Skip to main content

Advertisement

SpringerLink
Log in

A Distinct Role of CD4+ Th17- and Th17-Stimulated CD8+ CTL in the Pathogenesis of Type 1 Diabetes and Experimental Autoimmune Encephalomyelitis

  • Published:
Journal of Clinical Immunology Aims and scope Submit manuscript

Abstract

Both CD4+ Th17-cells and CD8+ cytotoxic T lymphocytes (CTLs) are involved in type 1 diabetes and experimental autoimmune encephalomyelitis (EAE). However, their relationship in pathogenesis of these autoimmune diseases is still elusive. We generated ovalbumin (OVA)- or myelin oligodendrocyte glycoprotein (MOG)-specific Th17 cells expressing RORγt and IL-17 by in vitro co-culturing OVA-pulsed and MOG35-55 peptide-pulsed dendritic cells (DCOVA and DCMOG) with CD4+ T cells derived from transgenic OTII and MOG-T cell receptor mice, respectively. We found that these Th17 cells when transferred into C57BL/6 mice stimulated OVA- and MOG-specific CTL responses, respectively. To assess the above question, we adoptively transferred OVA-specific Th17 cells into transgenic rat insulin promoter (RIP)-mOVA mice or RIP-mOVA mice treated with anti-CD8 antibody to deplete Th17-stimulated CD8+ T cells. We demonstrated that OVA-specific Th17-stimulated CTLs, but not Th17 cells themselves, induced diabetes in RIP-mOVA. We also transferred MOG-specific Th17 cells into C57BL/6 mice and H-2Kb−/− mice lacking of the ability to generate Th17-stimulated CTLs. We further found that MOG-specific Th17 cells, but not Th17-activated CTLs induced EAE in C57BL/6 mice. Taken together, our data indicate a distinct role of Th17 cells and Th17-stimulated CTLs in the pathogenesis of TID and EAE, which may have great impact on the overall understanding of Th17 cells in the pathogenesis of autoimmune diseases.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6

Similar content being viewed by others

References

  1. Dong C. TH17 cells in development: an updated view of their molecular identity and genetic programming. Nat Rev Immunol. 2008;8:337–48.

    Article  PubMed  CAS  Google Scholar 

  2. Weaver CT, Harrington LE, Mangan PR, Gavrieli M, Murphy KM. Th17: an effector CD4 T cell lineage with regulatory T cell ties. Immunity. 2006;24:677–88.

    Article  PubMed  CAS  Google Scholar 

  3. Bettelli E, Korn T, Kuchroo VK. Th17: the third member of the effector T cell trilogy. Curr Opin Immunol. 2007;19:652–7.

    Article  PubMed  CAS  Google Scholar 

  4. Steinman L. A brief history of T(H)17, the first major revision in the T(H)1/T(H)2 hypothesis of T cell-mediated tissue damage. Nat Med. 2007;13:139–45.

    Article  PubMed  CAS  Google Scholar 

  5. Ivanov II, McKenzie BS, Zhou L, Tadokoro CE, Lepelley A, Lafaille JJ, et al. The orphan nuclear receptor RORgammat directs the differentiation program of proinflammatory IL-17+ T helper cells. Cell. 2006;126:1121–33.

    Article  PubMed  CAS  Google Scholar 

  6. Fukushima T, Zapata JM, Singha NC, Thomas M, Kress CL, Krajewska M, et al. Critical function for SIP, a ubiquitin E3 ligase component of the beta-catenin degradation pathway, for thymocyte development and G1 checkpoint. Immunity. 2006;24:29–39.

    Article  PubMed  CAS  Google Scholar 

  7. Veldhoen M, Hocking RJ, Atkins CJ, Locksley RM, Stockinger B. TGFbeta in the context of an inflammatory cytokine milieu supports de novo differentiation of IL-17-producing T cells. Immunity. 2006;24:179–89.

    Article  PubMed  CAS  Google Scholar 

  8. Mangan PR, Harrington LE, O’Quinn DB, Helms WS, Bullard DC, Elson CO, et al. Transforming growth factor-beta induces development of the T(H)17 lineage. Nature. 2006;441:231–4.

    Article  PubMed  CAS  Google Scholar 

  9. Korn T, Bettelli E, Gao W, Awasthi A, Jager A, Strom TB, et al. IL-21 initiates an alternative pathway to induce proinflammatory T(H)17 cells. Nature. 2007;448:484–7.

