Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Article
  • Published:

Target cell defense prevents the development of diabetes after viral infection

Nature Immunology volume 3, pages 373–382 (2002)Cite this article

Abstract

The mechanisms that regulate susceptibility to virus-induced autoimmunity remain undefined. We establish here a fundamental link between the responsiveness of target pancreatic β cells to interferons (IFNs) and prevention of coxsackievirus B4 (CVB4)-induced diabetes. We found that an intact β cell response to IFNs was critical in preventing disease in infected hosts. The antiviral defense, raised by β cells in response to IFNs, resulted in a reduced permissiveness to infection and subsequent natural killer (NK) cell–dependent death. These results show that β cell defenses are critical for β cell survival during CVB4 infection and suggest an important role for IFNs in preserving NK cell tolerance to β cells during viral infection. Thus, alterations in target cell defenses can critically influence susceptibility to disease.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1: STAT1 is phosphorylated in insulin-producing cells after stimulation with IFNs.
Figure 2: SOCS-1 is expressed in pancreatic islets from SOCS-1–Tg NOD mice, but is absent in islets from non-Tg littermates.
Figure 3: An intact β cell response to IFNs is critical for the inhibition of CVB4 replication in vitro.
Figure 4: Acute onset of diabetes in SOCS-1–Tg NOD and NOD-SCID mice infected with CVB4.
Figure 5: Insulin-staining β cells are lost in SOCS-I–Tg NOD mice infected with CVB4.
Figure 6: The tropism of CVB4 for islet cells is altered when IFN signaling is perturbed.
Figure 7: CVB4 and insulin colocalize in the pancreatic islet cells of infected SOCS-1–Tg NOD mice.
Figure 8: Adaptive immunity is not necessary for the swift induction of diabetes in CVB4-infected SOCS-1–Tg NOD mice, but depletion of NK cells prevents diabetes development.
Figure 9: Depletion of NK cells prevents the loss of insulin-staining β cells after CVB4 infection of SOCS-1–Tg NOD mice.

Similar content being viewed by others

References

  1. Hyoty, H., Hiltunen, M. & Lonnrot, M. Enterovirus infections and insulin dependent diabetes mellitus – evidence for causality. Clin. Diagn. Virol. 9, 77–84 (1998).

    Article  CAS  PubMed  Google Scholar 

  2. Knip, M. & Akerblom, H. K. Environmental factors in the pathogenesis of type 1 diabetes mellitus. Exp. Clin. Endocrinol. Diabetes 107, 93–100 (1999).

    Article  Google Scholar 

  3. Robles, D. T. & Eisenbarth, G. S. Type 1a diabetes induced by infection and immunization. J. Autoimmun. 16, 355–362 (2001).

    Article  CAS  PubMed  Google Scholar 

  4. Horwitz, M. S. & Sarvetnick, N. Viruses, host responses, and autoimmunity. Immunol. Rev. 169, 241–253 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Whitton, J. L. & Fujinami, R. S. Viruses as triggers of autoimmunity: facts and fantasies. Curr. Opin. Microbiol. 2, 392–397 (1999).

    Article  CAS  PubMed  Google Scholar 

  6. Kukreja, A. & Maclaren, N. K. Current cases in which epitope mimicry is considered as a component cause of autoimmune disease: immune-mediated (type 1) diabetes. Cell. Mol. Life Sci. 57, 534–541 (2000).

    Article  CAS  PubMed  Google Scholar 

  7. Gladisch, R., Hofmann, W. & Waldherr, R. Myocarditis and insulitis following coxsackie virus infection. Z. Kardiol. 65, 837–849 (1976).

    CAS  PubMed  Google Scholar 

  8. Jenson, A. B., Rosenberg, H. S. & Notkins, A. L. Pancreatic islet-cell damage in children with fatal viral infections. Lancet 2, 354–358 (1980).

    CAS  PubMed  Google Scholar 

  9. Foulis, A. K., McGill, M., Farquharson, M. A. & Hilton, D. A. A search for evidence of viral infection in pancreases of newly diagnosed patients with IDDM. Diabetologia 40, 53–61 (1997).

