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Induction of Unique STAT Heterodimers by IL-21 Provokes IL-1RI Expression on CD8+ T Cells, Resulting in Enhanced IL-1β Dependent Effector Function

  • Dong Hyun Kim (Laboratory of Autoimmunity and Inflammation (LAI), Department of Biomedical Sciences, Seoul National University College of Medicine) ;
  • Hee Young Kim (Laboratory of Autoimmunity and Inflammation (LAI), Department of Biomedical Sciences, Seoul National University College of Medicine) ;
  • Won-Woo Lee (Laboratory of Autoimmunity and Inflammation (LAI), Department of Biomedical Sciences, Seoul National University College of Medicine)
  • Received : 2021.05.25
  • Accepted : 2021.08.23
  • Published : 2021.10.31
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Abstract

IL-1β plays critical roles in the priming and effector phases of immune responses such as the differentiation, commitment, and memory formation of T cells. In this context, several reports have suggested that the IL-1β signal is crucial for CTL-mediated immune responses to viral infections and tumors. However, little is known regarding whether IL-1β acts directly on CD8+ T cells and what the molecular mechanisms underlying expression of IL-1 receptors (IL-1Rs) on CD8+ T cells and features of IL-1R+ CD8+ T cells are. Here, we provide evidence that the expression of IL-1R type I (IL-1RI), the functional receptor of IL-1β, is preferentially induced by IL-21 on TCR-stimulated CD8+ T cells. Further, IL-1β enhances the effector function of CD8+ T cells expressing IL-21-induced IL-1RI by increasing cytokine production and release of cytotoxic granules containing granzyme B. The IL-21-IL-1RI-IL-1β axis is involved in an augmented effector function through regulation of transcription factors BATF, Blimp-1, and IRF4. Moreover, this axis confers a unique effector function to CD8+ T cells compared to conventional type 1 cytotoxic T cells differentiated with IL-12. Chemical inhibitor and immunoprecipitation assay demonstrated that IL-21 induces a unique pattern of STAT activation with the formation of both STAT1:STAT3 and STAT3:STAT5 heterodimers, which are critical for the induction of IL-1RI on TCR-stimulated CD8+ T cells. Taken together, we propose that induction of a novel subset of IL-1RI-expressing CD8+ T cells by IL-21 may be beneficial to the protective immune response against viral infections and is therefore important to consider for vaccine design.

Keywords

Acknowledgement

The authors thank Jiyeon Jang (Seoul National University College of Medicine) for assisting in the recruitment of human subjects and thank Core Lab, Clinical Trials Center, Seoul National University Hospital for drawing blood. This work was supported by a grant (NRF-2018R1A2B2006310 to W.-W. Lee) from the National Research Foundation of Korea (NRF) funded by Ministry of Science and ICT (MSIT), Republic of Korea.

References

  1. Ren K, Torres R. Role of interleukin-1beta during pain and inflammation. Brain Res Brain Res Rev 2009;60:57-64. https://doi.org/10.1016/j.brainresrev.2008.12.020
  2. Lasiglie D, Traggiai E, Federici S, Alessio M, Buoncompagni A, Accogli A, Chiesa S, Penco F, Martini A, Gattorno M. Role of IL-1 beta in the development of human T(H)17 cells: lesson from NLPR3 mutated patients. PLoS One 2011;6:e20014.
  3. Sims JE, Smith DE. The IL-1 family: regulators of immunity. Nat Rev Immunol 2010;10:89-102. https://doi.org/10.1038/nri2691
  4. Sha Y, Markovic-Plese S. A role of IL-1R1 signaling in the differentiation of Th17 cells and the development of autoimmune diseases. Self Nonself 2011;2:35-42. https://doi.org/10.4161/self.2.1.15639
  5. Garlanda C, Dinarello CA, Mantovani A. The interleukin-1 family: back to the future. Immunity 2013;39:1003-1018. https://doi.org/10.1016/j.immuni.2013.11.010
  6. Garlanda C, Riva F, Bonavita E, Gentile S, Mantovani A. Decoys and regulatory "receptors" of the il-1/toll-like receptor superfamily. Front Immunol 2013;4:180. https://doi.org/10.3389/fimmu.2013.00180
  7. Lee WW, Kang SW, Choi J, Lee SH, Shah K, Eynon EE, Flavell RA, Kang I. Regulating human Th17 cells via differential expression of IL-1 receptor. Blood 2010;115:530-540. https://doi.org/10.1182/blood-2009-08-236521
  8. Boniface K, Bak-Jensen KS, Li Y, Blumenschein WM, McGeachy MJ, McClanahan TK, McKenzie BS, Kastelein RA, Cua DJ, de Waal Malefyt R. Prostaglandin E2 regulates Th17 cell differentiation and function through cyclic AMP and EP2/EP4 receptor signaling. J Exp Med 2009;206:535-548. https://doi.org/10.1084/jem.20082293
  9. Yeste A, Mascanfroni ID, Nadeau M, Burns EJ, Tukpah AM, Santiago A, Wu C, Patel B, Kumar D, Quintana FJ. IL-21 induces IL-22 production in CD4+ T cells. Nat Commun 2014;5:3753.
