Editing T cell (section)

==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.