    Article  CAS  PubMed  Google Scholar 

  10. Yoon, J. W., Austin, M., Onodera, T. & Notkins, A. L. Isolation of a virus from the pancreas of a child with diabetic ketoacidosis. N. Engl. J. Med. 300, 1173–1179 (1979).

    Article  CAS  PubMed  Google Scholar 

  11. Szopa, T. M., Gamble, D. R. & Taylor, K. W. Coxsackie B4 virus induces short-term changes in the metabolic functions of mouse pancreatic islets in vitro. Cell. Biochem. Funct. 4, 181–187 (1986).

    Article  CAS  PubMed  Google Scholar 

  12. Szopa, T. M., Dronfield, D. M., Ward, T. & Taylor, K. W. In vivo infection of mice with Coxsackie B4 virus induces long-term functional changes in pancreatic islets with minimal alteration in blood glucose. Diabet. Med. 6, 314–319 (1989).

    Article  CAS  PubMed  Google Scholar 

  13. Frisk, G., Grapengiesser, E. & Diderholm, H. Impaired Ca2+ response to glucose in mouse β-cells infected with coxsackie B or Echo virus. Virus Res. 33, 229–240 (1994).

    Article  CAS  PubMed  Google Scholar 

  14. Roivainen, M. et al. Mechanisms of coxsackievirus-induced damage to human pancreatic β-cells. J. Clin. Endocrinol. Metab. 85, 432–440 (2000).

    CAS  PubMed  Google Scholar 

  15. Vreugdenhil, G. R. et al. Acute onset of type I diabetes mellitus after severe echovirus 9 infection: putative pathogenic pathways. Clin. Infect. Dis. 31, 1025–1031 (2000).

    Article  CAS  PubMed  Google Scholar 

  16. Ramsingh, A. I., Chapman, N. & Tracy, S. Coxsackieviruses and diabetes. Bioessays 19, 793–800 (1997).

    Article  CAS  PubMed  Google Scholar 

  17. Horwitz, M. S. et al. Diabetes induced by Coxsackie virus: initiation by bystander damage and not molecular mimicry. Nature Med. 4, 781–785 (1998).

    Article  CAS  PubMed  Google Scholar 

  18. Mena, I. et al. Coxsackievirus infection of the pancreas: evaluation of receptor expression, pathogenesis, and immunopathology. Virology 271, 276–288 (2000).

    Article  CAS  PubMed  Google Scholar 

  19. Flodström, M. et al. A critical role for inducible nitric oxide synthase (NOS2) in host survival following Coxsackievirus B4 infection. Virology 281, 205–215 (2001).

    Article  PubMed  CAS  Google Scholar 

  20. Torres, A., Garib, J. & Recurt, M. L. Coxsackie virus: a review. Bol. Asoc. Med. P. R. 76, 49–51 (1984).

    CAS  PubMed  Google Scholar 

  21. Ramsingh, A. I., Lee, W. T., Collins, D. N. & Armstrong, L. E. T cells contribute to disease severity during coxsackievirus B4 infection. J. Virol. 73, 3080–3086 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Nigro, G., Pacella, M. E., Patane, E. & Midulla, M. Multi-system coxsackievirus B-6 infection with findings suggestive of diabetes mellitus. Eur. J. Pediatr. 145, 557–559 (1986).

    Article  CAS  PubMed  Google Scholar 

  23. Champsaur, H. et al. Diabetes and Coxsackie virus B5 infection. Lancet 1, 251 (1980).

    Article  CAS  PubMed  Google Scholar 

  24. Yoon, J. W., McClintock, P. R., Onodera, T. & Notkins, A. L. Virus-induced diabetes mellitus. XVIII. Inhibition by a nondiabetogenic variant of encephalomyocarditis virus. J. Exp. Med. 152, 878–892 (1980).

    Article  CAS  PubMed  Google Scholar 

  25. Stark, G. R., Kerr, I. M., Williams, B. R., Silverman, R. H. & Schreiber, R. D. How cells respond to interferons. Annu. Rev. Biochem. 67, 227–264 (1998).

    Article  CAS  PubMed  Google Scholar 

  26. Goodbourn, S., Didcock, L. & Randall, R. E. Interferons: cell signalling, immune modulation, antiviral response and virus countermeasures. J. Gen. Virol. 81, 2341–2364 (2000).

