Toll-like receptor engagement converts T-cell autoreactivity into overt autoimmune disease

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  • A Corrigendum to this article was published on 01 November 2005

Abstract

Autoimmune diabetes mellitus in humans is characterized by immunological destruction of pancreatic beta islet cells. We investigated the circumstances under which CD8+ T cells specific for pancreatic beta-islet antigens induce disease in mice expressing lymphocytic choriomeningitis virus (LCMV) glycoprotein (GP) as a transgene under the control of the rat insulin promoter. In contrast to infection with LCMV, immunization with LCMV-GP derived peptide did not induce autoimmune diabetes despite large numbers of autoreactive cytotoxic T cells. Only subsequent treatment with Toll-like receptor ligands elicited overt autoimmune disease. This difference was critically regulated by the peripheral target organ itself, which upregulated class I major histocompatibility complex (MHC) in response to systemic Toll-like receptor–triggered interferon-α production. These data identify the 'inflammatory status' of the target organ as a separate and limiting factor determining the development of autoimmune disease.

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Figure 1: Expansion of CD8+ T cells specific for beta islet cell antigen alone does not necessarily induce diabetes.
Figure 2: Peptide immunization induces highly activated CTLs.
Figure 3: Pancreatic infiltration by activated beta islet-specific CD8+ T cells is not sufficient to induce diabetes.
Figure 4: LCMV infection, but not peptide immunization, results in MHC class I upregulation on beta islet cells.
Figure 5: Toll-like receptor stimulation induces MHC class I upregulation on beta islet cells.
Figure 6: Prevention of LCMV-induced diabetes by lack of MyD88 or IFN type I receptor.

References

  1. 1

    Roep, B.O. T-cell responses to autoantigens in IDDM. The search for the Holy Grail. Diabetes 45, 1147–1156 (1996).

  2. 2

    Yang, Y. & Santamaria, P. Dissecting autoimmune diabetes through genetic manipulation of non-obese diabetic mice. Diabetologia 46, 1447–1464 (2003).

  3. 3

    Erlich, H.A. HLA class II sequences and genetic susceptibility to insulin dependent diabetes mellitus. Baillieres Clin. Endocrinol. Metab. 5, 395–411 (1991).

  4. 4

    Trucco, M. & Dorman, J.S. Immunogenetics of insulin-dependent diabetes mellitus in humans. Crit. Rev. Immunol. 9, 201–245 (1989).

  5. 5

    Hyoty, H. & Taylor, K.W. The role of viruses in human diabetes. Diabetologia 45, 1353–1361 (2002).

  6. 6

    Roep, B.O. et al. Molecular mimicry in type 1 diabetes: immune cross-reactivity between islet autoantigen and human cytomegalovirus but not Coxsackie virus. Ann. NY Acad. Sci. 958, 163–165 (2002).

  7. 7

    Schloot, N.C. et al. Molecular mimicry in type 1 diabetes mellitus revisited: T-cell clones to GAD65 peptides with sequence homology to Coxsackie or proinsulin peptides do not crossreact with homologous counterpart. Hum. Immunol. 62, 299–309 (2001).

  8. 8

    Hiemstra, H.S. et al. Definition of natural T cell antigens with mimicry epitopes obtained from dedicated synthetic peptide libraries. J. Immunol. 161, 4078–4082 (1998).

  9. 9

    Potena, L. et al. Hydroxymethyl-glutaryl coenzyme a reductase inhibition limits cytomegalovirus infection in human endothelial cells. Circulation 109, 532–536 (2004).

  10. 10

    Roep, B.O. et al. T-cell reactivity to beta-cell membrane antigens associated with beta-cell destruction in IDDM. Diabetes 44, 278–283 (1995).

  11. 11

    Ohashi, P.S. et al. Ablation of 'tolerance' and induction of diabetes by virus infection in viral antigen transgenic mice. Cell 65, 305–317 (1991).

  12. 12

    von Herrath, M.G. & Oldstone, M.B. Interferon-gamma is essential for destruction of beta cells and development of insulin-dependent diabetes mellitus. J. Exp. Med. 185, 531–539 (1997).

