="pmid24636916">{{cite journal|vauthors=Dushek O, van der Merwe PA|title = An induced rebinding model of antigen discrimination|journal = Trends Immunol.|volume = 35|issue = 4|pages = 153–8|year = 2014|pmid = 24636916|pmc = 3989030|doi = 10.1016/j.it.2014.02.002}}</ref>

==Clinical significance==
===Deficiency===
{{Main|T cell deficiency}}
[[File:HIV-infected T cell (6813384933).jpg|thumb|[[HIV/AIDS|HIV]]-infected T cell]]

Causes of [[T cell deficiency]] include [[lymphocytopenia]] of T cells and/or defects on function of individual T cells. Complete insufficiency of T cell function can result from [[hereditary condition]]s such as [[severe combined immunodeficiency]] (SCID), [[Omenn syndrome]], and [[cartilage–hair hypoplasia]].<ref name=Schwartz2011>{{EMedicine|article|888372|T-Cell Disorders}}</ref> Causes of partial insufficiencies of T cell function include [[acquired immune deficiency syndrome]] (AIDS), and hereditary conditions such as [[DiGeorge syndrome]] (DGS), [[chromosomal breakage syndrome]]s (CBSs), and B cell and T cell combined disorders such as [[ataxia-telangiectasia]] (AT) and [[Wiskott–Aldrich syndrome]] (WAS).<ref name=Schwartz2011/>

The main pathogens of concern in T cell deficiencies are [[intracellular pathogen]]s, including ''[[Herpes simplex virus]]'', ''[[Mycobacterium]]'' and ''[[Listeria]]''.<ref name="isbn1-4051-2665-5">{{cite book|veditors=Jones J, Bannister BA, Gillespie SH|title = Infection: Microbiology and Management|publisher = Wiley-Blackwell|year = 2006|page = 435|isbn = 978-1-4051-2665-6|url = https://books.google.com/books?id=iPuvQDcqW88C&pg=PA435}}</ref> Also, [[Fungal infection in animals|fungal infections]] are also more common and severe in T cell deficiencies.<ref name = "isbn1-4051-2665-5"/>

===Cancer===
{{Further|T-cell lymphoma}}
[[Cancer]] of T cells is termed [[T-cell lymphoma]], and accounts for perhaps one in ten cases of [[non-Hodgkin lymphoma]].<ref name="The Lymphomas">{{cite web|url=http://www.leukemia-lymphoma.org/attachments/National/br_1161891669.pdf|title=The Lymphomas|access-date=2008-04-07|date=May 2006|publisher=The Leukemia & Lymphoma Society|page=2}}</ref> The main forms of T cell lymphoma are:
*[[Extranodal T cell lymphoma]]
*[[Cutaneous T cell lymphoma]]s: [[Sézary syndrome]] and [[Mycosis fungoides]]
*[[Anaplastic large cell lymphoma]]
*[[Angioimmunoblastic T cell lymphoma]]