  10. Williams MA, Tyznik AJ, Bevan MJ. Interleukin-2 signals during priming are required for secondary expansion of CD8+ memory T cells. Nature 2006;441:890-893. https://doi.org/10.1038/nature04790
  11. Pellegrini M, Calzascia T, Toe JG, Preston SP, Lin AE, Elford AR, Shahinian A, Lang PA, Lang KS, Morre M, et al. IL-7 engages multiple mechanisms to overcome chronic viral infection and limit organ pathology. Cell 2011;144:601-613. https://doi.org/10.1016/j.cell.2011.01.011
  12. Schurich A, Pallett LJ, Lubowiecki M, Singh HD, Gill US, Kennedy PT, Nastouli E, Tanwar S, Rosenberg W, Maini MK. The third signal cytokine IL-12 rescues the anti-viral function of exhausted HBV-specific CD8 T cells. PLoS Pathog 2013;9:e1003208.
  13. Elsaesser H, Sauer K, Brooks DG. IL-21 is required to control chronic viral infection. Science 2009;324:1569-1572. https://doi.org/10.1126/science.1174182
  14. Janas ML, Groves P, Kienzle N, Kelso A. IL-2 regulates perforin and granzyme gene expression in CD8+ T cells independently of its effects on survival and proliferation. J Immunol 2005;175:8003-8010. https://doi.org/10.4049/jimmunol.175.12.8003
  15. Duan MC, Huang Y, Zhong XN, Tang HJ. Th17 cell enhances CD8 T-cell cytotoxicity via IL-21 production in emphysema mice. Mediators Inflamm 2012;2012:898053.
  16. Novy P, Huang X, Leonard WJ, Yang Y. Intrinsic IL-21 signaling is critical for CD8 T cell survival and memory formation in response to vaccinia viral infection. J Immunol 2011;186:2729-2738. https://doi.org/10.4049/jimmunol.1003009
  17. Laidlaw BJ, Craft JE, Kaech SM. The multifaceted role of CD4(+) T cells in CD8(+) T cell memory. Nat Rev Immunol 2016;16:102-111. https://doi.org/10.1038/nri.2015.10
  18. Ben-Sasson SZ, Wang K, Cohen J, Paul WE. IL-1β strikingly enhances antigen-driven CD4 and CD8 T-cell responses. Cold Spring Harb Symp Quant Biol 2013;78:117-124. https://doi.org/10.1101/sqb.2013.78.021246
  19. Ben-Sasson SZ, Hogg A, Hu-Li J, Wingfield P, Chen X, Crank M, Caucheteux S, Ratner-Hurevich M, Berzofsky JA, Nir-Paz R, et al. IL-1 enhances expansion, effector function, tissue localization, and memory response of antigen-specific CD8 T cells. J Exp Med 2013;210:491-502. https://doi.org/10.1084/jem.20122006
  20. Joeckel LT, Wallich R, Metkar SS, Froelich CJ, Simon MM, Borner C. Interleukin-1R signaling is essential for induction of proapoptotic CD8 T cells, viral clearance, and pathology during lymphocytic choriomeningitis virus infection in mice. J Virol 2012;86:8713-8719. https://doi.org/10.1128/JVI.00682-12
  21. Tian T, Jin MQ, Dubin K, King SL, Hoetzenecker W, Murphy GF, Chen CA, Kupper TS, Fuhlbrigge RC. IL-1R type 1-deficient mice demonstrate an impaired host immune response against cutaneous vaccinia virus infection. J Immunol 2017;198:4341-4351. https://doi.org/10.4049/jimmunol.1500106
  22. Schmitz N, Kurrer M, Bachmann MF, Kopf M. Interleukin-1 is responsible for acute lung immunopathology but increases survival of respiratory influenza virus infection. J Virol 2005;79:6441-6448. https://doi.org/10.1128/JVI.79.10.6441-6448.2005
  23. Lapuente D, Storcksdieck Genannt Bonsmann M, Maaske A, Stab V, Heinecke V, Watzstedt K, Hess R, Westendorf AM, Bayer W, Ehrhardt C, et al. IL-1β as mucosal vaccine adjuvant: the specific induction of tissue-resident memory T cells improves the heterosubtypic immunity against influenza A viruses. Mucosal Immunol 2018;11:1265-1278. https://doi.org/10.1038/s41385-018-0017-4
  24. Kim DH, Kim HY, Cho S, Yoo SJ, Kim WJ, Yeon HR, Choi K, Choi JM, Kang SW, Lee WW. Induction of the IL-1RII decoy receptor by NFAT/FOXP3 blocks IL-1β-dependent response of Th17 cells. Elife 2021;10:e61841.