    Article  CAS  PubMed  Google Scholar 

  27. Le Page, C., Genin, P., Baines, M. G. & Hiscott, J. Interferon activation and innate immunity. Rev. Immunogenet. 2, 374–386 (2000).

    CAS  PubMed  Google Scholar 

  28. Ihle, J. N. The Stat family in cytokine signaling. Curr. Opin. Cell. Biol. 13, 211–217 (2001).

    Article  CAS  PubMed  Google Scholar 

  29. Heitmeier, M. R., Scarim, A. L. & Corbett, J. A. Prolonged STAT1 activation is associated with interferon-γ priming for interleukin-1-induced inducible nitric-oxide synthase expression by islets of Langerhans. J. Biol. Chem. 274, 29266–29273 (1999).

    Article  CAS  PubMed  Google Scholar 

  30. Hamaguchi, K., Gaskins, H. R. & Leiter, E. H. NIT-1, a pancreatic β-cell line established from a transgenic NOD/Lt mouse. Diabetes 40, 842–849 (1991).

    Article  CAS  PubMed  Google Scholar 

  31. Sakamoto, H., Kinjyo, I. & Yoshimura, A. The janus kinase inhibitor, Jab/SOCS-1, is an interferon-γ inducible gene and determines the sensitivity to interferons. Leuk. Lymphoma 38, 49–58 (2000).

    Article  CAS  PubMed  Google Scholar 

  32. Kile, B. T., Nicola, N. A. & Alexander, W. S. Negative regulators of cytokine signaling. Int. J. Hematol. 73, 292–298 (2001).

    Article  CAS  PubMed  Google Scholar 

  33. Sarvetnick, N., Liggitt, D., Pitts, S. L., Hansen, S. E. & Stewart, T. A. Insulin-dependent diabetes mellitus induced in transgenic mice by ectopic expression of class II MHC and interferon-γ. Cell 52, 773–782 (1988).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Cottet, S. et al. SOCS-1 protein prevents JAK/STAT-dependent inhibition of β cell insulin gene transcription and secretion in response to IFN-γ. J. Biol. Chem. 276, 25862–25870 (2001).

    Article  CAS  PubMed  Google Scholar 

  35. Frisk, G. & Diderholm, H. Tissue culture of isolated human pancreatic islets infected with different strains of coxsackievirus B4: assessment of virus replication and effects on islet morphology and insulin release. Int. J. Exp. Diabetes Res. 1, 165–175 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. van den Broek, M. F., Muller, U., Huang, S., Zinkernagel, R. M. & Aguet, M. Immune defence in mice lacking type I and/or type II interferon receptors. Immunol. Rev. 148, 5–18 (1995).

    Article  CAS  PubMed  Google Scholar 

  37. Kerr, J. F., Gobe, G. C., Winterford, C. M. & Harmon, B. V. Anatomical methods in cell death. Meth. Cell. Biol. 46, 1–27 (1995).

    Article  CAS  Google Scholar 

  38. Serreze, D. V., Ottendorfer, E. W., Ellis, T. M., Gauntt, C. J. & Atkinson, M. A. Acceleration of type 1 diabetes by a coxsackievirus infection requires a preexisting critical mass of autoreactive T-cells in pancreatic islets. Diabetes 49, 708–711 (2000).

    Article  CAS  PubMed  Google Scholar 

  39. Wicker, L. S., Todd, J. A. & Peterson, L. B. Genetic control of autoimmune diabetes in the NOD mouse. Annu. Rev. Immunol. 13, 179–200 (1995).

    Article  CAS  PubMed  Google Scholar 

  40. Horwitz, M. S., Krahl, T., Fine, C., Lee, J. & Sarvetnick, N. Protection from lethal coxsackievirus-induced pancreatitis by expression of γ interferon. J. Virol. 73, 1756–1766 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Rueckert, R. in Fields Virology (eds. Knipe, D. M. et al.) 609–654 (Lippincott - Raven Publishers, Philadelphia, PA, 1996).

    Google Scholar 

  42. Abbas, A. K., Lichtman, A. H. & Pober, J. S. Cellular and Molecular Immunology (W. B. Saunders Company, Philadelphia, PA, 2000).