===Exhaustion===
T cell exhaustion is a poorly defined or ambiguous term.<ref name="plos 2021">{{cite journal|vauthors = Kaminski H, Lemoine M, Pradeu T|title = Immunological exhaustion: How to make a disparate concept operational?|journal = PLOS Pathogens|volume = 17|issue = 9|pages = e1009892|date = September 2021|pmid = 34555119|pmc = 8460019|doi = 10.1371/journal.ppat.1009892 | doi-access=free }}</ref><ref>{{cite journal|vauthors = Blank CU, Haining WN, Held W, Hogan PG, Kallies A, Lugli E, Lynn RC, Philip M, Rao A, Restifo NP, Schietinger A, Schumacher TN, Schwartzberg PL, Sharpe AH, Speiser DE, Wherry EJ, Youngblood BA, Zehn D|display-authors = 6|title = Defining 'T cell exhaustion'|journal = Nature Reviews. Immunology|volume = 19|issue = 11|pages = 665–674|date = November 2019|pmid = 31570879|pmc = 7286441|doi = 10.1038/s41577-019-0221-9}}</ref> There are three approaches to its definition.<ref name="plos 2021"/> "The first approach primarily defines as exhausted the cells that present the same cellular dysfunction (typically, the absence of an expected effector response). The second approach primarily defines as exhausted the cells that are produced by a given cause (typically, but not necessarily, chronic exposure to an antigen). Finally, the third approach primarily defines as exhausted the cells that present the same molecular markers (typically, programmed cell death protein 1 [PD-1])."<ref name="plos 2021"/> Indeed, it is now starting to emerge that exhaustion might not be the only T cell dysfunctional state.<ref>{{cite journal|vauthors = Naulaerts S, Datsi A, Borras DM, Antoranz Martinez A, Messiaen J, Vanmeerbeek I, Sprooten J, Laureano RS, Govaerts J, Panovska D, Derweduwe M, Sabel MC, Rapp M, Ni W, Mackay S, Van Herck Y, Gelens L, Venken T, More S, Bechter O, Bergers G, Liston A, De Vleeschouwer S, Van Den Eynde BJ, Lambrechts D, Verfaillie M, Bosisio F, Tejpar S, Borst J, Sorg RV, De Smet F, Garg AD|title = Multiomics and spatial mapping characterizes human CD8+ T cell states in cancer|journal = Science Translational Medicine|volume = 15|issue = 691|pages = eadd1016|date = April 2023|doi = 10.1126/scitranslmed.add1016}}</ref> In fact, tolerization, anergy, cell death, ignorance, senesence and exclusion have recently emerged as additional sources and/or states of T cell dysfunction in cancer and chronic viral infection.<ref>{{cite journal|vauthors = Galluzzi L, Smith KN, Liston A, Garg AD|title = The diversity of CD8+ T cell dysfunction in cancer and viral infection|journal = Nature Reviews. Immunology|date = April 2025|doi = 10.1038/s41577-025-01161-6}}</ref>

Dysfunctional T cells are characterized by progressive loss of function, changes in transcriptional profiles and sustained expression of inhibitory receptors. At first, cells lose their ability to produce [[Interleukin 2|IL-2]] and [[Tumor necrosis factor alpha|TNFα]], which is followed by the loss of high proliferative capacity and cytotoxic potential, and eventually leads to their deletion. Exhausted T cells typically indicate higher levels of [[CD43]], [[CD69]] and inhibitory receptors combined with lower expression of [[L-selectin|CD62L]] and [[Interleukin-7 receptor-α|CD127]]. Exhaustion can develop during chronic infections, sepsis and cancer.<ref>{{cite journal|vauthors = Yi JS, Cox MA, Zajac AJ|title = T-cell exhaustion: characteristics, causes and conversion|journal = Immunology|volume = 129|issue = 4|pages = 474–81|date = April 2010|pmid = 20201977|pmc = 2842494|doi = 10.1111/j.1365-2567.2010.03255.x}}</ref> Exhausted T cells preserve their functional exhaustion even after repeated antigen exposure.<ref name="pmid29483916">{{cite journal|vauthors = Wang Q, Pan W, Liu Y, Luo J, Zhu D, Lu Y, Feng X, Yang X, Dittmer U, Lu M, Yang D, Liu J|title = Hepatitis B Virus-Specific CD8+ T Cells Maintain Functional Exhaustion after Antigen Reexposure in an Acute Activation Immune Environment|journal = Front Immunol|volume = 9|pages = 219|date = 2018|pmid = 29483916|pmc = 5816053|doi = 10.3389/fimmu.2018.00219|doi-access = free}}</ref>

