Editing T cell (section)

===Exhaustion===
T cell exhaustion is a poorly defined or ambiguous term.<ref name="plos 2021">{{cite journal|vauthors = Kaminski H, Lemoine M, Pradeu T|title = Immunological exhaustion: How to make a disparate concept operational?|journal = PLOS Pathogens|volume = 17|issue = 9|pages = e1009892|date = September 2021|pmid = 34555119|pmc = 8460019|doi = 10.1371/journal.ppat.1009892 | doi-access=free }}</ref><ref>{{cite journal|vauthors = Blank CU, Haining WN, Held W, Hogan PG, Kallies A, Lugli E, Lynn RC, Philip M, Rao A, Restifo NP, Schietinger A, Schumacher TN, Schwartzberg PL, Sharpe AH, Speiser DE, Wherry EJ, Youngblood BA, Zehn D|display-authors = 6|title = Defining 'T cell exhaustion'|journal = Nature Reviews. Immunology|volume = 19|issue = 11|pages = 665–674|date = November 2019|pmid = 31570879|pmc = 7286441|doi = 10.1038/s41577-019-0221-9}}</ref> There are three approaches to its definition.<ref name="plos 2021"/> "The first approach primarily defines as exhausted the cells that present the same cellular dysfunction (typically, the absence of an expected effector response). The second approach primarily defines as exhausted the cells that are produced by a given cause (typically, but not necessarily, chronic exposure to an antigen). Finally, the third approach primarily defines as exhausted the cells that present the same molecular markers (typically, programmed cell death protein 1 [PD-1])."<ref name="plos 2021"/> Indeed, it is now starting to emerge that exhaustion might not be the only T cell dysfunctional state.<ref>{{cite journal|vauthors = Naulaerts S, Datsi A, Borras DM, Antoranz Martinez A, Messiaen J, Vanmeerbeek I, Sprooten J, Laureano RS, Govaerts J, Panovska D, Derweduwe M, Sabel MC, Rapp M, Ni W, Mackay S, Van Herck Y, Gelens L, Venken T, More S, Bechter O, Bergers G, Liston A, De Vleeschouwer S, Van Den Eynde BJ, Lambrechts D, Verfaillie M, Bosisio F, Tejpar S, Borst J, Sorg RV, De Smet F, Garg AD|title = Multiomics and spatial mapping characterizes human CD8+ T cell states in cancer|journal = Science Translational Medicine|volume = 15|issue = 691|pages = eadd1016|date = April 2023|doi = 10.1126/scitranslmed.add1016}}</ref> In fact, tolerization, anergy, cell death, ignorance, senesence and exclusion have recently emerged as additional sources and/or states of T cell dysfunction in cancer and chronic viral infection.<ref>{{cite journal|vauthors = Galluzzi L, Smith KN, Liston A, Garg AD|title = The diversity of CD8+ T cell dysfunction in cancer and viral infection|journal = Nature Reviews. Immunology|date = April 2025|doi = 10.1038/s41577-025-01161-6}}</ref>

Dysfunctional T cells are characterized by progressive loss of function, changes in transcriptional profiles and sustained expression of inhibitory receptors. At first, cells lose their ability to produce [[Interleukin 2|IL-2]] and [[Tumor necrosis factor alpha|TNFα]], which is followed by the loss of high proliferative capacity and cytotoxic potential, and eventually leads to their deletion. Exhausted T cells typically indicate higher levels of [[CD43]], [[CD69]] and inhibitory receptors combined with lower expression of [[L-selectin|CD62L]] and [[Interleukin-7 receptor-α|CD127]]. Exhaustion can develop during chronic infections, sepsis and cancer.<ref>{{cite journal|vauthors = Yi JS, Cox MA, Zajac AJ|title = T-cell exhaustion: characteristics, causes and conversion|journal = Immunology|volume = 129|issue = 4|pages = 474–81|date = April 2010|pmid = 20201977|pmc = 2842494|doi = 10.1111/j.1365-2567.2010.03255.x}}</ref> Exhausted T cells preserve their functional exhaustion even after repeated antigen exposure.<ref name="pmid29483916">{{cite journal|vauthors = Wang Q, Pan W, Liu Y, Luo J, Zhu D, Lu Y, Feng X, Yang X, Dittmer U, Lu M, Yang D, Liu J|title = Hepatitis B Virus-Specific CD8+ T Cells Maintain Functional Exhaustion after Antigen Reexposure in an Acute Activation Immune Environment|journal = Front Immunol|volume = 9|pages = 219|date = 2018|pmid = 29483916|pmc = 5816053|doi = 10.3389/fimmu.2018.00219|doi-access = free}}</ref>