    Article  PubMed  CAS  Google Scholar 

  10. Zhou L, Ivanov II, Spolski R, Min R, Shenderov K, Egawa T, et al. IL-6 programs T(H)-17 cell differentiation by promoting sequential engagement of the IL-21 and IL-23 pathways. Nat Immunol. 2007;8:967–74.

    Article  PubMed  CAS  Google Scholar 

  11. Peck A, Mellins ED. Plasticity of T-cell phenotype and function: the T helper type 17 example. Immunology. 2010;129:147–53.

    Article  PubMed  CAS  Google Scholar 

  12. Taplin CE, Barker JM. Autoantibodies in type 1 diabetes. Autoimmunity. 2008;41:11–8.

    Article  PubMed  CAS  Google Scholar 

  13. Di Lorenzo TP, Peakman M, Roep BO. Translational mini-review series on type 1 diabetes: systematic analysis of T cell epitopes in autoimmune diabetes. Clin Exp Immunol. 2007;148:1–16.

    Article  PubMed  Google Scholar 

  14. Kay TW, Parker JL, Stephens LA, Thomas HE, Allison J. RIP-beta 2-microglobulin transgene expression restores insulitis, but not diabetes, in beta 2-microglobulin null nonobese diabetic mice. J Immunol. 1996;157:3688–93.

    PubMed  Google Scholar 

  15. Serreze DV, Gallichan WS, Snider DP, Croitoru K, Rosenthal KL, Leiter EH, et al. MHC class I-mediated antigen presentation and induction of CD8+ cytotoxic T-cell responses in autoimmune diabetes-prone NOD mice. Diabetes. 1996;45:902–8.

    Article  PubMed  CAS  Google Scholar 

  16. Wang B, Gonzalez A, Benoist C, Mathis D. The role of CD8+ T cells in the initiation of insulin-dependent diabetes mellitus. Eur J Immunol. 1996;26:1762–9.

    Article  PubMed  CAS  Google Scholar 

  17. Vukkadapu SS, Belli JM, Ishii K, Jegga AG, Hutton JJ, Aronow BJ, et al. Dynamic interaction between T cell-mediated beta-cell damage and beta-cell repair in the run up to autoimmune diabetes of the NOD mouse. Physiol Genomics. 2005;21:201–11.

    Article  PubMed  CAS  Google Scholar 

  18. Jain R, Tartar DM, Gregg RK, Divekar RD, Bell JJ, Lee HH, et al. Innocuous IFNgamma induced by adjuvant-free antigen restores normoglycemia in NOD mice through inhibition of IL-17 production. J Exp Med. 2008;205:207–18.

    Article  PubMed  CAS  Google Scholar 

  19. Sawcer S, Jones HB, Feakes R, Gray J, Smaldon N, Chataway J, et al. A genome screen in multiple sclerosis reveals susceptibility loci on chromosome 6p21 and 17q22. Nat Genet. 1996;13:464–8.

    Article  PubMed  CAS  Google Scholar 

  20. Ebers GC, Kukay K, Bulman DE, Sadovnick AD, Rice G, Anderson C, et al. A full genome search in multiple sclerosis. Nat Genet. 1996;13:472–6.

    Article  PubMed  CAS  Google Scholar 

  21. Haines JL, Ter-Minassian M, Bazyk A, Gusella JF, Kim DJ, Terwedow H, et al. A complete genomic screen for multiple sclerosis underscores a role for the major histocompatability complex. The Multiple Sclerosis Genetics Group. Nat Genet. 1996;13:469–71.

    Article  PubMed  CAS  Google Scholar 

  22. Yang Y, Weiner J, Liu Y, Smith AJ, Huss DJ, Winger R, et al. T-bet is essential for encephalitogenicity of both Th1 and Th17 cells. J Exp Med. 2009;206:1549–64.

    Article  PubMed  CAS  Google Scholar 

  23. Sutton C, Brereton C, Keogh B, Mills KH, Lavelle EC. A crucial role for interleukin (IL)-1 in the induction of IL-17-producing T cells that mediate autoimmune encephalomyelitis. J Exp Med. 2006;203:1685–91.