  25. Schluter T, Schelmbauer C, Karram K, Mufazalov IA. Regulation of IL-1 signaling by the decoy receptor IL-1R2. J Mol Med (Berl) 2018;96:983-992. https://doi.org/10.1007/s00109-018-1684-z
  26. McNamara MJ, Kasiewicz MJ, Linch SN, Dubay C, Redmond WL. Common gamma chain (γc) cytokines differentially potentiate TNFR family signaling in antigen-activated CD8(+) T cells. J Immunother Cancer 2014;2:28.
  27. Leonard WJ, Wan CK. Il-21 signaling in immunity. F1000Res 2016;5:F1000.
  28. Spolski R, Leonard WJ. Interleukin-21: a double-edged sword with therapeutic potential. Nat Rev Drug Discov 2014;13:379-395. https://doi.org/10.1038/nrd4296
  29. Ives ML, Ma CS, Palendira U, Chan A, Bustamante J, Boisson-Dupuis S, Arkwright PD, Engelhard D, Averbuch D, Magdorf K, et al. Signal transducer and activator of transcription 3 (stat3) mutations underlying autosomal dominant hyper-IgE syndrome impair human CD8(+) T-cell memory formation and function. J Allergy Clin Immunol 2013;132:400-411.e9. https://doi.org/10.1016/j.jaci.2013.05.029
  30. Hwang Y, Yu HT, Kim DH, Jang J, Kim HY, Kang I, Kim HC, Park S, Lee WW. Expansion of CD8(+) T cells lacking the IL-6 receptor α chain in patients with coronary artery diseases (CAD). Atherosclerosis 2016;249:44-51. https://doi.org/10.1016/j.atherosclerosis.2016.03.038
  31. Finbloom DS, Winestock KD. IL-10 induces the tyrosine phosphorylation of tyk2 and Jak1 and the differential assembly of STAT1 alpha and STAT3 complexes in human T cells and monocytes. J Immunol 1995;155:1079-1090. https://doi.org/10.4049/jimmunol.155.3.1079
  32. Tough DF, Borrow P, Sprent J. Induction of bystander T cell proliferation by viruses and type I interferon in vivo. Science 1996;272:1947-1950. https://doi.org/10.1126/science.272.5270.1947
  33. Delgoffe GM, Vignali DA. STAT heterodimers in immunity: a mixed message or a unique signal? JAKSTAT 2013;2:e23060.
  34. Ma Z, Liu J, Wu W, Zhang E, Zhang X, Li Q, Zelinskyy G, Buer J, Dittmer U, Kirschning CJ, et al. The IL-1R/TLR signaling pathway is essential for efficient CD8+ T-cell responses against hepatitis B virus in the hydrodynamic injection mouse model. Cell Mol Immunol 2017;14:997-1008. https://doi.org/10.1038/cmi.2017.43
  35. Spolski R, Leonard WJ. Interleukin-21: basic biology and implications for cancer and autoimmunity. Annu Rev Immunol 2008;26:57-79. https://doi.org/10.1146/annurev.immunol.26.021607.090316
  36. Mandraju R, Jain A, Gao Y, Ouyang Z, Norgard MV, Pasare C. Myd88 signaling in T cells is critical for effector CD4 T cell differentiation following a transitional T follicular helper cell stage. Infect Immun 2018;86:e00791-17.
