BMB Reports

Korean Society for Biochemistry and Molecular Biology (생화학분자생물학회)
권호 표지
DOI QR코드

DOI QR Code

Emerging role of bystander T cell activation in autoimmune diseases

  • Shim, Chae-Hyeon (Department of Life Science, College of Natural Sciences, Hanyang University) ;
  • Cho, Sookyung (Department of Life Science, College of Natural Sciences, Hanyang University) ;
  • Shin, Young-Mi (Department of Life Science, College of Natural Sciences, Hanyang University) ;
  • Choi, Je-Min (Department of Life Science, College of Natural Sciences, Hanyang University)
  • Received : 2021.11.26
  • Accepted : 2022.01.10
  • Published : 2022.02.28
Download PDF
⟨ Previous Next ⟩

Abstract

Autoimmune disease is known to be caused by unregulated self-antigen-specific T cells, causing tissue damage. Although antigen specificity is an important mechanism of the adaptive immune system, antigen non-related T cells have been found in the inflamed tissues in various conditions. Bystander T cell activation refers to the activation of T cells without antigen recognition. During an immune response to a pathogen, bystander activation of self-reactive T cells via inflammatory mediators such as cytokines can trigger autoimmune diseases. Other antigen-specific T cells can also be bystander-activated to induce innate immune response resulting in autoimmune disease pathogenesis along with self-antigen-specific T cells. In this review, we summarize previous studies investigating bystander activation of various T cell types (NKT, γδ T cells, MAIT cells, conventional CD4+, and CD8+ T cells) and discuss the role of innate-like T cell response in autoimmune diseases. In addition, we also review previous findings of bystander T cell function in infection and cancer. A better understanding of bystander-activated T cells versus antigen-stimulated T cells provides a novel insight to control autoimmune disease pathogenesis.

Keywords

Acknowledgement

This research was supported by the Basic Science Research Program (NRF-2019R1A2C3006155) of the National Research Foundation funded by the Korean government.

