Editing T cell (section)

==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>