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IL-15 in T-Cell Responses and Immunopathogenesis

  • Hoyoung Lee (The Center for Viral Immunology, Korea Virus Research Institute, Institute for Basic Science (IBS)) ;
  • Su-Hyung Park (Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology (KAIST)) ;
  • Eui-Cheol Shin (The Center for Viral Immunology, Korea Virus Research Institute, Institute for Basic Science (IBS))
  • Received : 2024.01.20
  • Accepted : 2024.02.01
  • Published : 2024.02.29
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Abstract

IL-15 belongs to the common gamma chain cytokine family and has pleiotropic immunological functions. IL-15 is a homeostatic cytokine essential for the development and maintenance of NK cells and memory CD8+ T cells. In addition, IL-15 plays a critical role in the activation, effector functions, tissue residency, and senescence of CD8+ T cells. IL-15 also activates virtual memory T cells, mucosal-associated invariant T cells and γδ T cells. Recently, IL-15 has been highlighted as a major trigger of TCR-independent activation of T cells. This mechanism is involved in T cell-mediated immunopathogenesis in diverse diseases, including viral infections and chronic inflammatory diseases. Deeper understanding of IL-15-mediated T-cell responses and their underlying mechanisms could optimize therapeutic strategies to ameliorate host injury by T cell-mediated immunopathogenesis. This review highlights recent advancements in comprehending the role of IL-15 in relation to T cell responses and immunopathogenesis under various host conditions.

Keywords

Acknowledgement

This work was supported by the Institute for Basic Science (IBS), Republic of Korea, under project code IBS-R801-D2.

References

  1. Grabstein KH, Eisenman J, Shanebeck K, Rauch C, Srinivasan S, Fung V, Beers C, Richardson J, Schoenborn MA, Ahdieh M, et al. Cloning of a T cell growth factor that interacts with the beta chain of the interleukin-2 receptor. Science 1994;264:965-968. https://doi.org/10.1126/science.8178155
  2. Giri JG, Ahdieh M, Eisenman J, Shanebeck K, Grabstein K, Kumaki S, Namen A, Park LS, Cosman D, Anderson D. Utilization of the beta and gamma chains of the IL-2 receptor by the novel cytokine IL-15. EMBO J 1994;13:2822-2830. https://doi.org/10.1002/j.1460-2075.1994.tb06576.x
  3. Leonard WJ, Lin JX, O'Shea JJ. The gamma(c) family of cytokines: basic biology to therapeutic ramifications. Immunity 2019;50:832-850. https://doi.org/10.1016/j.immuni.2019.03.028
  4. Bamford RN, Grant AJ, Burton JD, Peters C, Kurys G, Goldman CK, Brennan J, Roessler E, Waldmann TA. The interleukin (IL) 2 receptor beta chain is shared by IL-2 and a cytokine, provisionally designated IL-T, that stimulates T-cell proliferation and the induction of lymphokine-activated killer cells. Proc Natl Acad Sci U S A 1994;91:4940-4944. https://doi.org/10.1073/pnas.91.11.4940
  5. Kennedy MK, Glaccum M, Brown SN, Butz EA, Viney JL, Embers M, Matsuki N, Charrier K, Sedger L, Willis CR, et al. Reversible defects in natural killer and memory CD8 T cell lineages in interleukin 15-deficient mice. J Exp Med 2000;191:771-780. https://doi.org/10.1084/jem.191.5.771
  6. Hu Q, Ye X, Qu X, Cui D, Zhang L, Xu Z, Wan H, Zhang L, Tao W. Discovery of a novel IL-15 based protein with improved developability and efficacy for cancer immunotherapy. Sci Rep 2018;8:7675.
  7. Jabri B, Abadie V. IL-15 functions as a danger signal to regulate tissue-resident T cells and tissue destruction. Nat Rev Immunol 2015;15:771-783. https://doi.org/10.1038/nri3919
  8. Lee H, Jeong S, Shin EC. Significance of bystander T cell activation in microbial infection. Nat Immunol 2022;23:13-22. https://doi.org/10.1038/s41590-021-00985-3
  9. Yomogida K, Trsan T, Sudan R, Rodrigues PF, Ulezko Antonova A, Ingle H, Luccia BD, Collins PL, Cella M, Gilfillan S, et al. The transcription factor Aiolos restrains the activation of intestinal intraepithelial lymphocytes. Nat Immunol 2024;25:77-87.
  10. Ma S, Caligiuri MA, Yu J. Harnessing IL-15 signaling to potentiate NK cell-mediated cancer immunotherapy. Trends Immunol 2022;43:833-847. https://doi.org/10.1016/j.it.2022.08.004
  11. Quinn LS, Haugk KL, Grabstein KH. Interleukin-15: a novel anabolic cytokine for skeletal muscle. Endocrinology 1995;136:3669-3672. https://doi.org/10.1210/endo.136.8.7628408
  12. Musso T, Calosso L, Zucca M, Millesimo M, Ravarino D, Giovarelli M, Malavasi F, Ponzi AN, Paus R, Bulfone-Paus S. Human monocytes constitutively express membrane-bound, biologically active, and interferon-gamma-upregulated interleukin-15. Blood 1999;93:3531-3539. https://doi.org/10.1182/blood.V93.10.3531.410k32_3531_3539
  13. Ruckert R, Asadullah K, Seifert M, Budagian VM, Arnold R, Trombotto C, Paus R, Bulfone-Paus S. Inhibition of keratinocyte apoptosis by IL-15: a new parameter in the pathogenesis of psoriasis? J Immunol 2000;165:2240-2250. https://doi.org/10.4049/jimmunol.165.4.2240
  14. Mattei F, Schiavoni G, Belardelli F, Tough DF. IL-15 is expressed by dendritic cells in response to type I IFN, double-stranded RNA, or lipopolysaccharide and promotes dendritic cell activation. J Immunol 2001;167:1179-1187. https://doi.org/10.4049/jimmunol.167.3.1179
  15. Shinozaki M, Hirahashi J, Lebedeva T, Liew FY, Salant DJ, Maron R, Kelley VR. IL-15, a survival factor for kidney epithelial cells, counteracts apoptosis and inflammation during nephritis. J Clin Invest 2002;109:951-960. https://doi.org/10.1172/JCI0214574
  16. Reinecker HC, MacDermott RP, Mirau S, Dignass A, Podolsky DK. Intestinal epithelial cells both express and respond to interleukin 15. Gastroenterology 1996;111:1706-1713. https://doi.org/10.1016/S0016-5085(96)70036-7
  17. Dubois S, Mariner J, Waldmann TA, Tagaya Y. IL-15Ralpha recycles and presents IL-15 In trans to neighboring cells. Immunity 2002;17:537-547. https://doi.org/10.1016/S1074-7613(02)00429-6