    Article  PubMed  CAS  Google Scholar 

  24. Komiyama Y, Nakae S, Matsuki T, Nambu A, Ishigame H, Kakuta S, et al. IL-17 plays an important role in the development of experimental autoimmune encephalomyelitis. J Immunol. 2006;177:566–73.

    PubMed  CAS  Google Scholar 

  25. Bettelli E, Oukka M, Kuchroo VK. T(H)-17 cells in the circle of immunity and autoimmunity. Nat Immunol. 2007;8:345–50.

    Article  PubMed  CAS  Google Scholar 

  26. Stromnes IM, Cerretti LM, Liggitt D, Harris RA, Goverman JM. Differential regulation of central nervous system autoimmunity by T(H)1 and T(H)17 cells. Nat Med. 2008;14:337–42.

    Article  PubMed  CAS  Google Scholar 

  27. Tzartos JS, Friese MA, Craner MJ, Palace J, Newcombe J, Esiri MM, et al. Interleukin-17 production in central nervous system-infiltrating T cells and glial cells is associated with active disease in multiple sclerosis. Am J Pathol. 2008;172:146–55.

    Article  PubMed  CAS  Google Scholar 

  28. Ford ML, Evavold BD. Specificity, magnitude, and kinetics of MOG-specific CD8+ T cell responses during experimental autoimmune encephalomyelitis. Eur J Immunol. 2005;35:76–85.

    Article  PubMed  CAS  Google Scholar 

  29. Friese MA, Fugger L. Autoreactive CD8+ T cells in multiple sclerosis: a new target for therapy? Brain. 2005;128:1747–63.

    Article  PubMed  Google Scholar 

  30. Sun D, Zhang Y, Wei B, Peiper SC, Shao H, Kaplan HJ. Encephalitogenic activity of truncated myelin oligodendrocyte glycoprotein (MOG) peptides and their recognition by CD8+ MOG-specific T cells on oligomeric MHC class I molecules. Int Immunol. 2003;15:261–8.

    Article  PubMed  CAS  Google Scholar 

  31. Sun D, Whitaker JN, Huang Z, Liu D, Coleclough C, Wekerle H, et al. Myelin antigen-specific CD8+ T cells are encephalitogenic and produce severe disease in C57BL/6 mice. J Immunol. 2001;166:7579–87.

    PubMed  CAS  Google Scholar 

  32. Huseby ES, Liggitt D, Brabb T, Schnabel B, Ohlen C, Goverman J. A pathogenic role for myelin-specific CD8(+) T cells in a model for multiple sclerosis. J Exp Med. 2001;194:669–76.

    Article  PubMed  CAS  Google Scholar 

  33. Ahmed KA, Munegowda MA, Xie Y, Xiang J. Intercellular trogocytosis plays an important role in modulation of immune responses. Cell Mol Immunol. 2008;5:261–9.

    Article  PubMed  CAS  Google Scholar 

  34. Xiang J, Huang H, Liu Y. A new dynamic model of CD8+ T effector cell responses via CD4+ T helper-antigen-presenting cells. J Immunol. 2005;174:7497–505.

    PubMed  CAS  Google Scholar 

  35. Umeshappa CS, Huang H, Xie Y, Wei Y, Mulligan SJ, Deng Y, et al. CD4+ Th-APC with acquired peptide/MHC class I and II complexes stimulate type 1 helper CD4+ and central memory CD8+ T cell responses. J Immunol. 2009;182:193–206.

    PubMed  CAS  Google Scholar 

  36. Ye Z, Ahmed KA, Hao S, Zhang X, Xie Y, Munegowda MA, et al. Active CD4+ helper T cells directly stimulate CD8+ cytotoxic T lymphocyte responses in wild-type and MHC II gene knockout C57BL/6 mice and transgenic RIP-mOVA mice expressing islet beta-cell ovalbumin antigen leading to diabetes. Autoimmunity. 2008;41:501–11.

    Article  PubMed  CAS  Google Scholar 

  37. Ahmed KA, Xie Y, Zhang X, Xiang J. Acquired pMHC I complexes greatly enhance CD4(+) Th cell’s stimulatory effect on CD8(+) T cell-mediated diabetes in transgenic RIP-mOVA mice. Cell Mol Immunol. 2008;5:407–15.

