Self-protein

During T-cell development, early T-cell [[Progenitor cell|progenitors]] first move via [[chemokine]] gradients from the bone marrow into the [[thymus]], where [[T-cell receptor]]s are randomly [[V(D)J recombination|rearranged]] at the gene level to allow for T-cell receptor generation.{{cite journal | vauthors = Sambandam A, Bell JJ, Schwarz BA, Zediak VP, Chi AW, Zlotoff DA, Krishnamoorthy SL, Burg JM, Bhandoola A | display-authors = 6 | title = Progenitor migration to the thymus and T cell lineage commitment | journal = Immunologic Research | volume = 42 | issue = 1–3 | pages = 65–74 | date = 2008-09-16 | pmid = 18827982 | doi = 10.1007/s12026-008-8035-z | s2cid = 43186901 }} These T-cells have the potential to bind to anything, including self-proteins.{{cn|date=February 2023}}

During T-cell development, early T-cell [[Progenitor cell|progenitors]] first move via [[chemokine]] gradients from the bone marrow into the [[thymus]], where [[T-cell receptor]]s are randomly [[V(D)J recombination|rearranged]] at the gene level to allow for T-cell receptor generation.{{cite journal | vauthors = Sambandam A, Bell JJ, Schwarz BA, Zediak VP, Chi AW, Zlotoff DA, Krishnamoorthy SL, Burg JM, Bhandoola A | display-authors = 6 | title = Progenitor migration to the thymus and T cell lineage commitment | journal = Immunologic Research | volume = 42 | issue = 1–3 | pages = 65–74 | date = 2008-09-16 | pmid = 18827982 | doi = 10.1007/s12026-008-8035-z | s2cid = 43186901 }} These T-cells have the potential to bind to anything, including self-proteins.{{cn|date=February 2023}}

The immune system must differentiate the T-cells that have receptors capable of binding to self versus non-self proteins; T-cells that can bind to self-proteins must be destroyed to prevent development of an autoimmune disorder. In a process known as "[[Central tolerance|Central Tolerance]]", T-cells are exposed to [[Epithelium|cortical epithelial cells]] that express a variety of different [[Major histocompatibility complex|major histocompatibility complexes (MHC)]] of both [[MHC class I|class 1]] and [[MHC class II|class 2]], which have the ability to bind to T-cell receptors of CD8+ [[Cytotoxic T cell|cytotoxic T-cells]], and CD4+ [[T helper cell|helper T-cells]], respectively. The T-cells that display affinity for these MHC are positively selected to continue to the second stage of development, while those that cannot bind to MHC undergo [[apoptosis]].{{cite journal | vauthors = Xing Y, Hogquist KA | title = T-cell tolerance: central and peripheral | journal = Cold Spring Harbor Perspectives in Biology | volume = 4 | issue = 6 | article-number = a006957 | date = June 2012 | pmid = 22661634 | pmc = 3367546 | doi = 10.1101/cshperspect.a006957 }} In the second stage, immature T-cells are exposed to a variety of [[macrophage]]s, [[dendritic cell]]s, and medullary epithelial cells that express self-protein on [[MHC class II|MHC class 1]] and [[MHC class II|class 2]]. These epithelial cells also express the transcription factor labelled [[Autoimmune regulator|autoimmune regulator (AIRE)]] – this crucial transcription factor allows the medullary epithelial cells of the [[thymus]] to express proteins would normally be present in peripheral tissue rather than in an epithelial cell, such as [[insulin]]-like peptides, [[myelin]]-like peptides, and more.{{cite journal | vauthors = Anderson MS, Su MA | title = Aire and T cell development | journal = Current Opinion in Immunology | volume = 23 | issue = 2 | pages = 198–206 | date = April 2011 | pmid = 21163636 | pmc = 3073725 | doi = 10.1016/j.coi.2010.11.007 }} As these epithelial cells now present a large variety of self-proteins that could be encountered across the body, the immature T-cells are tested for affinity to self-protein and self-MHC. If any T-cell has strong affinity for self-protein and self-MHC, the cell undergoes apoptosis to prevent autoimmune function. T-cells that display low/medium affinity are allowed to leave the thymus and circulate throughout the body to react to novel non-self antigen. In this manner, the body attempts to systematically destroy T-cells that could lead to autoimmunity.{{cn|date=February 2023}}

The immune system must differentiate the T-cells that have receptors capable of binding to self versus non-self proteins; T-cells that can bind to self-proteins must be destroyed to prevent development of an autoimmune disorder. In a process known as "[[Central tolerance|Central Tolerance]]", T-cells are exposed to [[Epithelium|cortical epithelial cells]] that express a variety of different [[Major histocompatibility complex|major histocompatibility complexes (MHC)]] of both [[MHC class I|class 1]] and [[MHC class II|class 2]], which have the ability to bind to T-cell receptors of CD8+ [[Cytotoxic T cell|cytotoxic T-cells]], and CD4+ [[T helper cell|helper T-cells]], respectively. The T-cells that display affinity for these MHC are positively selected to continue to the second stage of development, while those that cannot bind to MHC undergo [[apoptosis]].{{cite journal | vauthors = Xing Y, Hogquist KA | title = T-cell tolerance: central and peripheral | journal = Cold Spring Harbor Perspectives in Biology | volume = 4 | issue = 6 | article-number = a006957 | date = June 2012 | pmid = 22661634 | pmc = 3367546 | doi = 10.1101/cshperspect.a006957 }} In the second stage, immature T-cells are exposed to a variety of [[macrophage]]s, [[dendritic cell]]s, and medullary epithelial cells that express self-protein on [[MHC class II|MHC class 1]] and [[MHC class II|class 2]]. These epithelial cells also express the transcription factor labelled [[Autoimmune regulator|autoimmune regulator (AIRE)]] – this crucial transcription factor allows the medullary epithelial cells of the [[thymus]] to express proteins that would normally be present in peripheral tissue rather than in an epithelial cell, such as [[insulin]]-like peptides, [[myelin]]-like peptides, and more.{{cite journal | vauthors = Anderson MS, Su MA | title = Aire and T cell development | journal = Current Opinion in Immunology | volume = 23 | issue = 2 | pages = 198–206 | date = April 2011 | pmid = 21163636 | pmc = 3073725 | doi = 10.1016/j.coi.2010.11.007 }} As these epithelial cells now present a large variety of self-proteins that could be encountered across the body, the immature T-cells are tested for affinity to self-protein and self-MHC. If any T-cell has strong affinity for self-protein and self-MHC, the cell undergoes apoptosis to prevent autoimmune function. T-cells that display low or medium affinity are allowed to leave the thymus and circulate throughout the body to react to novel non-self antigen. In this manner, the body attempts to systematically destroy T-cells that could lead to autoimmunity.{{cn|date=February 2023}}

== References ==

== References ==