  18. Mortier E, Woo T, Advincula R, Gozalo S, Ma A. IL-15Ralpha chaperones IL-15 to stable dendritic cell membrane complexes that activate NK cells via trans presentation. J Exp Med 2008;205:1213-1225. https://doi.org/10.1084/jem.20071913
  19. Ota N, Takase M, Uchiyama H, Olsen SK, Kanagawa O. No requirement of trans presentations of IL-15 for human CD8 T cell proliferation. J Immunol 2010;185:6041-6048. https://doi.org/10.4049/jimmunol.0901834
  20. Bergamaschi C, Bear J, Rosati M, Beach RK, Alicea C, Sowder R, Chertova E, Rosenberg SA, Felber BK, Pavlakis GN. Circulating IL-15 exists as heterodimeric complex with soluble IL-15Rα in human and mouse serum. Blood 2012;120:e1-e8. https://doi.org/10.1182/blood-2011-10-384362
  21. Lucas M, Schachterle W, Oberle K, Aichele P, Diefenbach A. Dendritic cells prime natural killer cells by trans-presenting interleukin 15. Immunity 2007;26:503-517. https://doi.org/10.1016/j.immuni.2007.03.006
  22. Colpitts SL, Stoklasek TA, Plumlee CR, Obar JJ, Guo C, Lefrancois L. Cutting edge: the role of IFN-α receptor and MyD88 signaling in induction of IL-15 expression in vivo. J Immunol 2012;188:2483-2487. https://doi.org/10.4049/jimmunol.1103609
  23. Colpitts SL, Stonier SW, Stoklasek TA, Root SH, Aguila HL, Schluns KS, Lefrancois L. Transcriptional regulation of IL-15 expression during hematopoiesis. J Immunol 2013;191:3017-3024. https://doi.org/10.4049/jimmunol.1301389
  24. Dominguez-Andres J, Feo-Lucas L, Minguito de la Escalera M, Gonzalez L, Lopez-Bravo M, Ardavin C. Inflammatory Ly6C(high) monocytes protect against candidiasis through IL-15-driven NK cell/neutrophil activation. Immunity 2017;46:1059-1072.e4. https://doi.org/10.1016/j.immuni.2017.05.009
  25. Kim TS, Rha MS, Shin EC. IFN-gamma induces IL-15 trans-presentation by epithelial cells via IRF1. J Immunol 2022;208:338-346. https://doi.org/10.4049/jimmunol.2100057
  26. Lee N, Shin MS, Kang KS, Yoo SA, Mohanty S, Montgomery RR, Shaw AC, Kang I. Human monocytes have increased IFN-γ-mediated IL-15 production with age alongside altered IFN-γ receptor signaling. Clin Immunol 2014;152:101-110. https://doi.org/10.1016/j.clim.2014.03.003
  27. Xie CB, Jiang B, Qin L, Tellides G, Kirkiles-Smith NC, Jane-Wit D, Pober JS. Complement-activated interferon-γ-primed human endothelium transpresents interleukin-15 to CD8+ T cells. J Clin Invest 2020;130:3437-3452. https://doi.org/10.1172/JCI135060
  28. Miyazaki T, Kawahara A, Fujii H, Nakagawa Y, Minami Y, Liu ZJ, Oishi I, Silvennoinen O, Witthuhn BA, Ihle JN, et al. Functional activation of Jak1 and Jak3 by selective association with IL-2 receptor subunits. Science 1994;266:1045-1047. https://doi.org/10.1126/science.7973659
  29. Lin JX, Migone TS, Tsang M, Friedmann M, Weatherbee JA, Zhou L, Yamauchi A, Bloom ET, Mietz J, John S, et al. The role of shared receptor motifs and common Stat proteins in the generation of cytokine pleiotropy and redundancy by IL-2, IL-4, IL-7, IL-13, and IL-15. Immunity 1995;2:331-339. https://doi.org/10.1016/1074-7613(95)90141-8
  30. Carson WE, Fehniger TA, Haldar S, Eckhert K, Lindemann MJ, Lai CF, Croce CM, Baumann H, Caligiuri MA. A potential role for interleukin-15 in the regulation of human natural killer cell survival. J Clin Invest 1997;99:937-943. https://doi.org/10.1172/JCI119258
  31. Lord JD, McIntosh BC, Greenberg PD, Nelson BH. The IL-2 receptor promotes lymphocyte proliferation and induction of the c-myc, bcl-2, and bcl-x genes through the trans-activation domain of Stat5. J Immunol 2000;164:2533-2541. https://doi.org/10.4049/jimmunol.164.5.2533
  32. Huntington ND, Puthalakath H, Gunn P, Naik E, Michalak EM, Smyth MJ, Tabarias H, Degli-Esposti MA, Dewson G, Willis SN, et al. Interleukin 15-mediated survival of natural killer cells is determined by interactions among Bim, Noxa and Mcl-1. Nat Immunol 2007;8:856-863. https://doi.org/10.1038/ni1487
  33. Gu H, Maeda H, Moon JJ, Lord JD, Yoakim M, Nelson BH, Neel BG. New role for Shc in activation of the phosphatidylinositol 3-kinase/Akt pathway. Mol Cell Biol 2000;20:7109-7120. https://doi.org/10.1128/MCB.20.19.7109-7120.2000
  34. Intlekofer AM, Takemoto N, Wherry EJ, Longworth SA, Northrup JT, Palanivel VR, Mullen AC, Gasink CR, Kaech SM, Miller JD, et al. Effector and memory CD8+ T cell fate coupled by T-bet and eomesodermin. Nat Immunol 2005;6:1236-1244. https://doi.org/10.1038/ni1268
  35. Li D, Wang Y, Yang M, Dong Z. mTORC1 and mTORC2 coordinate early NK cell development by differentially inducing E4BP4 and T-bet. Cell Death Differ 2021;28:1900-1909. https://doi.org/10.1038/s41418-020-00715-6
  36. Wang Y, Zhang Y, Yi P, Dong W, Nalin AP, Zhang J, Zhu Z, Chen L, Benson DM, Mundy-Bosse BL, et al. The IL-15-AKT-XBP1s signaling pathway contributes to effector functions and survival in human NK cells. Nat Immunol 2019;20:10-17. https://doi.org/10.1038/s41590-018-0265-1
  37. Miyazaki T, Liu ZJ, Kawahara A, Minami Y, Yamada K, Tsujimoto Y, Barsoumian EL, Permutter RM, Taniguchi T. Three distinct IL-2 signaling pathways mediated by bcl-2, c-myc, and lck cooperate in hematopoietic cell proliferation. Cell 1995;81:223-231. https://doi.org/10.1016/0092-8674(95)90332-1
  38. Bianchi T, Gasser S, Trumpp A, MacDonald HR. c-Myc acts downstream of IL-15 in the regulation of memory CD8 T-cell homeostasis. Blood 2006;107:3992-3999. https://doi.org/10.1182/blood-2005-09-3851
  39. Lin JX, Li P, Liu D, Jin HT, He J, Ata Ur Rasheed M, Rochman Y, Wang L, Cui K, Liu C, et al. Critical role of STAT5 transcription factor tetramerization for cytokine responses and normal immune function. Immunity 2012;36:586-599. https://doi.org/10.1016/j.immuni.2012.02.017
  40. Lin JX, Du N, Li P, Kazemian M, Gebregiorgis T, Spolski R, Leonard WJ. Critical functions for STAT5 tetramers in the maturation and survival of natural killer cells. Nat Commun 2017;8:1320.