====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>

====During transplantation====
While during infection T cell exhaustion can develop following persistent antigen exposure after graft transplant similar situation arises with alloantigen presence.<ref>{{cite journal|vauthors = Wells AD, Li XC, Strom TB, Turka LA|title = The role of peripheral T-cell deletion in transplantation tolerance|journal = Philosophical Transactions of the Royal Society of London. Series B, Biological Sciences|volume = 356|issue = 1409|pages = 617–23|date = May 2001|pmid = 11375065|pmc = 1088449|doi = 10.1098/rstb.2001.0845}}</ref> It was shown that T cell response diminishes over time after kidney transplant.<ref>{{cite journal|vauthors = Halloran PF, Chang J, Famulski K, Hidalgo LG, Salazar ID, Merino Lopez M, Matas A, Picton M, de Freitas D, Bromberg J, Serón D, Sellarés J, Einecke G, Reeve J|title = Disappearance of T Cell-Mediated Rejection Despite Continued Antibody-Mediated Rejection in Late Kidney Transplant Recipients|journal = Journal of the American Society of Nephrology|volume = 26|issue = 7|pages = 1711–20|date = July 2015|pmid = 25377077|pmc = 4483591|doi = 10.1681/ASN.2014060588}}</ref> These data suggest T cell exhaustion plays an important role in tolerance of a graft mainly by depletion of alloreactive CD8 T cells.<ref name="Boomer JS 2011"/><ref>{{cite journal|vauthors = Steger U, Denecke C, Sawitzki B, Karim M, Jones ND, Wood KJ|title = Exhaustive differentiation of alloreactive CD8+ T cells: critical for determination of graft acceptance or rejection|journal = Transplantation|volume = 85|issue = 9|pages = 1339–47|date = May 2008|pmid = 18475193|doi = 10.1097/TP.0b013e31816dd64a|s2cid = 33409478|url = http://pure-oai.bham.ac.uk/ws/files/9323851/0108BM3Tx.pdf}}</ref> Several studies showed positive effect of chronic infection on graft acceptance and its long-term survival mediated partly by T cell exhaustion.<ref>{{cite journal|vauthors = de Mare-Bredemeijer EL, Shi XL, Mancham S, van Gent R, van der Heide-Mulder M, de Boer R, Heemskerk MH, de Jonge J, van der Laan LJ, Metselaar HJ, Kwekkeboom J|title = Cytomegalovirus-Induced Expression of CD244 after Liver Transplantation Is Associated with CD8+ T Cell Hyporesponsiveness to Alloantigen|journal = Journal of Immunology|volume = 195|issue = 4|pages = 1838–48|date = August 2015|pmid = 26170387|doi = 10.4049/jimmunol.1500440|doi-access = free}}</ref><ref>{{cite journal|vauthors = Gassa A, Jian F, Kalkavan H, Duhan V, Honke N, Shaabani N, Friedrich SK, Dolff S, Wahlers T, Kribben A, Hardt C, Lang PA, Witzke O, Lang KS|title = IL-10 Induces T Cell Exhaustion During Transplantation of Virus Infected Hearts|language = en|journal = Cellular Physiology and Biochemistry|volume = 38|issue = 3|pages = 1171–81|date = 2016|pmid = 26963287|doi = 10.1159/000443067|doi-access = free}}</ref><ref>{{cite journal|vauthors = Shi XL, de Mare-Bredemeijer EL, Tapirdamaz Ö, Hansen BE, van Gent R, van Campenhout MJ, Mancham S, Litjens NH, Betjes MG, van der Eijk AA, Xia Q, van der Laan LJ, de Jonge J, Metselaar HJ, Kwekkeboom J|title = CMV Primary Infection Is Associated With Donor-Specific T Cell Hyporesponsiveness and Fewer Late Acute Rejections After Liver Transplantation|journal = American Journal of Transplantation|volume = 15|issue = 9|pages = 2431–42|date = September 2015|pmid = 25943855|doi = 10.1111/ajt.13288|s2cid = 5348557|doi-access = free}}</ref> It was also shown that recipient T cell exhaustion provides sufficient conditions for [[Natural killer cell|NK cell]] transfer.<ref>{{cite journal|vauthors = Williams RL, Cooley S, Bachanova V, Blazar BR, Weisdorf DJ, Miller JS, Verneris MR|title = Recipient T Cell Exhaustion and Successful Adoptive Transfer of Haploidentical Natural Killer Cells|journal = Biology of Blood and Marrow Transplantation|volume = 24|issue = 3|pages = 618–622|date = March 2018|pmid = 29197679|pmc = 5826878|doi = 10.1016/j.bbmt.2017.11.022}}</ref> While there are data showing that induction of T cell exhaustion can be beneficial for transplantation it also carries disadvantages among which can be counted increased number of infections and the risk of tumor development.<ref>{{cite journal|vauthors = Woo SR, Turnis ME, Goldberg MV, Bankoti J, Selby M, Nirschl CJ, Bettini ML, Gravano DM, Vogel P, Liu CL, Tangsombatvisit S, Grosso JF, Netto G, Smeltzer MP, Chaux A, Utz PJ, Workman CJ, Pardoll DM, Korman AJ, Drake CG, Vignali DA|title = Immune inhibitory molecules LAG-3 and PD-1 synergistically regulate T-cell function to promote tumoral immune escape|journal = Cancer Research|volume = 72|issue = 4|pages = 917–27|date = February 2012|pmid = 22186141|pmc = 3288154|doi = 10.1158/0008-5472.CAN-11-1620}}</ref>