References

  1. Kim J, Chang DY, Lee HW et al (2018) Innate-like cytotoxic function of bystander-activated CD8(+) T cells is associated with liver injury in acute hepatitis A. Immunity 48, 161-173.e165 https://doi.org/10.1016/j.immuni.2017.11.025
  2. Lee HG, Lee JU, Kim DH, Lim S, Kang I and Choi JM (2019) Pathogenic function of bystander-activated memory-like CD4(+) T cells in autoimmune encephalomyelitis. Nat Commun 10, 709 https://doi.org/10.1038/s41467-019-08482-w
  3. Simoni Y, Becht E, Fehlings M et al (2018) Bystander CD8(+) T cells are abundant and phenotypically distinct in human tumour infiltrates. Nature 557, 575-579 https://doi.org/10.1038/s41586-018-0130-2
  4. Tough DF, Borrow P and Sprent J (1996) Induction of bystander T cell proliferation by viruses and type I interferon in vivo. Science 272, 1947-1950 https://doi.org/10.1126/science.272.5270.1947
  5. Tough DF, Sun S and Sprent J (1997) T cell stimulation in vivo by lipopolysaccharide (LPS). J Exp Med 185, 2089-2094 https://doi.org/10.1084/jem.185.12.2089
  6. Gangappa S, Deshpande SP and Rouse BT (1999) Bystander activation of CD4(+) T cells can represent an exclusive means of immunopathology in a virus infection. Eur J Immunol 29, 3674-3682 https://doi.org/10.1002/(SICI)1521-4141(199911)29:11<3674::AID-IMMU3674>3.0.CO;2-7
  7. Yang HY, Dundon PL, Nahill SR and Welsh RM (1989) Virus-induced polyclonal cytotoxic T lymphocyte stimulation. J Immunol 142, 1710-1718
  8. Unutmaz D, Pileri P and Abrignani S (1994) Antigen-independent activation of naive and memory resting T cells by a cytokine combination. J Exp Med 180, 1159-1164 https://doi.org/10.1084/jem.180.3.1159
  9. Zarozinski CC and Welsh RM (1997) Minimal bystander activation of CD8 T cells during the virus-induced poly-clonal T cell response. J Exp Med 185, 1629-1639 https://doi.org/10.1084/jem.185.9.1629
  10. Murali-Krishna K, Altman JD, Suresh M et al (1998) Counting antigen-specific CD8 T cells: a reevaluation of bystander activation during viral infection. Immunity 8, 177-187 https://doi.org/10.1016/S1074-7613(00)80470-7
  11. Polley R, Zubairi S and Kaye PM (2005) The fate of heterologous CD4+ T cells during Leishmania donovani infection. Eur J Immunol 35, 498-504 https://doi.org/10.1002/eji.200425436
  12. Guo L, Wei G, Zhu J et al (2009) IL-1 family members and STAT activators induce cytokine production by Th2, Th17, and Th1 cells. Proc Natl Acad Sci U S A 106, 13463-13468 https://doi.org/10.1073/pnas.0906988106
  13. Guo L, Huang Y, Chen X, Hu-Li J, Urban JF Jr and Paul WE (2015) Innate immunological function of TH2 cells in vivo. Nat Immunol 16, 1051-1059 https://doi.org/10.1038/ni.3244
  14. Pellicci DG, Koay HF and Berzins SP (2020) Thymic development of unconventional T cells: how NKT cells, MAIT cells and γδ T cells emerge. Nat Rev Immunol 20, 756-770 https://doi.org/10.1038/s41577-020-0345-y
  15. Leite-De-Moraes MC, Hameg A, Arnould A et al (1999) A distinct IL-18-induced pathway to fully activate NK T lymphocytes independently from TCR engagement. J Immunol 163, 5871-5876
  16. Terashima A, Watarai H, Inoue S et al (2008) A novel subset of mouse NKT cells bearing the IL-17 receptor B responds to IL-25 and contributes to airway hyperreactivity. J Exp Med 205, 2727-2733 https://doi.org/10.1084/jem.20080698
  17. Doisne JM, Soulard V, Becourt C et al (2011) Cutting edge: crucial role of IL-1 and IL-23 in the innate IL-17 response of peripheral lymph node NK1.1- invariant NKT cells to bacteria. J Immunol 186, 662-666 https://doi.org/10.4049/jimmunol.1002725
  18. Ma R, Yuan D, Guo Y, Yan R and Li K (2020) Immune effects of γδ T cells in colorectal cancer: a review. Front Immunol 11, 1600 https://doi.org/10.3389/fimmu.2020.01600
  19. Haas JD, Gonzalez FH, Schmitz S et al (2009) CCR6 and NK1.1 distinguish between IL-17A and IFN-gamma-producing gammadelta effector T cells. Eur J Immunol 39, 3488-3497 https://doi.org/10.1002/eji.200939922
  20. Kjer-Nielsen L, Patel O, Corbett AJ et al (2012) MR1 presents microbial vitamin B metabolites to MAIT cells. Nature 491, 717-723 https://doi.org/10.1038/nature11605
  21. Ussher JE, Bilton M, Attwod E et al (2014) CD161++ CD8+ T cells, including the MAIT cell subset, are specifically activated by IL-12+IL-18 in a TCR-independent manner. Eur J Immunol 44, 195-203 https://doi.org/10.1002/eji.201343509
  22. van Wilgenburg B, Scherwitzl I, Hutchinson EC et al (2016) MAIT cells are activated during human viral infections. Nat Commun 7, 11653 https://doi.org/10.1038/ncomms11653
  23. Swain SL, Hu H and Huston G (1999) Class II-independent generation of CD4 memory T cells from effectors. Science 286, 1381-1383 https://doi.org/10.1126/science.286.5443.1381
  24. Eberl G, Brawand P and MacDonald HR (2000) Selective bystander proliferation of memory CD4+ and CD8+ T cells upon NK T or T cell activation. J Immunol 165, 4305-4311 https://doi.org/10.4049/jimmunol.165.8.4305
  25. Chakir H, Lam DK, Lemay AM and Webb JR (2003) "Bystander polarization" of CD4+ T cells: activation with high-dose IL-2 renders naive T cells responsive to IL-12 and/or IL-18 in the absence of TCR ligation. Eur J Immunol 33, 1788-1798 https://doi.org/10.1002/eji.200323398
  26. Chung Y, Chang SH, Martinez GJ et al (2009) Critical regulation of early Th17 cell differentiation by interleukin-1 signaling. Immunity 30, 576-587 https://doi.org/10.1016/j.immuni.2009.02.007
  27. Ben-Sasson SZ, Caucheteux S, Crank M, Hu-Li J and Paul WE (2011) IL-1 acts on T cells to enhance the magnitude of in vivo immune responses. Cytokine 56, 122-125 https://doi.org/10.1016/j.cyto.2011.07.006
  28. Lee YK, Landuyt AE, Lobionda S, Sittipo P, Zhao Q and Maynard CL (2017) TCR-independent functions of Th17 cells mediated by the synergistic actions of cytokines of the IL-12 and IL-1 families. PLoS One 12, e0186351 https://doi.org/10.1371/journal.pone.0186351
  29. Jiang W, Younes SA, Funderburg NT et al (2014) Cycling memory CD4+ T cells in HIV disease have a diverse T cell receptor repertoire and a phenotype consistent with bystander activation. J Virol 88, 5369-5380 https://doi.org/10.1128/JVI.00017-14
  30. van Aalst S, Ludwig IS, van der Zee R, van Eden W and Broere F (2017) Bystander activation of irrelevant CD4+ T cells following antigen-specific vaccination occurs in the presence and absence of adjuvant. PLoS One 12, e0177365 https://doi.org/10.1371/journal.pone.0177365
  31. Zhang X, Sun S, Hwang I, Tough DF and Sprent J (1998) Potent and selective stimulation of memory-phenotype CD8+ T cells in vivo by IL-15. Immunity 8, 591-599 https://doi.org/10.1016/S1074-7613(00)80564-6
  32. Lu J, Giuntoli RL 2nd, Omiya R, Kobayashi H, Kennedy R and Celis E (2002) Interleukin 15 promotes antigen-independent in vitro expansion and long-term survival of antitumor cytotoxic T lymphocytes. Clin Cancer Res 8, 3877-3884
  33. Tietze JK, Wilkins DE, Sckisel GD et al (2012) Delineation of antigen-specific and antigen-nonspecific CD8(+) memory T-cell responses after cytokine-based cancer immunotherapy. Blood 119, 3073-3083 https://doi.org/10.1182/blood-2011-07-369736
  34. Chu T, Tyznik AJ, Roepke S et al (2013) Bystander-activated memory CD8 T cells control early pathogen load in an innate-like, NKG2D-dependent manner. Cell Rep 3, 701-708 https://doi.org/10.1016/j.celrep.2013.02.020
  35. Crosby EJ, Goldschmidt MH, Wherry EJ and Scott P (2014) Engagement of NKG2D on bystander memory CD8 T cells promotes increased immunopathology following Leishmania major infection. PLoS Pathog 10, e1003970 https://doi.org/10.1371/journal.ppat.1003970
  36. Younes SA, Freeman ML, Mudd JC et al (2016) IL-15 promotes activation and expansion of CD8+ T cells in HIV-1 infection. J Clin Invest 126, 2745-2756 https://doi.org/10.1172/jci85996
  37. Seo IH, Eun HS, Kim JK et al (2021) IL-15 enhances CCR5-mediated migration of memory CD8(+) T cells by upregulating CCR5 expression in the absence of TCR stimulation. Cell Rep 36, 109438 https://doi.org/10.1016/j.celrep.2021.109438
  38. Lees JR, Sim J and Russell JH (2010) Encephalitogenic T-cells increase numbers of CNS T-cells regardless of antigen specificity by both increasing T-cell entry and preventing egress. J Neuroimmunol 220, 10-16 https://doi.org/10.1016/j.jneuroim.2009.11.017
  39. Walsh JT, Hendrix S, Boato F et al (2015) MHCII-independent CD4+ T cells protect injured CNS neurons via IL-4. J Clin Invest 125, 699-714 https://doi.org/10.1172/JCI76210
  40. Van Kaer L, Postoak JL, Wang C, Yang G and Wu L (2019) Innate, innate-like and adaptive lymphocytes in the pathogenesis of MS and EAE. Cell Mol Immunol 16, 531-539 https://doi.org/10.1038/s41423-019-0221-5
  41. Jones RE, Kay T, Keller T and Bourdette D (2003) Nonmyelinspecific T cells accelerate development of central nervous system APC and increase susceptibility to experimental autoimmune encephalomyelitis. J Immunol 170, 831-837 https://doi.org/10.4049/jimmunol.170.2.831
  42. Reynolds JM, Pappu BP, Peng J et al (2010) Toll-like receptor 2 signaling in CD4(+) T lymphocytes promotes T helper 17 responses and regulates the pathogenesis of autoimmune disease. Immunity 32, 692-702 https://doi.org/10.1016/j.immuni.2010.04.010
  43. Reynolds JM, Martinez GJ, Chung Y and Dong C (2012) Toll-like receptor 4 signaling in T cells promotes autoimmune inflammation. Proc Natl Acad Sci U S A 109, 13064-13069 https://doi.org/10.1073/pnas.1120585109
  44. Ferreira TB, Hygino J, Wing AC et al (2018) Different interleukin-17-secreting Toll-like receptor(+) T-cell subsets are associated with disease activity in multiple sclerosis. Immunology 154, 239-252 https://doi.org/10.1111/imm.12872
  45. Nogai A, Siffrin V, Bonhagen K et al (2005) Lipopolysaccharide injection induces relapses of experimental autoimmune encephalomyelitis in nontransgenic mice via bystander activation of autoreactive CD4+ cells. J Immunol 175, 959-966 https://doi.org/10.4049/jimmunol.175.2.959
  46. Tan LC, Mowat AG, Fazou C et al (2000) Specificity of T cells in synovial fluid: high frequencies of CD8(+) T cells that are specific for certain viral epitopes. Arthritis Res 2, 154-164 https://doi.org/10.1186/ar80
  47. Kobayashi M, Yasui N, Ishimaru N, Arakaki R and Hayashi Y (2004) Development of autoimmune arthritis with aging via bystander T cell activation in the mouse model of Sjogren's syndrome. Arthritis Rheum 50, 3974-3984 https://doi.org/10.1002/art.20679
  48. Sobek V, Birkner N, Falk I et al (2004) Direct Toll-like receptor 2 mediated co-stimulation of T cells in the mouse system as a basis for chronic inflammatory joint disease. Arthritis Res Ther 6, R433-446 https://doi.org/10.1186/ar1212
  49. Brennan FM, Smith NM, Owen S et al (2008) Resting CD4+ effector memory T cells are precursors of bystander-activated effectors: a surrogate model of rheumatoid arthritis synovial T-cell function. Arthritis Res Ther 10, R36 https://doi.org/10.1186/ar2390
  50. Horwitz MS, Bradley LM, Harbertson J, Krahl T, Lee J and Sarvetnick N (1998) Diabetes induced by Coxsackie virus: initiation by bystander damage and not molecular mimicry. Nat Med 4, 781-785 https://doi.org/10.1038/nm0798-781