  41. Delconte RB, Kolesnik TB, Dagley LF, Rautela J, Shi W, Putz EM, Stannard K, Zhang JG, Teh C, Firth M, et al. CIS is a potent checkpoint in NK cell-mediated tumor immunity. Nat Immunol 2016;17:816-824. https://doi.org/10.1038/ni.3470
  42. Wang X, Sun R, Hao X, Lian ZX, Wei H, Tian Z. IL-17 constrains natural killer cell activity by restraining IL-15-driven cell maturation via SOCS3. Proc Natl Acad Sci U S A 2019;116:17409-17418. https://doi.org/10.1073/pnas.1904125116
  43. Tan S, Guo X, Li M, Wang T, Wang Z, Li C, Wu Z, Li N, Gao L, Liang X, et al. Transcription factor Zhx2 restricts NK cell maturation and suppresses their antitumor immunity. J Exp Med 2021;218:e20210009.
  44. Zhou X, Yu J, Cheng X, Zhao B, Manyam GC, Zhang L, Schluns K, Li P, Wang J, Sun SC. The deubiquitinase Otub1 controls the activation of CD8+ T cells and NK cells by regulating IL-15-mediated priming. Nat Immunol 2019;20:879-889. https://doi.org/10.1038/s41590-019-0405-2
  45. Bi J, Cheng C, Zheng C, Huang C, Zheng X, Wan X, Chen YH, Tian Z, Sun H. TIPE2 is a checkpoint of natural killer cell maturation and antitumor immunity. Sci Adv 2021;7:eabi6515.
  46. Deng Y, Kerdiles Y, Chu J, Yuan S, Wang Y, Chen X, Mao H, Zhang L, Zhang J, Hughes T, et al. Transcription factor Foxo1 is a negative regulator of natural killer cell maturation and function. Immunity 2015;42:457-470. https://doi.org/10.1016/j.immuni.2015.02.006
  47. Becker TC, Wherry EJ, Boone D, Murali-Krishna K, Antia R, Ma A, Ahmed R. Interleukin 15 is required for proliferative renewal of virus-specific memory CD8 T cells. J Exp Med 2002;195:1541-1548. https://doi.org/10.1084/jem.20020369
  48. Gattinoni L, Lugli E, Ji Y, Pos Z, Paulos CM, Quigley MF, Almeida JR, Gostick E, Yu Z, Carpenito C, et al. A human memory T cell subset with stem cell-like properties. Nat Med 2011;17:1290-1297. https://doi.org/10.1038/nm.2446
  49. Yajima T, Yoshihara K, Nakazato K, Kumabe S, Koyasu S, Sad S, Shen H, Kuwano H, Yoshikai Y. IL-15 regulates CD8+ T cell contraction during primary infection. J Immunol 2006;176:507-515. https://doi.org/10.4049/jimmunol.176.1.507
  50. Kaech SM, Wherry EJ, Ahmed R. Effector and memory T-cell differentiation: implications for vaccine development. Nat Rev Immunol 2002;2:251-262. https://doi.org/10.1038/nri778
  51. Deshpande P, Cavanagh MM, Le Saux S, Singh K, Weyand CM, Goronzy JJ. IL-7- and IL-15-mediated TCR sensitization enables T cell responses to self-antigens. J Immunol 2013;190:1416-1423. https://doi.org/10.4049/jimmunol.1201620
  52. Banerjee A, Li D, Guo Y, Mei Z, Lau C, Chen K, Westwick J, Klauda JB, Schrum A, Lazear ER, et al. A reengineered common chain cytokine augments CD8+ T cell-dependent immunotherapy. JCI Insight 2022;7:e158889.