====During chronic infection and sepsis====
T cell exhaustion can be triggered by several factors like persistent antigen exposure and lack of CD4 T cell help.<ref>{{cite journal|vauthors = Matloubian M, Concepcion RJ, Ahmed R|title = CD4<sup>+</sup> T cells are required to sustain CD8+ cytotoxic T-cell responses during chronic viral infection|journal = Journal of Virology|volume = 68|issue = 12|pages = 8056–63|date = December 1994|doi = 10.1128/JVI.68.12.8056-8063.1994|pmid = 7966595|pmc = 237269}}</ref> Antigen exposure also has effect on the course of exhaustion because longer exposure time and higher viral load increases the severity of T cell exhaustion. At least 2–4 weeks exposure is needed to establish exhaustion.<ref>{{cite journal|vauthors = Angelosanto JM, Blackburn SD, Crawford A, Wherry EJ|title = Progressive loss of memory T cell potential and commitment to exhaustion during chronic viral infection|journal = Journal of Virology|volume = 86|issue = 15|pages = 8161–70|date = August 2012|pmid = 22623779|pmc = 3421680|doi = 10.1128/JVI.00889-12}}</ref> Another factor able to induce exhaustion are inhibitory receptors including [[Programmed cell death 1|programmed cell death protein 1]] (PD1), [[CTLA-4]], T cell membrane protein-3 (TIM3), and [[LAG3|lymphocyte activation gene 3 protein]] (LAG3).<ref>{{cite journal|vauthors = Wherry EJ|title = T cell exhaustion|journal = Nature Immunology|volume = 12|issue = 6|pages = 492–9|date = June 2011|pmid = 21739672|doi = 10.1038/ni.2035|s2cid = 11052693}}</ref><ref>{{cite journal|vauthors = Okagawa T, Konnai S, Nishimori A, Maekawa N, Goto S, Ikebuchi R, Kohara J, Suzuki Y, Yamada S, Kato Y, Murata S, Ohashi K|title = + T cells during bovine leukemia virus infection|language = En|journal = Veterinary Research|volume = 49|issue = 1|pages = 50|date = June 2018|pmid = 29914540|pmc = 6006750|doi = 10.1186/s13567-018-0543-9 | doi-access=free }}</ref> Soluble molecules such as cytokines [[Interleukin 10|IL-10]] or [[Transforming growth factor beta|TGF-β]] are also able to trigger exhaustion.<ref>{{cite journal|vauthors = Brooks DG, Trifilo MJ, Edelmann KH, Teyton L, McGavern DB, [[Michael Oldstone|Oldstone MB]]|title = Interleukin-10 determines viral clearance or persistence in vivo|journal = Nature Medicine|volume = 12|issue = 11|pages = 1301–9|date = November 2006|pmid = 17041596|pmc = 2535582|doi = 10.1038/nm1492}}</ref><ref>{{cite journal|vauthors = Tinoco R, Alcalde V, Yang Y, Sauer K, Zuniga EI|title = Cell-intrinsic transforming growth factor-beta signaling mediates virus-specific CD8+ T cell deletion and viral persistence in vivo|journal = Immunity|volume = 31|issue = 1|pages = 145–57|date = July 2009|pmid = 19604493|pmc = 3039716|doi = 10.1016/j.immuni.2009.06.015}}</ref> Last known factors that can play a role in T cell exhaustion are regulatory cells. [[Regulatory T cell|Treg]] cells can be a source of IL-10 and TGF-β and therefore they can play a role in T cell exhaustion.