    Google Scholar 

  43. Bach, J. F. & Mathis, D. The NOD mouse. Res. Immunol. 148, 285–286 (1997).

    Article  CAS  PubMed  Google Scholar 

  44. Prochazka, M., Gaskins, H. R., Shultz, L. D. & Leiter, E. H. The nonobese diabetic scid mouse: model for spontaneous thymomagenesis associated with immunodeficiency. Proc. Natl Acad. Sci. USA 89, 3290–3294 (1992).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Tay, C. H., Szomolanyi-Tsuda, E. & Welsh, R. M. Control of infections by NK cells. Curr. Top. Microbiol. Immunol. 230, 193–220 (1998).

    CAS  PubMed  Google Scholar 

  46. Biron, C. A., Nguyen, K. B., Pien, G. C., Cousens, L. P. & Salazar-Mather, T. P. Natural killer cells in antiviral defense: function and regulation by innate cytokines. Annu. Rev. Immunol. 17, 189–220 (1999).

    Article  CAS  PubMed  Google Scholar 

  47. Wiltrout, R. H., Salup, R. R., Twilley, T. A. & Talmadge, J. E. Immunomodulation of natural killer activity by polyribonucleotides. J. Biol. Response Mod. 4, 512–517 (1985).

    CAS  PubMed  Google Scholar 

  48. Kasai, M. et al. In vivo effect of anti-asialo GM1 antibody on natural killer activity. Nature 291, 334–335 (1981).

    Article  CAS  PubMed  Google Scholar 

  49. Lee, U., Santa, K., Habu, S. & Nishimura, T. Murine asialo GM1+CD8+ T cells as novel interleukin-12-responsive killer T cell precursors. Jpn. J. Cancer Res. 87, 429–432 (1996).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Doherty, P. C. & Allan, J. E. Anti-asialo GM1 eliminates both inflammatory process and cytotoxic T-cell function in the lymphocytic choriomeningitis adoptive transfer model. Cell. Immunol. 107, 1–7 (1987).

    Article  CAS  PubMed  Google Scholar 

  51. Parker, S. E., Sun, Y. H. & Sears, D. W. Differential expression of the ASGM1 antigen on anti-reovirus and alloreactive cytotoxic T lymphocytes (CTL). J. Immunogenet. 15, 215–226 (1988).

    Article  CAS  PubMed  Google Scholar 

  52. Slifka, M. K., Pagarigan, R. R. & Whitton, J. L. NK markers are expressed on a high percentage of virus-specific CD8+ and CD4+ T cells. J. Immunol. 164, 2009–2015 (2000).

    Article  CAS  PubMed  Google Scholar 

  53. Gombert, J. M. et al. Early quantitative and functional deficiency of NK1+-like thymocytes in the NOD mouse. Eur. J. Immunol. 26, 2989–2998 (1996).

    Article  CAS  PubMed  Google Scholar 

  54. Harada, M. et al. Natural killer cells inhibit the development of autoantibody production in (C57BL/6 x DBA/2) F1 hybrid mice injected with DBA/2 spleen cells. Cell. Immunol. 161, 42–49 (1995).

    Article  CAS  PubMed  Google Scholar 

  55. Godeny, E. K. & Gauntt, C. J. Murine natural killer cells limit coxsackievirus B3 replication. J. Immunol. 139, 913–918 (1987).

    CAS  PubMed  Google Scholar 

  56. Vella, C. & Festenstein, H. Coxsackievirus B4 infection of the mouse pancreas: the role of natural killer cells in the control of virus replication and resistance to infection. J. Gen. Virol. 73, 1379–1386 (1992).

    Article  CAS  PubMed  Google Scholar 

  57. Bergelson, J. M. et al. Isolation of a common receptor for Coxsackie B viruses and adenoviruses 2 and 5. Science 275, 1320–1323 (1997).

    Article  CAS  PubMed  Google Scholar 

  58. Bergelson, J. M. et al. Clinical coxsackievirus B isolates differ from laboratory strains in their interaction with two cell surface receptors. J. Infect. Dis. 175, 697–700 (1997).