  53. Richer MJ, Pewe LL, Hancox LS, Hartwig SM, Varga SM, Harty JT. Inflammatory IL-15 is required for optimal memory T cell responses. J Clin Invest 2015;125:3477-3490. https://doi.org/10.1172/JCI81261
  54. Setoguchi R. IL-15 boosts the function and migration of human terminally differentiated CD8+ T cells by inducing a unique gene signature. Int Immunol 2016;28:293-305. https://doi.org/10.1093/intimm/dxw004
  55. Sharif-Askari E, Fawaz LM, Tran P, Ahmad A, Menezes J. Interleukin 15-mediated induction of cytotoxic effector cells capable of eliminating Epstein-Barr virus-transformed/immortalized lymphocytes in culture. J Natl Cancer Inst 2001;93:1724-1732. https://doi.org/10.1093/jnci/93.22.1724
  56. Schluns KS, Williams K, Ma A, Zheng XX, Lefrancois L. Cutting edge: requirement for IL-15 in the generation of primary and memory antigen-specific CD8 T cells. J Immunol 2002;168:4827-4831. https://doi.org/10.4049/jimmunol.168.10.4827
  57. Mueller YM, Bojczuk PM, Halstead ES, Kim AH, Witek J, Altman JD, Katsikis PD. IL-15 enhances survival and function of HIV-specific CD8+ T cells. Blood 2003;101:1024-1029. https://doi.org/10.1182/blood-2002-07-1957
  58. Saito K, Yajima T, Kumabe S, Doi T, Yamada H, Sad S, Shen H, Yoshikai Y. Impaired protection against Mycobacterium bovis bacillus Calmette-Guerin infection in IL-15-deficient mice. J Immunol 2006;176:2496-2504. https://doi.org/10.4049/jimmunol.176.4.2496
  59. Yajima T, Nishimura H, Ishimitsu R, Yamamura K, Watase T, Busch DH, Pamer EG, Kuwano H, Yoshikai Y. Memory phenotype CD8(+) T cells in IL-15 transgenic mice are involved in early protection against a primary infection with Listeria monocytogenes. Eur J Immunol 2001;31:757-766. https://doi.org/10.1002/1521-4141(200103)31:3<757::AID-IMMU757>3.0.CO;2-Q
  60. Khan IA, Moretto M, Wei XQ, Williams M, Schwartzman JD, Liew FY. Treatment with soluble interleukin-15Ralpha exacerbates intracellular parasitic infection by blocking the development of memory CD8+ T cell response. J Exp Med 2002;195:1463-1470. https://doi.org/10.1084/jem.20011915
  61. Henson SM, Lanna A, Riddell NE, Franzese O, Macaulay R, Griffiths SJ, Puleston DJ, Watson AS, Simon AK, Tooze SA, et al. p38 signaling inhibits mTORC1-independent autophagy in senescent human CD8+ T cells. J Clin Invest 2014;124:4004-4016. https://doi.org/10.1172/JCI75051
  62. Plunkett FJ, Franzese O, Finney HM, Fletcher JM, Belaramani LL, Salmon M, Dokal I, Webster D, Lawson AD, Akbar AN. The loss of telomerase activity in highly differentiated CD8+CD28-CD27- T cells is associated with decreased Akt (Ser473) phosphorylation. J Immunol 2007;178:7710-7719. https://doi.org/10.4049/jimmunol.178.12.7710
  63. Romero P, Zippelius A, Kurth I, Pittet MJ, Touvrey C, Iancu EM, Corthesy P, Devevre E, Speiser DE, Rufer N. Four functionally distinct populations of human effector-memory CD8+ T lymphocytes. J Immunol 2007;178:4112-4119. https://doi.org/10.4049/jimmunol.178.7.4112
  64. Chiu WK, Fann M, Weng NP. Generation and growth of CD28nullCD8+ memory T cells mediated by IL-15 and its induced cytokines. J Immunol 2006;177:7802-7810. https://doi.org/10.4049/jimmunol.177.11.7802
  65. Goronzy JJ, Li G, Yu M, Weyand CM. Signaling pathways in aged T cells - a reflection of T cell differentiation, cell senescence and host environment. Semin Immunol 2012;24:365-372. https://doi.org/10.1016/j.smim.2012.04.003
  66. Choi YJ, Lee H, Kim JH, Kim SY, Koh JY, Sa M, Park SH, Shin EC. CD5 suppresses IL-15-induced proliferation of human memory CD8(+) T cells by inhibiting mTOR pathways. J Immunol 2022;209:1108-1117. https://doi.org/10.4049/jimmunol.2100854
  67. Morris SR, Chen B, Mudd JC, Panigrahi S, Shive CL, Sieg SF, Cameron CM, Zidar DA, Funderburg NT, Younes SA, et al. Inflammescent CX3CR1+CD57+CD8+ T cells are generated and expanded by IL-15. JCI Insight 2020;5:e132963.
  68. Herndler-Brandstetter D, Brunner S, Weiskopf D, van Rijn R, Landgraf K, Dejaco C, Duftner C, Schirmer M, Kloss F, Gassner R, et al. Post-thymic regulation of CD5 levels in human memory T cells is inversely associated with the strength of responsiveness to interleukin-15. Hum Immunol 2011;72:627-631. https://doi.org/10.1016/j.humimm.2011.03.028
  69. Kim YJ, Rho KN, Jeong S, Lee GW, Kim HO, Cho HJ, Bae WK, Oh IJ, Lee SW, Cho JH. CD5 expression dynamically changes during the differentiation of human CD8(+) T cells predicting clinical response to immunotherapy. Immune Netw 2023;23:e35.
  70. Correia MP, Costa AV, Uhrberg M, Cardoso EM, Arosa FA. IL-15 induces CD8+ T cells to acquire functional NK receptors capable of modulating cytotoxicity and cytokine secretion. Immunobiology 2011;216:604-612. https://doi.org/10.1016/j.imbio.2010.09.012
  71. Balin SJ, Pellegrini M, Klechevsky E, Won ST, Weiss DI, Choi AW, Hakimian J, Lu J, Ochoa MT, Bloom BR, et al. Human antimicrobial cytotoxic T lymphocytes, defined by NK receptors and antimicrobial proteins, kill intracellular bacteria. Sci Immunol 2018;3:eaat7668.
  72. Correia MP, Stojanovic A, Bauer K, Juraeva D, Tykocinski LO, Lorenz HM, Brors B, Cerwenka A. Distinct human circulating NKp30+FcεRIγ+CD8+ T cell population exhibiting high natural killer-like antitumor potential. Proc Natl Acad Sci U S A 2018;115:E5980-E5989. https://doi.org/10.1073/pnas.1720564115
  73. Laphanuwat P, Gomes DCO, Akbar AN. Senescent T cells: beneficial and detrimental roles. Immunol Rev 2023;316:160-175. https://doi.org/10.1111/imr.13206
  74. Lanna A, Gomes DC, Muller-Durovic B, McDonnell T, Escors D, Gilroy DW, Lee JH, Karin M, Akbar AN. A sestrin-dependent Erk-Jnk-p38 MAPK activation complex inhibits immunity during aging. Nat Immunol 2017;18:354-363. https://doi.org/10.1038/ni.3665
  75. Pereira BI, De Maeyer RPH, Covre LP, Nehar-Belaid D, Lanna A, Ward S, Marches R, Chambers ES, Gomes DCO, Riddell NE, et al. Sestrins induce natural killer function in senescent-like CD8+ T cells. Nat Immunol 2020;21:684-694. https://doi.org/10.1038/s41590-020-0643-3
  76. Seok J, Cho SD, Seo SJ, Park SH. Roles of virtual memory T cells in diseases. Immune Netw 2023;23:e11.
  77. White JT, Cross EW, Kedl RM. Antigen-inexperienced memory CD8+ T cells: where they come from and why we need them. Nat Rev Immunol 2017;17:391-400. https://doi.org/10.1038/nri.2017.34
  78. Sosinowski T, White JT, Cross EW, Haluszczak C, Marrack P, Gapin L, Kedl RM. CD8α+ dendritic cell trans presentation of IL-15 to naive CD8+ T cells produces antigen-inexperienced T cells in the periphery with memory phenotype and function. J Immunol 2013;190:1936-1947. https://doi.org/10.4049/jimmunol.1203149
  79. White JT, Cross EW, Burchill MA, Danhorn T, McCarter MD, Rosen HR, O'Connor B, Kedl RM. Virtual memory T cells develop and mediate bystander protective immunity in an IL-15-dependent manner. Nat Commun 2016;7:11291.
