Editing T cell (section)

===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.