    Article  CAS  PubMed  Google Scholar 

  59. Frisk, G., Elfstrom, T. & Diderholm, H. The replication of certain Coxsackie B virus strains in CHO cells. J. Virol. Meth. 98, 161–165 (2001).

    Article  CAS  Google Scholar 

  60. Chehadeh, W. et al. Persistent infection of human pancreatic islets by coxsackievirus B is associated with α interferon synthesis in β cells. J. Virol. 74, 10153–10164 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Tomko, R. P., Xu, R. & Philipson, L. HCAR and MCAR: the human and mouse cellular receptors for subgroup C adenoviruses and group B coxsackieviruses. Proc. Natl Acad. Sci. USA 94, 3352–3356 (1997).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Bergelson, J. M. et al. The murine CAR homolog is a receptor for coxsackie B viruses and adenoviruses. J. Virol. 72, 415–419 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Lyles, D. S. Cytopathogenesis and inhibition of host gene expression by RNA viruses. Microbiol. Mol. Biol. Rev. 64, 709–724 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Foulis, A. K., Farquharson, M. A. & Meager, A. Immunoreactive α-interferon in insulin-secreting β cells in type 1 diabetes mellitus. Lancet 2, 1423–1427 (1987).

    Article  CAS  PubMed  Google Scholar 

  65. Somoza, N. et al. Pancreas in recent onset insulin-dependent diabetes mellitus. Changes in HLA, adhesion molecules and autoantigens, restricted T cell receptor V β usage, and cytokine profile. J. Immunol. 153, 1360–1377 (1994).

    CAS  PubMed  Google Scholar 

  66. Huang, X. et al. Interferon expression in the pancreases of patients with type I diabetes. Diabetes 44, 658–664 (1995).

    Article  CAS  PubMed  Google Scholar 

  67. Rhodes, C. J. & Taylor, K. W. Effect of human lymphoblastoid interferon on insulin synthesis and secretion in isolated human pancreatic islets. Diabetologia 27, 601–603 (1984).

    Article  CAS  PubMed  Google Scholar 

  68. Rhodes, C. J. & Taylor, K. W. Effect of interferon and double-stranded RNA on B-cell function in mouse islets of Langerhans. Biochem. J. 228, 87–94 (1985).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Shimizu, F., Shimizu, M. & Kamiyama, K. Inhibitory effect of interferon on the production of insulin. Endocrinology 117, 2081–2084 (1985).

    Article  CAS  PubMed  Google Scholar 

  70. Stewart, T. A. et al. Induction of type I diabetes by interferon-α in transgenic mice. Science 260, 1942–1946 (1993).

    Article  CAS  PubMed  Google Scholar 

  71. Pelegrin, M. et al. Evidence from transgenic mice that interferon-β may be involved in the onset of diabetes mellitus. J. Biol. Chem. 273, 12332–12340 (1998).

    Article  CAS  PubMed  Google Scholar 

  72. Stauffer, Y. et al. Interferon-α-induced endogenous superantigen. a model linking environment and autoimmunity. Immunity 15, 591–601 (2001).

    Article  CAS  PubMed  Google Scholar 

  73. Imagawa, A., Hanafusa, T., Miyagawa, J. & Matsuzawa, Y. A novel subtype of type 1 diabetes mellitus characterized by a rapid onset and an absence of diabetes-related antibodies. Osaka IDDM Study Group. N. Engl. J. Med. 342, 301–307 (2000).

    Article  CAS  PubMed  Google Scholar 

  74. Imagawa, A., Hanafusa, T., Miyagawa, J. & Matsuzawa, Y. A proposal of three distinct subtypes of type 1 diabetes mellitus based on clinical and pathological evidence. Ann. Med. 32, 539–543 (2000).

    Article  CAS  PubMed  Google Scholar 

  75. Bach, J. F. New concepts of the etiopathogenesis and treatment of insulin-dependent diabetes mellitus. Clin. Rev. Allergy Immunol. 19, 217–225 (2000).

    Article  CAS  PubMed  Google Scholar 

  76. Hiltunen, M. et al. Islet cell antibody seroconversion in children is temporally associated with enterovirus infections. Childhood Diabetes in Finland (DiMe) Study Group. J. Infect. Dis. 175, 554–560 (1997).