  80. Jacomet F, Cayssials E, Basbous S, Levescot A, Piccirilli N, Desmier D, Robin A, Barra A, Giraud C, Guilhot F, et al. Evidence for eomesodermin-expressing innate-like CD8(+) KIR/NKG2A(+) T cells in human adults and cord blood samples. Eur J Immunol 2015;45:1926-1933. https://doi.org/10.1002/eji.201545539
  81. Quinn KM, Fox A, Harland KL, Russ BE, Li J, Nguyen THO, Loh L, Olshanksy M, Naeem H, Tsyganov K, et al. Age-related decline in primary CD8(+) T cell responses is associated with the development of senescence in virtual memory CD8(+) T cells. Cell Rep 2018;23:3512-3524. https://doi.org/10.1016/j.celrep.2018.05.057
  82. Choi SJ, Koh JY, Rha MS, Seo IH, Lee H, Jeong S, Park SH, Shin EC. KIR+CD8+ and NKG2A+CD8+ T cells are distinct innate-like populations in humans. Cell Rep 2023;42:112236.
  83. Kok L, Masopust D, Schumacher TN. The precursors of CD8+ tissue resident memory T cells: from lymphoid organs to infected tissues. Nat Rev Immunol 2022;22:283-293. https://doi.org/10.1038/s41577-021-00590-3
  84. Schenkel JM, Fraser KA, Beura LK, Pauken KE, Vezys V, Masopust D. T cell memory. Resident memory CD8 T cells trigger protective innate and adaptive immune responses. Science 2014;346:98-101. https://doi.org/10.1126/science.1254536
  85. Ariotti S, Hogenbirk MA, Dijkgraaf FE, Visser LL, Hoekstra ME, Song JY, Jacobs H, Haanen JB, Schumacher TN. T cell memory. Skin-resident memory CD8+ T cells trigger a state of tissue-wide pathogen alert. Science 2014;346:101-105. https://doi.org/10.1126/science.1254803
  86. Mackay LK, Rahimpour A, Ma JZ, Collins N, Stock AT, Hafon ML, Vega-Ramos J, Lauzurica P, Mueller SN, Stefanovic T, et al. The developmental pathway for CD103(+)CD8+ tissue-resident memory T cells of skin. Nat Immunol 2013;14:1294-1301. https://doi.org/10.1038/ni.2744
  87. Holz LE, Prier JE, Freestone D, Steiner TM, English K, Johnson DN, Mollard V, Cozijnsen A, Davey GM, Godfrey DI, et al. CD8(+) T cell activation leads to constitutive formation of liver tissue-resident memory T cells that seed a large and flexible niche in the liver. Cell Rep 2018;25:68-79.e4. https://doi.org/10.1016/j.celrep.2018.08.094
  88. Mackay LK, Wynne-Jones E, Freestone D, Pellicci DG, Mielke LA, Newman DM, Braun A, Masson F, Kallies A, Belz GT, et al. T-box transcription factors combine with the cytokines TGF-beta and IL-15 to control tissue-resident memory T cell fate. Immunity 2015;43:1101-1111. https://doi.org/10.1016/j.immuni.2015.11.008
  89. Schenkel JM, Fraser KA, Casey KA, Beura LK, Pauken KE, Vezys V, Masopust D. IL-15-independent maintenance of tissue-resident and boosted effector memory CD8 T cells. J Immunol 2016;196:3920-3926. https://doi.org/10.4049/jimmunol.1502337
  90. Adachi T, Kobayashi T, Sugihara E, Yamada T, Ikuta K, Pittaluga S, Saya H, Amagai M, Nagao K. Hair follicle-derived IL-7 and IL-15 mediate skin-resident memory T cell homeostasis and lymphoma. Nat Med 2015;21:1272-1279. https://doi.org/10.1038/nm.3962
  91. Jarjour NN, Wanhainen KM, Peng C, Gavil NV, Maurice NJ, Borges da Silva H, Martinez RJ, Dalzell TS, Huggins MA, Masopust D, et al. Responsiveness to interleukin-15 therapy is shared between tissue-resident and circulating memory CD8+ T cell subsets. Proc Natl Acad Sci U S A 2022;119:e2209021119.
  92. Koh JY, Kim DU, Moon BH, Shin EC. Human CD8(+) T-cell populations that express natural killer receptors. Immune Netw 2023;23:e8.
  93. Arlettaz L, Villard J, de Rham C, Degermann S, Chapuis B, Huard B, Roosnek E. Activating CD94:NKG2C and inhibitory CD94:NKG2A receptors are expressed by distinct subsets of committed CD8+ TCR alphabeta lymphocytes. Eur J Immunol 2004;34:3456-3464. https://doi.org/10.1002/eji.200425210
  94. Guma M, Busch LK, Salazar-Fontana LI, Bellosillo B, Morte C, Garcia P, Lopez-Botet M. The CD94/NKG2C killer lectin-like receptor constitutes an alternative activation pathway for a subset of CD8+ T cells. Eur J Immunol 2005;35:2071-2080. https://doi.org/10.1002/eji.200425843
  95. Kefalakes H, Horgan XJ, Jung MK, Amanakis G, Kapuria D, Bolte FJ, Kleiner DE, Koh C, Heller T, Rehermann B. Liver-resident bystander CD8+ T cells contribute to liver disease pathogenesis in chronic hepatitis D virus infection. Gastroenterology 2021;161:1567-1583.e9. https://doi.org/10.1053/j.gastro.2021.07.027
  96. Koh JY, Rha MS, Choi SJ, Lee HS, Han JW, Nam H, Kim DU, Lee JG, Kim MS, Park JY, et al. Identification of a distinct NK-like hepatic T-cell population activated by NKG2C in a TCR-independent manner. J Hepatol 2022;77:1059-1070. https://doi.org/10.1016/j.jhep.2022.05.020
  97. Ruf B, Greten TF, Korangy F. Innate lymphoid cells and innate-like T cells in cancer - at the crossroads of innate and adaptive immunity. Nat Rev Cancer 2023;23:351-371. https://doi.org/10.1038/s41568-023-00562-w
  98. Godfrey DI, Koay HF, McCluskey J, Gherardin NA. The biology and functional importance of MAIT cells. Nat Immunol 2019;20:1110-1128. https://doi.org/10.1038/s41590-019-0444-8
  99. Tao H, Pan Y, Chu S, Li L, Xie J, Wang P, Zhang S, Reddy S, Sleasman JW, Zhong XP. Differential controls of MAIT cell effector polarization by mTORC1/mTORC2 via integrating cytokine and costimulatory signals. Nat Commun 2021;12:2029.