    Article  PubMed  Google Scholar 

  38. Kurts C, Heath WR, Kosaka H, Miller JF, Carbone FR. The peripheral deletion of autoreactive CD8+ T cells induced by cross-presentation of self-antigens involves signaling through CD95 (Fas, Apo-1). J Exp Med. 1998;188:415–20.

    Article  PubMed  CAS  Google Scholar 

  39. Chen Z, Dehm S, Bonham K, Kamencic H, Juurlink B, Zhang X, et al. DNA array and biological characterization of the impact of the maturation status of mouse dendritic cells on their phenotype and antitumor vaccination efficacy. Cell Immunol. 2001;214:60–71.

    Article  PubMed  CAS  Google Scholar 

  40. Xia D, Hao S, Xiang J. CD8+ cytotoxic T-APC stimulate central memory CD8+ T cell responses via acquired peptide-MHC class I complexes and CD80 costimulation, and IL-2 secretion. J Immunol. 2006;177:2976–84.

    PubMed  CAS  Google Scholar 

  41. Xiang J, Moyana T. Cytotoxic CD4+ T cells associated with the expression of major histocompatibility complex class II antigen of mouse myeloma cells secreting interferon-gamma are cytolytic in vitro and tumoricidal in vivo. Cancer Gene Ther. 1998;5:313–20.

    PubMed  CAS  Google Scholar 

  42. Sas S, Chan T, Sami A, El-Gayed A, Xiang J. Vaccination of fiber-modified adenovirus-transfected dendritic cells to express HER-2/neu stimulates efficient HER-2/neu-specific humoral and CTL responses and reduces breast carcinogenesis in transgenic mice. Cancer Gene Ther. 2008;15:655–66.

    Article  PubMed  CAS  Google Scholar 

  43. Stockinger B, Veldhoen M. Differentiation and function of Th17 T cells. Curr Opin Immunol. 2007;19:281–6.

    Article  PubMed  CAS  Google Scholar 

  44. Atkinson MA, Eisenbarth GS. Type 1 diabetes: new perspectives on disease pathogenesis and treatment. Lancet. 2001;358:221–9.

    Article  PubMed  CAS  Google Scholar 

  45. Haskins K, Portas M, Bradley B, Wegmann D, Lafferty K. T-lymphocyte clone specific for pancreatic islet antigen. Diabetes. 1988;37:1444–8.

    Article  PubMed  CAS  Google Scholar 

  46. Jones EY, Fugger L, Strominger JL, Siebold C. MHC class II proteins and disease: a structural perspective. Nat Rev Immunol. 2006;6:271–82.

    Article  PubMed  CAS  Google Scholar 

  47. Faustman DL, Davis M. The primacy of CD8 T lymphocytes in type 1 diabetes and implications for therapies. J Mol Med. 2009;87:1173–8.

    Article  PubMed  CAS  Google Scholar 

  48. Katz JD, Benoist C, Mathis D. T helper cell subsets in insulin-dependent diabetes. Science. 1995;268:1185–8.

    Article  PubMed  CAS  Google Scholar 

  49. Bending D, De La Peña H, Veldhoen M, Phillips JM, Catherine U, Stockinger B, et al. Highly purified Th17 cells from BDC2.5NOD mice convert into Th1-like cells in NOD/SCID recipient mice. J Clin Invest. 2009;119.

  50. Faustman D, Li XP, Lin HY, Fu YE, Eisenbarth G, Avruch J, et al. Linkage of faulty major histocompatibility complex class I to autoimmune diabetes. Science. 1991;254:1756–61.

    Article  PubMed  CAS  Google Scholar 

  51. Yan G, Fu Y, Faustman DL. Reduced expression of Tap1 and Lmp2 antigen-processing genes in the nonobese diabetic (NOD) mouse due to a mutation in their shared bidirectional promoter. J Immunol. 1997;159:3068–80.

    PubMed  CAS  Google Scholar 

  52. Li F, Guo J, Fu Y, Yan G, Faustman D. Abnormal class I assembly and peptide presentation in the nonobese diabetic mouse. Proc Natl Acad Sci USA. 1994;91:11128–32.

    Article  PubMed  CAS  Google Scholar 

  53. Yan G, Shi L, Faustman D. Novel splicing of the human MHC-encoded peptide transporter confers unique properties. J Immunol. 1999;162:852–9.

    PubMed  CAS  Google Scholar 

  54. Qu HQ, Lu Y, Marchand L, Bacot F, Frechette R, Tessier MC, et al. Genetic control of alternative splicing in the TAP2 gene: possible implication in the genetics of type 1 diabetes. Diabetes. 2007;56:270–5.

    Article  PubMed  CAS  Google Scholar 

  55. Christianson SW, Shultz LD, Leiter EH. Adoptive transfer of diabetes into immunodeficient NOD-scid/scid mice. Relative contributions of CD4+ and CD8+ T-cells from diabetic versus prediabetic NOD.NON-Thy-1a donors. Diabetes. 1993;42:44–55.

    Article  PubMed  CAS  Google Scholar 

  56. Wong FS, Karttunen J, Dumont C, Wen L, Visintin I, Pilip IM, et al. Identification of an MHC class I-restricted autoantigen in type 1 diabetes by screening an organ-specific cDNA library. Nat Med. 1999;5:1026–31.

    Article  PubMed  CAS  Google Scholar 

  57. Martin-Orozco N, Chung Y, Chang SH, Wang YH, Dong C. Th17 cells promote pancreatic inflammation but only induce diabetes efficiently in lymphopenic hosts after conversion into Th1 cells. Eur J Immunol. 2009;39:216–24.

    Article  PubMed  CAS  Google Scholar 

  58. Pinkse GG, Tysma OH, Bergen CA, Kester MG, Ossendorp F, van Veelen PA, et al. Autoreactive CD8 T cells associated with beta cell destruction in type 1 diabetes. Proc Natl Acad Sci USA. 2005;102:18425–30.

    Article  PubMed  CAS  Google Scholar 

  59. Russell JH, Ley TJ. Lymphocyte-mediated cytotoxicity. Annu Rev Immunol. 2002;20:323–70.

    Article  PubMed  CAS  Google Scholar 

  60. Bolitho P, Voskoboinik I, Trapani JA, Smyth MJ. Apoptosis induced by the lymphocyte effector molecule perforin. Curr Opin Immunol. 2007;19:339–47.

    Article  PubMed  CAS  Google Scholar 

  61. Merkler D, Oertle T, Buss A, Pinschewer DD, Schnell L, Bareyre FM, et al. Rapid induction of autoantibodies against Nogo-A and MOG in the absence of an encephalitogenic T cell response: implication for immunotherapeutic approaches in neurological diseases. FASEB J. 2003;17:2275–7.

    PubMed  CAS  Google Scholar 

  62. Abdul-Majid KB, Wefer J, Stadelmann C, Stefferl A, Lassmann H, Olsson T, et al. Comparing the pathogenesis of experimental autoimmune encephalomyelitis in CD4−/− and CD8−/− DBA/1 mice defines qualitative roles of different T cell subsets. J Neuroimmunol. 2003;141:10–9.

    Article  PubMed  CAS  Google Scholar 

  63. Ishigame H, Kakuta S, Nagai T, Kadoki M, Nambu A, Komiyama Y, et al. Differential roles of interleukin-17A and -17 F in host defense against mucoepithelial bacterial infection and allergic responses. Immunity. 2009;30:108–19.

    Article  PubMed  CAS  Google Scholar 

  64. Kolls JK, Linden A. Interleukin-17 family members and inflammation. Immunity. 2004;21:467–76.

    Article  PubMed  CAS  Google Scholar 

  65. Park H, Li Z, Yang XO, Chang SH, Nurieva R, Wang YH, et al. A distinct lineage of CD4 T cells regulates tissue inflammation by producing interleukin 17. Nat Immunol. 2005;6:1133–41.

    Article  PubMed  CAS  Google Scholar 

  66. Furuzawa-Carballeda J, Vargas-Rojas MI, Cabral AR. Autoimmune inflammation from the Th17 perspective. Autoimmun Rev. 2007;6:169–75.

    Article  PubMed  CAS  Google Scholar 

  67. Guo B, Chang EY, Cheng G. The type I IFN induction pathway constrains Th17-mediated autoimmune inflammation in mice. J Clin Invest. 2008;118:1680–90.

    Article  PubMed  CAS  Google Scholar 

  68. Ando DG, Clayton J, Kono D, Urban JL, Sercarz EE. Encephalitogenic T cells in the B10.PL model of experimental allergic encephalomyelitis (EAE) are of the Th-1 lymphokine subtype. Cell Immunol. 1989;124:132–43.

    Article  PubMed  CAS  Google Scholar 

  69. Wensky AK, Furtado GC, Marcondes MC, Chen S, Manfra D, Lira SA, et al. IFN-gamma determines distinct clinical outcomes in autoimmune encephalomyelitis. J Immunol. 2005;174:1416–23.

    PubMed  CAS  Google Scholar 

  70. Cua DJ, Sherlock J, Chen Y, Murphy CA, Joyce B, Seymour B, et al. Interleukin-23 rather than interleukin-12 is the critical cytokine for autoimmune inflammation of the brain. Nature. 2003;421:744–8.

    Article  PubMed  CAS  Google Scholar 

  71. Langrish CL, Chen Y, Blumenschein WM, Mattson J, Basham B, Sedgwick JD, et al. IL-23 drives a pathogenic T cell population that induces autoimmune inflammation. J Exp Med. 2005;201:233–40.

    Article  PubMed  CAS  Google Scholar 

  72. O’Connor RA, Prendergast CT, Sabatos CA, Lau CW, Leech MD, Wraith DC, et al. Cutting edge: Th1 cells facilitate the entry of Th17 cells to the central nervous system during experimental autoimmune encephalomyelitis. J Immunol. 2008;181:3750–4.

    PubMed  Google Scholar 

  73. Jager A, Dardalhon V, Sobel RA, Bettelli E, Kuchroo VK. Th1, Th17, and Th9 effector cells induce experimental autoimmune encephalomyelitis with different pathological phenotypes. J Immunol. 2009;183:7169–77.

    Article  PubMed  Google Scholar 

  74. Axtell RC, de Jong BA, Boniface K, van der Voort LF, Bhat R, De Sarno P, et al. T helper type 1 and 17 cells determine efficacy of interferon-beta in multiple sclerosis and experimental encephalomyelitis. Nat Med. 2010;16:406–12.

    Article  PubMed  CAS  Google Scholar 

  75. Kikly K, Liu L, Na S, Sedgwick JD. The IL-23/Th(17) axis: therapeutic targets for autoimmune inflammation. Curr Opin Immunol. 2006;18:670–5.

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgment

This study was supported by Canadian Institute of Health Research (MOP 405674). Manjunatha Ankathatti Munegowda was supported by Dean’s Scholarship of University of Saskatchewan.

Author information

Authors and Affiliations

  1. Research Unit, Saskatchewan Cancer Agency, Department of Oncology, Saskatoon Cancer Center, 20 Campus Drive, Saskatoon, Saskatchewan, S7N 4H4, Canada

    Manjunatha Ankathatti Munegowda, Yulin Deng & Jim Xiang

  2. Department of Pathology, University of Saskatchewan, Saskatoon, Saskatchewan, Canada

    Manjunatha Ankathatti Munegowda, Rajni Chibbar, Qingyong Xu, Andrew Freywald & Jim Xiang

  3. Department of Physiology, University of Saskatchewan, Saskatoon, Saskatchewan, Canada

    Sean J. Mulligan

  4. Vaccine and Infectious Disease Organization, University of Saskatchewan, Saskatoon, Saskatchewan, Canada

    Sylvia van Drunen Littel-van den Hurk

  5. Doheny Eye Institute, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA

    Deming Sun

  6. Institute of Medical Sciences, Soocow University, Suzhou, China

    Sidong Xiong

Authors
  1. Manjunatha Ankathatti Munegowda
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Yulin Deng
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Rajni Chibbar
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Qingyong Xu
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Andrew Freywald
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Sean J. Mulligan
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Sylvia van Drunen Littel-van den Hurk
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Deming Sun
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Sidong Xiong
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Jim Xiang
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Jim Xiang.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Ankathatti Munegowda, M., Deng, Y., Chibbar, R. et al. A Distinct Role of CD4+ Th17- and Th17-Stimulated CD8+ CTL in the Pathogenesis of Type 1 Diabetes and Experimental Autoimmune Encephalomyelitis. J Clin Immunol 31, 811–826 (2011). https://doi.org/10.1007/s10875-011-9549-z

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10875-011-9549-z

Keywords

Search

Navigation