<ref>{{cite journal|vauthors = Veiga-Parga T, Sehrawat S, Rouse BT|title = Role of regulatory T cells during virus infection|journal = Immunological Reviews|volume = 255|issue = 1|pages = 182–96|date = September 2013|pmid = 23947355|pmc = 3748387|doi = 10.1111/imr.12085}}</ref> Furthermore, T cell exhaustion is reverted after depletion of Treg cells and blockade of PD1.<ref>{{cite journal|vauthors = Penaloza-MacMaster P, Kamphorst AO, Wieland A, Araki K, Iyer SS, West EE, O'Mara L, Yang S, Konieczny BT, Sharpe AH, Freeman GJ, Rudensky AY, Ahmed R|title = Interplay between regulatory T cells and PD-1 in modulating T cell exhaustion and viral control during chronic LCMV infection|journal = The Journal of Experimental Medicine|volume = 211|issue = 9|pages = 1905–18|date = August 2014|pmid = 25113973|pmc = 4144726|doi = 10.1084/jem.20132577}}</ref> T cell exhaustion can also occur during sepsis as a result of cytokine storm. Later after the initial septic encounter anti-inflammatory cytokines and pro-apoptotic proteins take over to protect the body from damage. Sepsis also carries high antigen load and inflammation. In this stage of sepsis T cell exhaustion increases.<ref>{{cite journal|vauthors = Otto GP, Sossdorf M, Claus RA, Rödel J, Menge K, Reinhart K, Bauer M, Riedemann NC|title = The late phase of sepsis is characterized by an increased microbiological burden and death rate|language = En|journal = Critical Care|volume = 15|issue = 4|pages = R183|date = July 2011|pmid = 21798063|pmc = 3387626|doi = 10.1186/cc10332 | doi-access=free }}</ref><ref name="Boomer JS 2011">{{cite journal|vauthors = Boomer JS, To K, Chang KC, Takasu O, Osborne DF, Walton AH, Bricker TL, Jarman SD, Kreisel D, Krupnick AS, Srivastava A, Swanson PE, Green JM, Hotchkiss RS|title = Immunosuppression in patients who die of sepsis and multiple organ failure|journal = JAMA|volume = 306|issue = 23|pages = 2594–605|date = December 2011|pmid = 22187279|pmc = 3361243|doi = 10.1001/jama.2011.1829}}</ref> Currently there are studies aiming to utilize inhibitory receptor blockades in treatment of sepsis.<ref>{{cite journal|vauthors = Shindo Y, McDonough JS, Chang KC, Ramachandra M, Sasikumar PG, Hotchkiss RS|title = Anti-PD-L1 peptide improves survival in sepsis|journal = The Journal of Surgical Research|volume = 208|pages = 33–39|date = February 2017|pmid = 27993215|pmc = 5535083|doi = 10.1016/j.jss.2016.08.099}}</ref><ref>{{cite journal|vauthors = Patera AC, Drewry AM, Chang K, Beiter ER, Osborne D, Hotchkiss RS|title = Frontline Science: Defects in immune function in patients with sepsis are associated with PD-1 or PD-L1 expression and can be restored by antibodies targeting PD-1 or PD-L1|journal = Journal of Leukocyte Biology|volume = 100|issue = 6|pages = 1239–1254|date = December 2016|pmid = 27671246|pmc = 5110001|doi = 10.1189/jlb.4hi0616-255r}}</ref><ref name="pmid29689313">{{cite journal|vauthors = Wei Z, Li P, Yao Y, Deng H, Yi S, Zhang C, Wu H, Xie X, Xia M, He R, Yang XP, Tang ZH|title = Alpha-lactose reverses liver injury via blockade of Tim-3-mediated CD8 apoptosis in sepsis|journal = Clinical Immunology|volume = 192|pages = 78–84|date = July 2018|pmid = 29689313|doi = 10.1016/j.clim.2018.04.010|s2cid = 21657071}}</ref>