  100. van Wilgenburg B, Scherwitzl I, Hutchinson EC, Leng T, Kurioka A, Kulicke C, de Lara C, Cole S, Vasanawathana S, Limpitikul W, et al. MAIT cells are activated during human viral infections. Nat Commun 2016;7:11653.
  101. Sattler A, Dang-Heine C, Reinke P, Babel N. IL-15 dependent induction of IL-18 secretion as a feedback mechanism controlling human MAIT-cell effector functions. Eur J Immunol 2015;45:2286-2298. https://doi.org/10.1002/eji.201445313
  102. Silva-Santos B, Mensurado S, Coffelt SB. γδ T cells: pleiotropic immune effectors with therapeutic potential in cancer. Nat Rev Cancer 2019;19:392-404. https://doi.org/10.1038/s41568-019-0153-5
  103. Lee HW, Chung YS, Kim TJ. Heterogeneity of human gammadelta T cells and their role in cancer immunity. Immune Netw 2020;20:e5.
  104. Hu Y, Hu Q, Li Y, Lu L, Xiang Z, Yin Z, Kabelitz D, Wu Y. γδ T cells: origin and fate, subsets, diseases and immunotherapy. Signal Transduct Target Ther 2023;8:434.
  105. Baccala R, Witherden D, Gonzalez-Quintial R, Dummer W, Surh CD, Havran WL, Theofilopoulos AN. Gamma delta T cell homeostasis is controlled by IL-7 and IL-15 together with subset-specific factors. J Immunol 2005;174:4606-4612. https://doi.org/10.4049/jimmunol.174.8.4606
  106. Wang H, Wang X, Wang W, Chai W, Song W, Zhang H, Mou W, Pei M, Su Y, Ma X, et al. Interleukin-15 enhanced the survival of human γδT cells by regulating the expression of Mcl-1 in neuroblastoma. Cell Death Dis 2022;8:139.
  107. Van Acker HH, Anguille S, Willemen Y, Van den Bergh JM, Berneman ZN, Lion E, Smits EL, Van Tendeloo VF. Interleukin-15 enhances the proliferation, stimulatory phenotype, and antitumor effector functions of human gamma delta T cells. J Hematol Oncol 2016;9:101.
  108. Waldmann TA. The biology of interleukin-2 and interleukin-15: implications for cancer therapy and vaccine design. Nat Rev Immunol 2006;6:595-601. https://doi.org/10.1038/nri1901
  109. Liu RB, Engels B, Schreiber K, Ciszewski C, Schietinger A, Schreiber H, Jabri B. IL-15 in tumor microenvironment causes rejection of large established tumors by T cells in a noncognate T cell receptor-dependent manner. Proc Natl Acad Sci U S A 2013;110:8158-8163. https://doi.org/10.1073/pnas.1301022110
  110. Mathios D, Park CK, Marcus WD, Alter S, Rhode PR, Jeng EK, Wong HC, Pardoll DM, Lim M. Therapeutic administration of IL-15 superagonist complex ALT-803 leads to long-term survival and durable antitumor immune response in a murine glioblastoma model. Int J Cancer 2016;138:187-194. https://doi.org/10.1002/ijc.29686
  111. Kim KH, Kim HK, Kim HD, Kim CG, Lee H, Han JW, Choi SJ, Jeong S, Jeon M, Kim H, et al. PD-1 blockade-unresponsive human tumor-infiltrating CD8+ T cells are marked by loss of CD28 expression and rescued by IL-15. Cell Mol Immunol 2021;18:385-397. https://doi.org/10.1038/s41423-020-0427-6
  112. Lee J, Lee K, Bae H, Lee K, Lee S, Ma J, Jo K, Kim I, Jee B, Kang M, et al. IL-15 promotes self-renewal of progenitor exhausted CD8 T cells during persistent antigenic stimulation. Front Immunol 2023;14:1117092.
  113. Wrangle JM, Velcheti V, Patel MR, Garrett-Mayer E, Hill EG, Ravenel JG, Miller JS, Farhad M, Anderton K, Lindsey K, et al. ALT-803, an IL-15 superagonist, in combination with nivolumab in patients with metastatic non-small cell lung cancer: a non-randomised, open-label, phase 1b trial. Lancet Oncol 2018;19:694-704. https://doi.org/10.1016/S1470-2045(18)30148-7
  114. Leidner R, Conlon K, McNeel DG, Wang-Gillam A, Gupta S, Wesolowski R, Chaudhari M, Hassounah N, Lee JB, Ho Lee L, et al. First-in-human phase I/Ib study of NIZ985, a recombinant heterodimer of IL-15 and IL-15Rα, as a single agent and in combination with spartalizumab in patients with advanced and metastatic solid tumors. J Immunother Cancer 2023;11:e007725.
  115. Miyazaki T, Maiti M, Hennessy M, Chang T, Kuo P, Addepalli M, Obalapur P, Sheibani S, Wilczek J, Pena R, et al. NKTR-255, a novel polymer-conjugated rhIL-15 with potent antitumor efficacy. J Immunother Cancer 2021;9:e002024.
