Editing T cell (section)

====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>