====During cancer====
{{See also|Immunosenescence#T cell functional dysregulation as a biomarker for immunosenescence|label 1 = Immunosenescence}}

During cancer T cell exhaustion plays a role in tumor protection. According to research some cancer-associated cells as well as tumor cells themselves can actively induce T cell exhaustion at the site of tumor.<ref>{{cite journal|vauthors = Zelle-Rieser C, Thangavadivel S, Biedermann R, Brunner A, Stoitzner P, Willenbacher E, Greil R, Jöhrer K|display-authors = 6|title = T cells in multiple myeloma display features of exhaustion and senescence at the tumor site|language = En|journal = Journal of Hematology & Oncology|volume = 9|issue = 1|pages = 116|date = November 2016|pmid = 27809856|pmc = 5093947|doi = 10.1186/s13045-016-0345-3|doi-access = free}}</ref><ref>{{cite journal|vauthors = Lakins MA, Ghorani E, Munir H, Martins CP, Shields JD|title = Cancer-associated fibroblasts induce antigen-specific deletion of CD8 <sup>+</sup> T Cells to protect tumour cells|journal = Nature Communications|volume = 9|issue = 1|pages = 948|date = March 2018|pmid = 29507342|pmc = 5838096|doi = 10.1038/s41467-018-03347-0|bibcode=2018NatCo...9..948L }}</ref><ref>{{cite journal|vauthors = Conforti L|title = The ion channel network in T lymphocytes, a target for immunotherapy|journal = Clinical Immunology|volume = 142|issue = 2|pages = 105–106|date = February 2012|pmid = 22189042|doi = 10.1016/j.clim.2011.11.009}}</ref> T cell exhaustion can also play a role in cancer relapses as was shown on leukemia.<ref>{{cite journal|vauthors = Liu L, Chang YJ, Xu LP, Zhang XH, Wang Y, Liu KY, Huang XJ|title = T cell exhaustion characterized by compromised MHC class I and II restricted cytotoxic activity associates with acute B lymphoblastic leukemia relapse after allogeneic hematopoietic stem cell transplantation|journal = Clinical Immunology|volume = 190|pages = 32–40|date = May 2018|pmid = 29477343|doi = 10.1016/j.clim.2018.02.009}}</ref> Some studies have suggested that it is possible to predict relapse of leukemia based on expression of inhibitory receptors PD-1 and TIM-3 by T cells.<ref>{{cite journal|vauthors = Kong Y, Zhang J, Claxton DF, Ehmann WC, Rybka WB, Zhu L, Zeng H, Schell TD, Zheng H|display-authors = 6|title = PD-1(hi)TIM-3(+) T cells associate with and predict leukemia relapse in AML patients post allogeneic stem cell transplantation|language = En|journal = Blood Cancer Journal|volume = 5|issue = 7|pages = e330|date = July 2015|pmid = 26230954|pmc = 4526784|doi = 10.1038/bcj.2015.58}}</ref> Many experiments and clinical trials have focused on immune checkpoint blockers in cancer therapy, with some of these approved as valid therapies that are now in clinical use.<ref>{{Cite news|url=https://medi-paper.com/us-fda-approved-immune-checkpoint-inhibitors-approved-immunotherapies/|title=U.S. FDA Approved Immune-Checkpoint Inhibitors and Immunotherapies|date=2018-08-21|work=Medical Writer Agency {{!}} 香港醫學作家 {{!}} MediPR {{!}} MediPaper Hong Kong|access-date=2018-09-22|language=en-GB}}</ref> Inhibitory receptors targeted by those medical procedures are vital in T cell exhaustion and blocking them can reverse these changes.<ref>{{cite journal|vauthors = Bhadra R, Gigley JP, Weiss LM, Khan IA|title = Control of Toxoplasma reactivation by rescue of dysfunctional CD8+ T-cell response via PD-1-PDL-1 blockade|journal = Proceedings of the National Academy of Sciences of the United States of America|volume = 108|issue = 22|pages = 9196–9201|date = May 2011|pmid = 21576466|pmc = 3107287|doi = 10.1073/pnas.1015298108|doi-access = free|bibcode = 2011PNAS..108.9196B}}</ref>