  116. Rhode PR, Egan JO, Xu W, Hong H, Webb GM, Chen X, Liu B, Zhu X, Wen J, You L, et al. Comparison of the superagonist complex, ALT-803, to IL15 as cancer immunotherapeutics in animal models. Cancer Immunol Res 2016;4:49-60. https://doi.org/10.1158/2326-6066.CIR-15-0093-T
  117. Kim PS, Kwilas AR, Xu W, Alter S, Jeng EK, Wong HC, Schlom J, Hodge JW. IL-15 superagonist/IL-15RαSushi-Fc fusion complex (IL-15SA/IL-15RαSu-Fc; ALT-803) markedly enhances specific subpopulations of NK and memory CD8+ T cells, and mediates potent anti-tumor activity against murine breast and colon carcinomas. Oncotarget 2016;7:16130-16145. https://doi.org/10.18632/oncotarget.7470
  118. Knudson KM, Hodge JW, Schlom J, Gameiro SR. Rationale for IL-15 superagonists in cancer immunotherapy. Expert Opin Biol Ther 2020;20:705-709. https://doi.org/10.1080/14712598.2020.1738379
  119. Chamie K, Lee JH, Rock A, Rhode PR, Soon-Shiong P. Preliminary phase 2 clinical results of IL-15RαFc superagonist N-803 with BCG in BCG-unresponsive non-muscle invasive bladder cancer (NMIBC) patients. J Clin Oncol 2019;37:4561.
  120. Alizadeh D, Wong RA, Yang X, Wang D, Pecoraro JR, Kuo CF, Aguilar B, Qi Y, Ann DK, Starr R, et al. IL15 enhances CAR-T cell antitumor activity by reducing mTORC1 activity and preserving their stem cell memory phenotype. Cancer Immunol Res 2019;7:759-772. https://doi.org/10.1158/2326-6066.CIR-18-0466
  121. Singh N, Perazzelli J, Grupp SA, Barrett DM. Early memory phenotypes drive T cell proliferation in patients with pediatric malignancies. Sci Transl Med 2016;8:320ra3.
  122. Kochenderfer JN, Somerville RPT, Lu T, Shi V, Bot A, Rossi J, Xue A, Goff SL, Yang JC, Sherry RM, et al. Lymphoma remissions caused by anti-CD19 chimeric antigen receptor T cells are associated with high serum interleukin-15 levels. J Clin Oncol 2017;35:1803-1813. https://doi.org/10.1200/JCO.2016.71.3024
  123. Hurton LV, Singh H, Najjar AM, Switzer KC, Mi T, Maiti S, Olivares S, Rabinovich B, Huls H, Forget MA, et al. Tethered IL-15 augments antitumor activity and promotes a stem-cell memory subset in tumor-specific T cells. Proc Natl Acad Sci U S A 2016;113:E7788-E7797. https://doi.org/10.1073/pnas.1610544113
  124. Simoni Y, Becht E, Fehlings M, Loh CY, Koo SL, Teng KWW, Yeong JPS, Nahar R, Zhang T, Kared H, et al. Bystander CD8+ T cells are abundant and phenotypically distinct in human tumour infiltrates. Nature 2018;557:575-579. https://doi.org/10.1038/s41586-018-0130-2
  125. Tietze JK, Wilkins DE, Sckisel GD, Bouchlaka MN, Alderson KL, Weiss JM, Ames E, Bruhn KW, Craft N, Wiltrout RH, et al. Delineation of antigen-specific and antigen-nonspecific CD8(+) memory T-cell responses after cytokine-based cancer immunotherapy. Blood 2012;119:3073-3083. https://doi.org/10.1182/blood-2011-07-369736
  126. Liu K, Catalfamo M, Li Y, Henkart PA, Weng NP. IL-15 mimics T cell receptor crosslinking in the induction of cellular proliferation, gene expression, and cytotoxicity in CD8+ memory T cells. Proc Natl Acad Sci U S A 2002;99:6192-6197. https://doi.org/10.1073/pnas.092675799
  127. Maurice NJ, Taber AK, Prlic M. The ugly duckling turned to swan: a change in perception of bystander-activated memory CD8 T cells. J Immunol 2021;206:455-462. https://doi.org/10.4049/jimmunol.2000937
  128. Younes SA, Freeman ML, Mudd JC, Shive CL, Reynaldi A, Panigrahi S, Estes JD, Deleage C, Lucero C, Anderson J, et al. IL-15 promotes activation and expansion of CD8+ T cells in HIV-1 infection. J Clin Invest 2016;126:2745-2756. https://doi.org/10.1172/JCI85996
  129. Chu T, Tyznik AJ, Roepke S, Berkley AM, Woodward-Davis A, Pattacini L, Bevan MJ, Zehn D, Prlic M. Bystander-activated memory CD8 T cells control early pathogen load in an innate-like, NKG2D-dependent manner. Cell Rep 2013;3:701-708. https://doi.org/10.1016/j.celrep.2013.02.020
  130. Yajima T, Nishimura H, Sad S, Shen H, Kuwano H, Yoshikai Y. A novel role of IL-15 in early activation of memory CD8+ CTL after reinfection. J Immunol 2005;174:3590-3597. https://doi.org/10.4049/jimmunol.174.6.3590
  131. Soudja SM, Ruiz AL, Marie JC, Lauvau G. Inflammatory monocytes activate memory CD8(+) T and innate NK lymphocytes independent of cognate antigen during microbial pathogen invasion. Immunity 2012;37:549-562. https://doi.org/10.1016/j.immuni.2012.05.029
  132. Bastidas S, Graw F, Smith MZ, Kuster H, Gunthard HF, Oxenius A. CD8+ T cells are activated in an antigen-independent manner in HIV-infected individuals. J Immunol 2014;192:1732-1744. https://doi.org/10.4049/jimmunol.1302027
  133. Kim J, Chang DY, Lee HW, Lee H, Kim JH, Sung PS, Kim KH, Hong SH, Kang W, Lee J, et al. Innate-like cytotoxic function of bystander-activated CD8(+) T cells is associated with liver injury in acute hepatitis a. Immunity 2018;48:161-173.e5. https://doi.org/10.1016/j.immuni.2017.11.025
  134. Seo IH, Eun HS, Kim JK, Lee H, Jeong S, Choi SJ, Lee J, Lee BS, Kim SH, Rou WS, et al. IL-15 enhances CCR5-mediated migration of memory CD8+ T cells by upregulating CCR5 expression in the absence of TCR stimulation. Cell Rep 2021;36:109438.