  37. Ikeda S, Saijo S, Murayama MA, Shimizu K, Akitsu A, Iwakura Y. Excess IL-1 signaling enhances the development of Th17 cells by downregulating TGF-β-induced Foxp3 expression. J Immunol 2014;192:1449-1458. https://doi.org/10.4049/jimmunol.1300387
  38. Sha Y, Markovic-Plese S. Activated IL-1RI signaling pathway induces Th17 cell differentiation via interferon regulatory factor 4 signaling in patients with relapsing-remitting multiple sclerosis. Front Immunol 2016;7:543.
  39. Koenders MI, Devesa I, Marijnissen RJ, Abdollahi-Roodsaz S, Boots AM, Walgreen B, di Padova FE, Nicklin MJ, Joosten LA, van den Berg WB. Interleukin-1 drives pathogenic Th17 cells during spontaneous arthritis in interleukin-1 receptor antagonist-deficient mice. Arthritis Rheum 2008;58:3461-3470. https://doi.org/10.1002/art.23957
  40. Leonard WJ, Spolski R. Interleukin-21: a modulator of lymphoid proliferation, apoptosis and differentiation. Nat Rev Immunol 2005;5:688-698. https://doi.org/10.1038/nri1688
  41. Zeng R, Spolski R, Casas E, Zhu W, Levy DE, Leonard WJ. The molecular basis of IL-21-mediated proliferation. Blood 2007;109:4135-4142. https://doi.org/10.1182/blood-2006-10-054973
  42. Rawlings JS, Rosler KM, Harrison DA. The JAK/STAT signaling pathway. J Cell Sci 2004;117:1281-1283. https://doi.org/10.1242/jcs.00963
  43. Novak U, Mui A, Miyajima A, Paradiso L. Formation of STAT5-containing DNA binding complexes in response to colony-stimulating factor-1 and platelet-derived growth factor. J Biol Chem 1996;271:18350-18354. https://doi.org/10.1074/jbc.271.31.18350
  44. Haan S, Keller JF, Behrmann I, Heinrich PC, Haan C. Multiple reasons for an inefficient STAT1 response upon IL-6-type cytokine stimulation. Cell Signal 2005;17:1542-1550. https://doi.org/10.1016/j.cellsig.2005.03.010
  45. Ben-Sasson SZ, Caucheteux S, Crank M, Hu-Li J, Paul WE. IL-1 acts on T cells to enhance the magnitude of in vivo immune responses. Cytokine 2011;56:122-125. https://doi.org/10.1016/j.cyto.2011.07.006
  46. Santarlasci V, Cosmi L, Maggi L, Liotta F, Annunziato F. IL-1 and T helper immune responses. Front Immunol 2013;4:182.
  47. Lee PH, Yamamoto TN, Gurusamy D, Sukumar M, Yu Z, Hu-Li J, Kawabe T, Gangaplara A, Kishton RJ, Henning AN, et al. Host conditioning with IL-1β improves the antitumor function of adoptively transferred T cells. J Exp Med 2019;216:2619-2634. https://doi.org/10.1084/jem.20181218
  48. Sarkar S, Yuzefpolskiy Y, Xiao H, Baumann FM, Yim S, Lee DJ, Schenten D, Kalia V. Programming of CD8 T cell quantity and polyfunctionality by direct IL-1 signals. J Immunol 2018;201:3641-3650. https://doi.org/10.4049/jimmunol.1800906
  49. Bartholdy C, Christensen JE, Grujic M, Christensen JP, Thomsen AR. T-cell intrinsic expression of MyD88 is required for sustained expansion of the virus-specific CD8+ T-cell population in LCMV-infected mice. J Gen Virol 2009;90:423-431. https://doi.org/10.1099/vir.0.004960-0
  50. Luckel C, Picard FS, Huber M. Tc17 biology and function: novel concepts. Eur J Immunol 2020;50:1257-1267. https://doi.org/10.1002/eji.202048627
  51. Srenathan U, Steel K, Taams LS. IL-17+ CD8+ T cells: differentiation, phenotype and role in inflammatory disease. Immunol Lett 2016;178:20-26. https://doi.org/10.1016/j.imlet.2016.05.001
  52. Hamada H, Garcia-Hernandez ML, Reome JB, Misra SK, Strutt TM, McKinstry KK, Cooper AM, Swain SL, Dutton RW. Tc17, a unique subset of CD8 T cells that can protect against lethal influenza challenge. J Immunol 2009;182:3469-3481. https://doi.org/10.4049/jimmunol.0801814
  53. Naik S, Bouladoux N, Linehan JL, Han SJ, Harrison OJ, Wilhelm C, Conlan S, Himmelfarb S, Byrd AL, Deming C, et al. Commensal-dendritic-cell interaction specifies a unique protective skin immune signature. Nature 2015;520:104-108. https://doi.org/10.1038/nature14052
  54. Nanjappa SG, McDermott AJ, Fites JS, Galles K, Wuthrich M, Deepe GS Jr, Klein BS. Antifungal Tc17 cells are durable and stable, persisting as long-lasting vaccine memory without plasticity towards IFNγ cells. PLoS Pathog 2017;13:e1006356.