====During transplantation====
While during infection T cell exhaustion can develop following persistent antigen exposure after graft transplant similar situation arises with alloantigen presence.<ref>{{cite journal|vauthors = Wells AD, Li XC, Strom TB, Turka LA|title = The role of peripheral T-cell deletion in transplantation tolerance|journal = Philosophical Transactions of the Royal Society of London. Series B, Biological Sciences|volume = 356|issue = 1409|pages = 617–23|date = May 2001|pmid = 11375065|pmc = 1088449|doi = 10.1098/rstb.2001.0845}}</ref> It was shown that T cell response diminishes over time after kidney transplant.<ref>{{cite journal|vauthors = Halloran PF, Chang J, Famulski K, Hidalgo LG, Salazar ID, Merino Lopez M, Matas A, Picton M, de Freitas D, Bromberg J, Serón D, Sellarés J, Einecke G, Reeve J|title = Disappearance of T Cell-Mediated Rejection Despite Continued Antibody-Mediated Rejection in Late Kidney Transplant Recipients|journal = Journal of the American Society of Nephrology|volume = 26|issue = 7|pages = 1711–20|date = July 2015|pmid = 25377077|pmc = 4483591|doi = 10.1681/ASN.2014060588}}</ref> These data suggest T cell exhaustion plays an important role in tolerance of a graft mainly by depletion of alloreactive CD8 T cells.<ref name="Boomer JS 2011"/><ref>{{cite journal|vauthors = Steger U, Denecke C, Sawitzki B, Karim M, Jones ND, Wood KJ|title = Exhaustive differentiation of alloreactive CD8+ T cells: critical for determination of graft acceptance or rejection|journal = Transplantation|volume = 85|issue = 9|pages = 1339–47|date = May 2008|pmid = 18475193|doi = 10.1097/TP.0b013e31816dd64a|s2cid = 33409478|url = http://pure-oai.bham.ac.uk/ws/files/9323851/0108BM3Tx.pdf}}</ref> Several studies showed positive effect of chronic infection on graft acceptance and its long-term survival mediated partly by T cell exhaustion.<ref>{{cite journal|vauthors = de Mare-Bredemeijer EL, Shi XL, Mancham S, van Gent R, van der Heide-Mulder M, de Boer R, Heemskerk MH, de Jonge J, van der Laan LJ, Metselaar HJ, Kwekkeboom J|title = Cytomegalovirus-Induced Expression of CD244 after Liver Transplantation Is Associated with CD8+ T Cell Hyporesponsiveness to Alloantigen|journal = Journal of Immunology|volume = 195|issue = 4|pages = 1838–48|date = August 2015|pmid = 26170387|doi = 10.4049/jimmunol.1500440|doi-access = free}}</ref><ref>{{cite journal|vauthors = Gassa A, Jian F, Kalkavan H, Duhan V, Honke N, Shaabani N, Friedrich SK, Dolff S, Wahlers T, Kribben A, Hardt C, Lang PA, Witzke O, Lang KS|title = IL-10 Induces T Cell Exhaustion During Transplantation of Virus Infected Hearts|language = en|journal = Cellular Physiology and Biochemistry|volume = 38|issue = 3|pages = 1171–81|date = 2016|pmid = 26963287|doi = 10.1159/000443067|doi-access = free}}</ref><ref>{{cite journal|vauthors = Shi XL, de Mare-Bredemeijer EL, Tapirdamaz Ö, Hansen BE, van Gent R, van Campenhout MJ, Mancham S, Litjens NH, Betjes MG, van der Eijk AA, Xia Q, van der Laan LJ, de Jonge J, Metselaar HJ, Kwekkeboom J|title = CMV Primary Infection Is Associated With Donor-Specific T Cell Hyporesponsiveness and Fewer Late Acute Rejections After Liver Transplantation|journal = American Journal of Transplantation|volume = 15|issue = 9|pages = 2431–42|date = September 2015|pmid = 25943855|doi = 10.1111/ajt.13288|s2cid = 5348557|doi-access = free}}</ref> It was also shown that recipient T cell exhaustion provides sufficient conditions for [[Natural killer cell|NK cell]] transfer.<ref>{{cite journal|vauthors = Williams RL, Cooley S, Bachanova V, Blazar BR, Weisdorf DJ, Miller JS, Verneris MR|title = Recipient T Cell Exhaustion and Successful Adoptive Transfer of Haploidentical Natural Killer Cells|journal = Biology of Blood and Marrow Transplantation|volume = 24|issue = 3|pages = 618–622|date = March 2018|pmid = 29197679|pmc = 5826878|doi = 10.1016/j.bbmt.2017.11.022}}</ref> While there are data showing that induction of T cell exhaustion can be beneficial for transplantation it also carries disadvantages among which can be counted increased number of infections and the risk of tumor development.<ref>{{cite journal|vauthors = Woo SR, Turnis ME, Goldberg MV, Bankoti J, Selby M, Nirschl CJ, Bettini ML, Gravano DM, Vogel P, Liu CL, Tangsombatvisit S, Grosso JF, Netto G, Smeltzer MP, Chaux A, Utz PJ, Workman CJ, Pardoll DM, Korman AJ, Drake CG, Vignali DA|title = Immune inhibitory molecules LAG-3 and PD-1 synergistically regulate T-cell function to promote tumoral immune escape|journal = Cancer Research|volume = 72|issue = 4|pages = 917–27|date = February 2012|pmid = 22186141|pmc = 3288154|doi = 10.1158/0008-5472.CAN-11-1620}}</ref>