  135. Huang CH, Fan JH, Jeng WJ, Chang ST, Yang CK, Teng W, Wu TH, Hsieh YC, Chen WT, Chen YC, et al. Innate-like bystander-activated CD38+ HLA-DR+ CD8+ T cells play a pathogenic role in patients with chronic hepatitis C. Hepatology 2022;76:803-818. https://doi.org/10.1002/hep.32349
  136. Freeman CM, Han MK, Martinez FJ, Murray S, Liu LX, Chensue SW, Polak TJ, Sonstein J, Todt JC, Ames TM, et al. Cytotoxic potential of lung CD8(+) T cells increases with chronic obstructive pulmonary disease severity and with in vitro stimulation by IL-18 or IL-15. J Immunol 2010;184:6504-6513. https://doi.org/10.4049/jimmunol.1000006
  137. Sacramento LA, Farias Amorim C, Campos TM, Saldanha M, Arruda S, Carvalho LP, Beiting DP, Carvalho EM, Novais FO, Scott P. NKG2D promotes CD8 T cell-mediated cytotoxicity and is associated with treatment failure in human cutaneous leishmaniasis. PLoS Negl Trop Dis 2023;17:e0011552.
  138. Shin EC, Sung PS, Park SH. Immune responses and immunopathology in acute and chronic viral hepatitis. Nat Rev Immunol 2016;16:509-523. https://doi.org/10.1038/nri.2016.69
  139. Wilkinson PC, Liew FY. Chemoattraction of human blood T lymphocytes by interleukin-15. J Exp Med 1995;181:1255-1259. https://doi.org/10.1084/jem.181.3.1255
  140. Verbist KC, Cole CJ, Field MB, Klonowski KD. A role for IL-15 in the migration of effector CD8 T cells to the lung airways following influenza infection. J Immunol 2011;186:174-182. https://doi.org/10.4049/jimmunol.1002613
  141. Nolz JC, Harty JT. IL-15 regulates memory CD8+ T cell O-glycan synthesis and affects trafficking. J Clin Invest 2014;124:1013-1026.
  142. Rha MS, Han JW, Kim JH, Koh JY, Park HJ, Kim SI, Kim MS, Lee JG, Lee HW, Lee DH, et al. Human liver CD8+ MAIT cells exert TCR/MR1-independent innate-like cytotoxicity in response to IL-15. J Hepatol 2020;73:640-650. https://doi.org/10.1016/j.jhep.2020.03.033
  143. Lee H, Jung MK, Noh JY, Park SH, Chung Y, Ha SJ, Shin EC. Better understanding CD8+ T cells in cancer and viral infections. Nat Immunol 2023;24:1794-1796. https://doi.org/10.1038/s41590-023-01630-x
  144. Jeong S, Jeon M, Lee H, Kim SY, Park SH, Shin EC. IFITM3 is upregulated characteristically in IL-15-mediated bystander-activated CD8(+) T cells during influenza infection. J Immunol 2022;208:1901-1911. https://doi.org/10.4049/jimmunol.2100629
  145. Meresse B, Chen Z, Ciszewski C, Tretiakova M, Bhagat G, Krausz TN, Raulet DH, Lanier LL, Groh V, Spies T, et al. Coordinated induction by IL15 of a TCR-independent NKG2D signaling pathway converts CTL into lymphokine-activated killer cells in celiac disease. Immunity 2004;21:357-366. https://doi.org/10.1016/j.immuni.2004.06.020
  146. Hue S, Mention JJ, Monteiro RC, Zhang S, Cellier C, Schmitz J, Verkarre V, Fodil N, Bahram S, Cerf-Bensussan N, et al. A direct role for NKG2D/MICA interaction in villous atrophy during celiac disease. Immunity 2004;21:367-377. https://doi.org/10.1016/j.immuni.2004.06.018
  147. Hoytema van Konijnenburg DP, Reis BS, Pedicord VA, Farache J, Victora GD, Mucida D. Intestinal epithelial and intraepithelial T cell crosstalk mediates a dynamic response to infection. Cell 2017;171:783-794.e13. https://doi.org/10.1016/j.cell.2017.08.046
  148. Zhao H, Nguyen H, Kang J. Interleukin 15 controls the generation of the restricted T cell receptor repertoire of gamma delta intestinal intraepithelial lymphocytes. Nat Immunol 2005;6:1263-1271. https://doi.org/10.1038/ni1267
  149. Mayassi T, Barreiro LB, Rossjohn J, Jabri B. A multilayered immune system through the lens of unconventional T cells. Nature 2021;595:501-510. https://doi.org/10.1038/s41586-021-03578-0
  150. Simpson SJ, Hollander GA, Mizoguchi E, Allen D, Bhan AK, Wang B, Terhorst C. Expression of proinflammatory cytokines by TCR alpha beta+ and TCR gamma delta+ T cells in an experimental model of colitis. Eur J Immunol 1997;27:17-25. https://doi.org/10.1002/eji.1830270104
  151. Kawaguchi-Miyashita M, Shimada S, Kurosu H, Kato-Nagaoka N, Matsuoka Y, Ohwaki M, Ishikawa H, Nanno M. An accessory role of TCRgammadelta (+) cells in the exacerbation of inflammatory bowel disease in TCRalpha mutant mice. Eur J Immunol 2001;31:980-988. https://doi.org/10.1002/1521-4141(200104)31:4<980::AID-IMMU980>3.0.CO;2-U
  152. Xing L, Dai Z, Jabbari A, Cerise JE, Higgins CA, Gong W, de Jong A, Harel S, DeStefano GM, Rothman L, et al. Alopecia areata is driven by cytotoxic T lymphocytes and is reversed by JAK inhibition. Nat Med 2014;20:1043-1049. https://doi.org/10.1038/nm.3645
  153. Seok J, Cho SD, Lee J, Choi Y, Kim SY, Lee SM, Kim SH, Jeong S, Jeon M, Lee H, et al. A virtual memory CD8+ T cell-originated subset causes alopecia areata through innate-like cytotoxicity. Nat Immunol 2023;24:1308-1317. https://doi.org/10.1038/s41590-023-01547-5
  154. Masle-Farquhar E, Jackson KJL, Peters TJ, Al-Eryani G, Singh M, Payne KJ, Rao G, Avery DT, Apps G, Kingham J, et al. STAT3 gain-of-function mutations connect leukemia with autoimmune disease by pathological NKG2Dhi CD8+ T cell dysregulation and accumulation. Immunity 2022;55:2386-2404.e8. https://doi.org/10.1016/j.immuni.2022.11.001
  155. Dudek M, Pfister D, Donakonda S, Filpe P, Schneider A, Laschinger M, Hartmann D, Huser N, Meiser P, Bayerl F, et al. Auto-aggressive CXCR6+ CD8 T cells cause liver immune pathology in NASH. Nature 2021;592:444-449. https://doi.org/10.1038/s41586-021-03233-8