  51. Pane JA and Coulson BS (2015) Lessons from the mouse: potential contribution of bystander lymphocyte activation by viruses to human type 1 diabetes. Diabetologia 58, 1149-1159 https://doi.org/10.1007/s00125-015-3562-3
  52. Simoni Y, Gautron AS, Beaudoin L et al (2011) NOD mice contain an elevated frequency of iNKT17 cells that exacerbate diabetes. Eur J Immunol 41, 3574-3585 https://doi.org/10.1002/eji.201141751
  53. Markle JG, Mortin-Toth S, Wong AS, Geng L, Hayday A and Danska JS (2013) γδ T cells are essential effectors of type 1 diabetes in the nonobese diabetic mouse model. J Immunol 190, 5392-5401 https://doi.org/10.4049/jimmunol.1203502
  54. Rouxel O, Da Silva J, Beaudoin L et al (2017) Cytotoxic and regulatory roles of mucosal-associated invariant T cells in type 1 diabetes. Nat Immunol 18, 1321-1331 https://doi.org/10.1038/ni.3854
  55. Lertmemongkolchai G, Cai G, Hunter CA and Bancroft GJ (2001) Bystander activation of CD8+ T cells contributes to the rapid production of IFN-gamma in response to bacterial pathogens. J Immunol 166, 1097-1105 https://doi.org/10.4049/jimmunol.166.2.1097
  56. Doisne JM, Urrutia A, Lacabaratz-Porret C et al (2004) CD8+ T cells specific for EBV, cytomegalovirus, and influenza virus are activated during primary HIV infection. J Immunol 173, 2410-2418 https://doi.org/10.4049/jimmunol.173.4.2410
  57. Bastidas S, Graw F, Smith MZ, Kuster H, Gunthard HF and Oxenius A (2014) CD8+ T cells are activated in an antigen-independent manner in HIV-infected individuals. J Immunol 192, 1732-1744 https://doi.org/10.4049/jimmunol.1302027
  58. Nakamura R, Maeda N, Shibata K, Yamada H, Kase T and Yoshikai Y (2010) Interleukin-15 is critical in the pathogenesis of influenza a virus-induced acute lung injury. J Virol 84, 5574-5582 https://doi.org/10.1128/JVI.02030-09
  59. Gregorova M, Morse D, Brignoli T et al (2020) Post-acute COVID-19 associated with evidence of bystander T-cell activation and a recurring antibiotic-resistant bacterial pneumonia. Elife 9, e63430 https://doi.org/10.7554/eLife.63430
  60. Joncker NT, Marloie MA, Chernysheva A et al (2006) Antigen-independent accumulation of activated effector/memory T lymphocytes into human and murine tumors. Int J Cancer 118, 1205-1214 https://doi.org/10.1002/ijc.21472
  61. Duhen T, Duhen R, Montler R et al (2018) Co-expression of CD39 and CD103 identifies tumor-reactive CD8 T cells in human solid tumors. Nat Commun 9, 2724 https://doi.org/10.1038/s41467-018-05072-0
  62. Scheper W, Kelderman S, Fanchi LF et al (2019) Low and variable tumor reactivity of the intratumoral TCR repertoire in human cancers. Nat Med 25, 89-94 https://doi.org/10.1038/s41591-018-0266-5
  63. Ponzetta A, Carriero R, Carnevale S et al (2019) Neutrophils driving unconventional T cells mediate resistance against murine sarcomas and selected human tumors. Cell 178, 346-360.e324 https://doi.org/10.1016/j.cell.2019.05.047
  64. Rosato PC, Wijeyesinghe S, Stolley JM et al (2019) Virusspecific memory T cells populate tumors and can be repurposed for tumor immunotherapy. Nat Commun 10, 567 https://doi.org/10.1038/s41467-019-08534-1
  65. Danahy DB, Berton RR and Badovinac VP (2020) Cutting edge: antitumor immunity by pathogen-specific CD8 T cells in the absence of cognate antigen recognition. J Immunol 204, 1431-1435 https://doi.org/10.4049/jimmunol.1901172
  66. Newman JH, Chesson CB, Herzog NL et al (2020) Intratumoral injection of the seasonal flu shot converts immunologically cold tumors to hot and serves as an immunotherapy for cancer. Proc Natl Acad Sci U S A 117, 1119-1128 https://doi.org/10.1073/pnas.1904022116