====During cancer====
{{See also|Immunosenescence#T cell functional dysregulation as a biomarker for immunosenescence|label 1 = Immunosenescence}}

During cancer T cell exhaustion plays a role in tumor protection. According to research some cancer-associated cells as well as tumor cells themselves can actively induce T cell exhaustion at the site of tumor.<ref>{{cite journal|vauthors = Zelle-Rieser C, Thangavadivel S, Biedermann R, Brunner A, Stoitzner P, Willenbacher E, Greil R, Jöhrer K|display-authors = 6|title = T cells in multiple myeloma display features of exhaustion and senescence at the tumor site|language = En|journal = Journal of Hematology & Oncology|volume = 9|issue = 1|pages = 116|date = November 2016|pmid = 27809856|pmc = 5093947|doi = 10.1186/s13045-016-0345-3|doi-access = free}}</ref><ref>{{cite journal|vauthors = Lakins MA, Ghorani E, Munir H, Martins CP, Shields JD|title = Cancer-associated fibroblasts induce antigen-specific deletion of CD8 <sup>+</sup> T Cells to protect tumour cells|journal = Nature Communications|volume = 9|issue = 1|pages = 948|date = March 2018|pmid = 29507342|pmc = 5838096|doi = 10.1038/s41467-018-03347-0|bibcode=2018NatCo...9..948L }}</ref><ref>{{cite journal|vauthors = Conforti L|title = The ion channel network in T lymphocytes, a target for immunotherapy|journal = Clinical Immunology|volume = 142|issue = 2|pages = 105–106|date = February 2012|pmid = 22189042|doi = 10.1016/j.clim.2011.11.009}}</ref> T cell exhaustion can also play a role in cancer relapses as was shown on leukemia.<ref>{{cite journal|vauthors = Liu L, Chang YJ, Xu LP, Zhang XH, Wang Y, Liu KY, Huang XJ|title = T cell exhaustion characterized by compromised MHC class I and II restricted cytotoxic activity associates with acute B lymphoblastic leukemia relapse after allogeneic hematopoietic stem cell transplantation|journal = Clinical Immunology|volume = 190|pages = 32–40|date = May 2018|pmid = 29477343|doi = 10.1016/j.clim.2018.02.009}}</ref> Some studies have suggested that it is possible to predict relapse of leukemia based on expression of inhibitory receptors PD-1 and TIM-3 by T cells.<ref>{{cite journal|vauthors = Kong Y, Zhang J, Claxton DF, Ehmann WC, Rybka WB, Zhu L, Zeng H, Schell TD, Zheng H|display-authors = 6|title = PD-1(hi)TIM-3(+) T cells associate with and predict leukemia relapse in AML patients post allogeneic stem cell transplantation|language = En|journal = Blood Cancer Journal|volume = 5|issue = 7|pages = e330|date = July 2015|pmid = 26230954|pmc = 4526784|doi = 10.1038/bcj.2015.58}}</ref> Many experiments and clinical trials have focused on immune checkpoint blockers in cancer therapy, with some of these approved as valid therapies that are now in clinical use.<ref>{{Cite news|url=https://medi-paper.com/us-fda-approved-immune-checkpoint-inhibitors-approved-immunotherapies/|title=U.S. FDA Approved Immune-Checkpoint Inhibitors and Immunotherapies|date=2018-08-21|work=Medical Writer Agency {{!}} 香港醫學作家 {{!}} MediPR {{!}} MediPaper Hong Kong|access-date=2018-09-22|language=en-GB}}</ref> Inhibitory receptors targeted by those medical procedures are vital in T cell exhaustion and blocking them can reverse these changes.<ref>{{cite journal|vauthors = Bhadra R, Gigley JP, Weiss LM, Khan IA|title = Control of Toxoplasma reactivation by rescue of dysfunctional CD8+ T-cell response via PD-1-PDL-1 blockade|journal = Proceedings of the National Academy of Sciences of the United States of America|volume = 108|issue = 22|pages = 9196–9201|date = May 2011|pmid = 21576466|pmc = 3107287|doi = 10.1073/pnas.1015298108|doi-access = free|bibcode = 2011PNAS..108.9196B}}</ref>

==See also==
*[[Chimeric antigen receptor T cell]]
*[[Gut-specific homing]]
*[[Immunoblast]]
*[[Immunosenescence]]
*[[Parafollicular cell]] also called C cell

==References==
{{Reflist}}

==Further reading==
{{refbegin}}
*{{cite book|vauthors = Janeway Jr CA, Travers P, Walport M, Shlomchik MJ|title=Immunobiology 5 : the immune system in health and disease|date=2001|publisher=Garland Science|location=New York|isbn=978-0-8153-3642-6|edition=5th|url = https://www.ncbi.nlm.nih.gov/books/NBK10757/?depth=2}}
*{{cite web|url = https://www.niaid.nih.gov/publications/immune/the_immune_system.pdf|archive-url = https://web.archive.org/web/20090625012519/https://www.niaid.nih.gov/publications/immune/the_immune_system.pdf|archive-date = 25 June 2009|title = The Immune System|work = National Institute of Allergy and Infectious Diseases|date = September 2003}}
{{refend}}

{{Lymphocytes}}
{{Lymphocytic immune system}}
{{Authority control}}

{{DEFAULTSORT:T Cell}}
[[Category:T cells]]
[[Category:Human cells]]
[[Category:Immune system]]
[[Category:Immunology]]