  55. Huber M, Heink S, Pagenstecher A, Reinhard K, Ritter J, Visekruna A, Guralnik A, Bollig N, Jeltsch K, Heinemann C, et al. IL-17A secretion by CD8+ T cells supports Th17-mediated autoimmune encephalomyelitis. J Clin Invest 2013;123:247-260. https://doi.org/10.1172/JCI63681
  56. Cheuk S, Schlums H, Gallais Serezal I, Martini E, Chiang SC, Marquardt N, Gibbs A, Detlofsson E, Introini A, Forkel M, et al. CD49a expression defines tissue-resident CD8+ T cells poised for cytotoxic function in human skin. Immunity 2017;46:287-300. https://doi.org/10.1016/j.immuni.2017.01.009
  57. Kuen DS, Kim BS, Chung Y. IL-17-producing cells in tumor immunity: Friends or foes? Immune Netw 2020;20:e6.
  58. Zhuang Y, Peng LS, Zhao YL, Shi Y, Mao XH, Chen W, Pang KC, Liu XF, Liu T, Zhang JY, et al. CD8(+) T cells that produce interleukin-17 regulate myeloid-derived suppressor cells and are associated with survival time of patients with gastric cancer. Gastroenterology 2012;143:951-962.e8. https://doi.org/10.1053/j.gastro.2012.06.010
  59. Hinrichs CS, Kaiser A, Paulos CM, Cassard L, Sanchez-Perez L, Heemskerk B, Wrzesinski C, Borman ZA, Muranski P, Restifo NP. Type 17 CD8+ T cells display enhanced antitumor immunity. Blood 2009;114:596-599. https://doi.org/10.1182/blood-2009-02-203935
  60. Kim BS, Kuen DS, Koh CH, Kim HD, Chang SH, Kim S, Jeon YK, Park YJ, Choi G, Kim J, et al. Type 17 immunity promotes the exhaustion of CD8+ T cells in cancer. J Immunother Cancer 2021;9:e002603.
  61. Chen HW, Tsai JP, Yao TY, Hsieh CL, Chen IH, Liu SJ. TGF-β and IL-21 cooperatively stimulate activated CD8(+) T cells to differentiate into Tc17 cells. Immunol Lett 2016;174:23-27. https://doi.org/10.1016/j.imlet.2016.04.006
  62. Karnowski A, Chevrier S, Belz GT, Mount A, Emslie D, D'Costa K, Tarlinton DM, Kallies A, Corcoran LM. B and T cells collaborate in antiviral responses via IL-6, IL-21, and transcriptional activator and coactivator, Oct2 and OBF-1. J Exp Med 2012;209:2049-2064. https://doi.org/10.1084/jem.20111504
  63. Xin G, Schauder DM, Lainez B, Weinstein JS, Dai Z, Chen Y, Esplugues E, Wen R, Wang D, Parish IA, et al. A critical role of IL-21-induced BATF in sustaining CD8-T-cell-mediated chronic viral control. Cell Reports 2015;13:1118-1124. https://doi.org/10.1016/j.celrep.2015.09.069
  64. Kratchmarov R, Magun AM, Reiner SL. TCF1 expression marks self-renewing human CD8+ T cells. Blood Adv 2018;2:1685-1690. https://doi.org/10.1182/bloodadvances.2018016279
  65. Tian Y, Zajac AJ. Il-21 and T cell differentiation: consider the context. Trends Immunol 2016;37:557-568. https://doi.org/10.1016/j.it.2016.06.001
  66. Yi JS, Ingram JT, Zajac AJ. IL-21 deficiency influences CD8 T cell quality and recall responses following an acute viral infection. J Immunol 2010;185:4835-4845. https://doi.org/10.4049/jimmunol.1001032