    Article  CAS  PubMed  Google Scholar 

  77. Andreoletti, L. et al. Coxsackie B virus infection and β cell autoantibodies in newly diagnosed IDDM adult patients. Clin. Diagn. Virol. 9, 125–133 (1998).

    Article  CAS  PubMed  Google Scholar 

  78. Lönnrot, M. et al. Enterovirus infection as a risk factor for β-cell autoimmunity in a prospectively observed birth cohort: the Finnish Diabetes Prediction and Prevention Study. Diabetes 49, 1314–1318 (2000).

    Article  PubMed  Google Scholar 

  79. Luppi, P. et al. Restricted TCR V β gene expression and enterovirus infection in type I diabetes: a pilot study. Diabetologia 43, 1484–1497 (2000).

    Article  CAS  PubMed  Google Scholar 

  80. Ludewig, B., Junt, T., Hengartner, H. & Zinkernagel, R. M. Dendritic cells in autoimmune diseases. Curr. Opin. Immunol. 13, 657–662 (2001).

    Article  CAS  PubMed  Google Scholar 

  81. Graves, P. M., Norris, J. M., Pallansch, M. A., Gerling, I. C. & Rewers, M. The role of enteroviral infections in the development of IDDM: limitations of current approaches. Diabetes 46, 161–168 (1997).

    Article  CAS  PubMed  Google Scholar 

  82. Endo, T. A. et al. A new protein containing an SH2 domain that inhibits JAK kinases. Nature 387, 921–924 (1997).

    Article  CAS  PubMed  Google Scholar 

  83. Naka, T. et al. Structure and function of a new STAT-induced STAT inhibitor. Nature 387, 924–929 (1997).

    Article  CAS  PubMed  Google Scholar 

  84. Starr, R. et al. A family of cytokine-inducible inhibitors of signalling. Nature 387, 917–921 (1997).

    Article  CAS  PubMed  Google Scholar 

  85. Flodström, M. & Eizirik, D. L. Interferon-γ-induced interferon regulatory factor-1 (IRF-1) expression in rodent and human islet cells precedes nitric oxide production. Endocrinology 138, 2747–2753 (1997).

    Article  PubMed  Google Scholar 

  86. Flodström, M., Tyrberg, B., Eizirik, D. L. & Sandler, S. Reduced sensitivity of inducible nitric oxide synthase-deficient mice to multiple low-dose streptozotocin-induced diabetes. Diabetes 48, 706–713 (1999).

    Article  PubMed  Google Scholar 

Download references

Acknowledgements

We thank L. Mocknic, A. Ilic and L. Tucker for excellent technical assistance; N. Hill, M. Horwitz, C. King, M. Kritzik, S. Pakala, F. Shi and other members of the Sarvetnick laboratory for discussions and suggestions; P. Minick for editing the manuscript; and B. Smith and M. Wood (Core Electron Microscope Facility, The Scripps Research Institute) for assistance with electron and confocal microscopy. Supported by National Institutes of Health grants (ROI: AI42231), the National Multiple Sclerosis Society (M. F.) and the Juvenile Diabetes Research Foundation (M. F.).

Author information

Authors and Affiliations

  1. Department of Immunology, IMM-23, The Scripps Research Institute, 10550 N. Torrey Pines Road, La Jolla, 92037, CA, USA

    Malin Flodström, Amy Maday, Deepika Balakrishna, Mary Malo Cleary & Nora Sarvetnick

  2. Molecular and Cellular Immunology, Medical Institute of Bioregulation, Kyushu University 3-1-1 Maidashi, Higashi-ku, 812-8582, Fukuoka, Japan

    Akihiko Yoshimura

Authors
  1. Malin Flodström
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Amy Maday
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Deepika Balakrishna
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Mary Malo Cleary
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Akihiko Yoshimura
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Nora Sarvetnick
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Nora Sarvetnick.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Flodström, M., Maday, A., Balakrishna, D. et al. Target cell defense prevents the development of diabetes after viral infection. Nat Immunol 3, 373–382 (2002). https://doi.org/10.1038/ni771

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/ni771

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing