Influence of Interferon-${\gamma}$ Deficiency in Immune Tolerance Induced by Male Islet Transplantation

  • Kim, Yong-Hee (Department of Microbiology and Immunology, Seoul National University College of Medicine) ;
  • Lim, Young-Kyoung (Department of Microbiology and Immunology, Seoul National University College of Medicine) ;
  • Park, Chung-Gyu (Department of Microbiology and Immunology, Seoul National University College of Medicine)
  • Received : 2011.10.04
  • Accepted : 2011.10.25
  • Published : 2011.12.31


Background: Traditionally, interferon-${\gamma}$ (IFN-${\gamma}$) was regarded as a pro-inflammatory cytokine, however, recent reports suggested role of IFN-${\gamma}$ in immune tolerance. In our previous report, we could induce tolerance to male antigen (HY) just by male islet transplantation in wild type C57BL/6 mice without any immunological intervention. We tried to investigate the influence of IFN-${\gamma}$ deficiency on tolerance induction by male islet transplantation. Methods: To examine the immunogenicity of male tissue in the absence of IFN-${\gamma}$, we transplanted male IFN-${\gamma}$ knock-out (KO) skin to female IFN-${\gamma}$ KO mice. Next, we analyzed male IFN-${\gamma}$ KO islet to streptozotocin-induced diabetic female IFN-${\gamma}$ KO mice. And, we checked the functionality of grafted islet by graft removal and insulin staining. Results: As our previous results in wild type C57BL/6 mice, female IFN-${\gamma}$ KO mice rejected male IFN-${\gamma}$ KO skin within 29 days, and did not reject male IFN-${\gamma}$ KO islet. The maintenance of normal blood glucose level was dependent on the presence of grafted male islet. And the male islet recipient did not reject 2nd challenge of male islet graft also. Conclusion: Deficiency of IFN-${\gamma}$ does not have influence on the result of male skin graft and male islet transplantation. Conclusively, male islet transplantation induced T cell tolerance is not dependent on the presence of IFN-${\gamma}$.


  1. Millrain M, Chandler P, Dazzi F, Scott D, Simpson E, Dyson PJ: Examination of HY response: T cell expansion, immunodominance, and cross-priming revealed by HY tetramer analysis. J Immunol 167;3756-3764, 2001.
  2. Simpson E, Scott D, Chandler P: The male-specific histocompatibility antigen, H-Y: a history of transplantation, immune response genes, sex determination and expression cloning. Annu Rev Immunol 15;39-61, 1997.
  3. Yoon IH, Choi SE, Kim YH, Yang SH, Park JH, Park CS, Kim Y, Kim JS, Kim SJ, Simpson E, Park CG: Pancreatic islets induce CD4(+) [corrected] CD25(-)Foxp3(+) [corrected] T-cell regulated tolerance to HY-mismatched skin grafts. Transplantation 86;1352-1360, 2008.
  4. Kelchtermans H, Billiau A, Matthys P: How interferon-gamma keeps autoimmune diseases in check. Trends Immunol 29;479-486, 2008.
  5. Manoury-Schwartz B, Chiocchia G, Bessis N, Abehsira-Amar O, Batteux F, Muller S, Huang S, Boissier MC, Fournier C: High susceptibility to collagen-induced arthritis in mice lacking IFN-gamma receptors. J Immunol 158;5501-5506, 1997.
  6. Vermeire K, Heremans H, Vandeputte M, Huang S, Billiau A, Matthys P: Accelerated collagen-induced arthritis in IFNgamma receptor-deficient mice. J Immunol 158; 5507- 5513, 1997.
  7. Billiau A, Heremans H, Vandekerckhove F, Dijkmans R, Sobis H, Meulepas E, Carton H: Enhancement of experimental allergic encephalomyelitis in mice by antibodies against IFNgamma. J Immunol 140;1506-1510, 1988.
  8. Caspi RR, Chan CC, Grubbs BG, Silver PB, Wiggert B, Parsa CF, Bahmanyar S, Billiau A, Heremans H: Endogenous systemic IFN-gamma has a protective role against ocular autoimmunity in mice. J Immunol 152;890-899, 1994.
  9. Eriksson U, Kurrer MO, Sebald W, Brombacher F, Kopf M: Dual role of the IL-12/IFN-gamma axis in the development of autoimmune myocarditis: induction by IL-12 and protection by IFN-gamma. J Immunol 167;5464-5469, 2001.
  10. Ferber IA, Brocke S, Taylor-Edwards C, Ridgway W, Dinisco C, Steinman L, Dalton D, Fathman CG: Mice with a disrupted IFN-gamma gene are susceptible to the induction of experimental autoimmune encephalomyelitis (EAE). J Immunol 156;5-7, 1996.
  11. Jones LS, Rizzo LV, Agarwal RK, Tarrant TK, Chan CC, Wiggert B, Caspi RR: IFN-gamma-deficient mice develop experimental autoimmune uveitis in the context of a deviant effector response. J Immunol 158;5997-6005, 1997.
  12. Ring GH, Dai Z, Saleem S, Baddoura FK, Lakkis FG: Increased susceptibility to immunologically mediated glomerulonephritis in IFN-gamma-deficient mice. J Immunol 163; 2243-2248, 1999.
  13. Willenborg DO, Fordham S, Bernard CC, Cowden WB, Ramshaw IA: IFN-gamma plays a critical down-regulatory role in the induction and effector phase of myelin oligodendrocyte glycoprotein-induced autoimmune encephalomyelitis. J Immunol 157;3223-3227, 1996.
  14. Nishibori T, Tanabe Y, Su L, David M: Impaired development of $CD4^{+}$ $CD25^{+}$ regulatory T cells in the absence of STAT1: increased susceptibility to autoimmune disease. J Exp Med 199;25-34, 2004.
  15. Wang Z, Hong J, Sun W, Xu G, Li N, Chen X, Liu A, Xu L, Sun B, Zhang JZ: Role of IFN-gamma in induction of Foxp3 and conversion of CD4+ CD25- T cells to CD4+ Tregs. J Clin Invest 116;2434-2441, 2006.
  16. Hong J, Li N, Zhang X, Zheng B, Zhang JZ: Induction of $CD4^{+}$$CD25^{+}$ regulatory T cells by copolymer-I through activation of transcription factor Foxp3. Proc Natl Acad Sci U S A 102;6449-6454, 2005.
  17. Feng G, Gao W, Strom TB, Oukka M, Francis RS, Wood KJ, Bushell A: Exogenous IFN-gamma ex vivo shapes the alloreactive T-cell repertoire by inhibition of Th17 responses and generation of functional $Foxp3^{+}$ regulatory T cells. Eur J Immunol 38;2512-2527, 2008.
  18. Sawitzki B, Kingsley CI, Oliveira V, Karim M, Herber M, Wood KJ: IFN-gamma production by alloantigen-reactive regulatory T cells is important for their regulatory function in vivo. J Exp Med 201;1925-1935, 2005
  19. Fallarino F, Grohmann U, Hwang KW, Orabona C, Vacca C, Bianchi R, Belladonna ML, Fioretti MC, Alegre ML, Puccetti P: Modulation of tryptophan catabolism by regulatory T cells. Nat Immunol 4;1206-1212, 2003.
  20. Moffett JR, Namboodiri MA: Tryptophan and the immune response. Immunol Cell Biol 81;247-265, 2003.
  21. Mellor AL, Munn DH: IDO expression by dendritic cells: tolerance and tryptophan catabolism. Nat Rev Immunol 4;762-774, 2004.
  22. Nast CC, Zuo XJ, Prehn J, Danovitch GM, Wilkinson A, Jordan SC: Gamma-interferon gene expression in human renal allograft fine-needle aspirates. Transplantation 57;498-502, 1994.
  23. Cobbold SP, Castejon R, Adams E, Zelenika D, Graca L, Humm S, Waldmann H: Induction of foxP3+ regulatory T cells in the periphery of T cell receptor transgenic mice tolerized to transplants. J Immunol 172;6003-6010, 2004
  24. Lechler RI, Garden OA, Turka LA: The complementary roles of deletion and regulation in transplantation tolerance. Nat Rev Immunol 3;147-158, 2003.
  25. Lechler RI, Garden OA, Turka LA: The complementary roles of deletion and regulation in transplantation tolerance. Nat Rev Immunol 3;147-158, 2003.
  26. Lechler RI, Garden OA, Turka LA: The complementary roles of deletion and regulation in transplantation tolerance. Nat Rev Immunol 3;147-158, 2003.
  27. Waldmann H, Cobbold S: Regulating the immune response to transplants. A role for CD4+ regulatory cells? Immunity 14;399-406, 2001.
  28. Zhang L, Yi H, Xia XP, Zhao Y: Transforming growth factor- beta: an important role in $CD4^{+}$$CD25^{+}$ regulatory T cells and immune tolerance. Autoimmunity 39;269-276, 2006.
  29. Tanaka K, Albin MJ, Yuan X, Yamaura K, Habicht A, Murayama T, Grimm M, Waaga AM, Ueno T, Padera RF, Yagita H, Azuma M, Shin T, Blazar BR, Rothstein DM, Sayegh MH, Najafian N: PDL1 is required for peripheral transplantation tolerance and protection from chronic allograft rejection. J Immunol 179;5204-5210, 2007.