  13. 13

    Ludewig, B., Odermatt, B., Landmann, S., Hengartner, H. & Zinkernagel, R.M. Dendritic cells induce autoimmune diabetes and maintain disease via de novo formation of local lymphoid tissue. J. Exp. Med. 188, 1493–1501 (1998).

  14. 14

    Ohashi, P.S. et al. Induction of diabetes is influenced by the infectious virus and local expression of MHC class I and tumor necrosis factor-alpha. J. Immunol. 150, 5185–5194 (1993).

  15. 15

    Nansen, A., Marker, O., Bartholdy, C. & Thomsen, A.R. CCR2+ and CCR5+ CD8+ T cells increase during viral infection and migrate to sites of infection. Eur. J. Immunol. 30, 1797–1806 (2000).

  16. 16

    Frigerio, S. et al. Beta cells are responsible for CXCR3-mediated T-cell infiltration in insulitis. Nat. Med. 8, 1414–1420 (2002).

  17. 17

    Hoshino, K., Kaisho, T., Iwabe, T., Takeuchi, O. & Akira, S. Differential involvement of IFN-β in Toll-like receptor-stimulated dendritic cell activation. Int. Immunol. 14, 1225–1231 (2002).

  18. 18

    Krug, A. et al. Toll-like receptor expression reveals CpG DNA as a unique microbial stimulus for plasmacytoid dendritic cells which synergizes with CD40 ligand to induce high amounts of IL-12. Eur. J. Immunol. 31, 3026–3037 (2001).

  19. 19

    Kaisho, T. & Akira, S. Regulation of dendritic cell function through Toll-like receptors. Curr. Mol. Med. 3, 759–771 (2003).

  20. 20

    Dalod, M. et al. Interferon α /β and interleukin 12 responses to viral infections: pathways regulating dendritic cell cytokine expression in vivo. J. Exp. Med. 195, 517–528 (2002).

  21. 21

    Doughty, L., Nguyen, K., Durbin, J. & Biron, C. A role for IFN-α β in virus infection-induced sensitization to endotoxin. J. Immunol. 166, 2658–2664 (2001).

  22. 22

    Zhang, D. et al. A Toll-like receptor that prevents infection by uropathogenic bacteria. Science 303, 1522–1526 (2004).

  23. 23

    Alexopoulou, L., Holt, A.C., Medzhitov, R. & Flavell, R.A. Recognition of double-stranded RNA and activation of NF-κB by Toll-like receptor 3. Nature 413, 732–738 (2001).

  24. 24

    Heil, F. et al. Species-specific recognition of single-stranded RNA via Toll-like receptor 7 and 8. Science 303, 1526–1529 (2004).

  25. 25

    Hemmi, H. et al. A Toll-like receptor recognizes bacterial DNA. Nature 408, 740–745 (2000).

  26. 26

    Poltorak, A. et al. Defective LPS signaling in C3H/HeJ and C57BL/10ScCr mice: mutations in Tlr4 gene. Science 282, 2085–2088 (1998).

  27. 27

    Meagher, C. et al. Cytokines and chemokines in the pathogenesis of murine type 1 diabetes. Adv. Exp. Med. Biol. 520, 133–158 (2003).

  28. 28

    Luther, S.A., Lopez, T., Bai, W., Hanahan, D. & Cyster, J.G. BLC expression in pancreatic islets causes B cell recruitment and lymphotoxin-dependent lymphoid neogenesis. Immunity 12, 471–481 (2000).

  29. 29

    Biron, C.A. Role of early cytokines, including alpha and beta interferons (IFN-α /β), in innate and adaptive immune responses to viral infections. Semin. Immunol. 10, 383–390 (1998).

  30. 30

    Diebold, S.S., Kaisho, T., Hemmi, H., Akira, S. & Reis, E.S.C. Innate antiviral responses by means of TLR7-mediated recognition of single-stranded RNA. Science 303, 1529–1531 (2004).

  31. 31

    Diebold, S.S. et al. Viral infection switches non-plasmacytoid dendritic cells into high interferon producers. Nature 424, 324–328 (2003).

  32. 32

    Hemmi, H. et al. Small anti-viral compounds activate immune cells via the TLR7 MyD88-dependent signaling pathway. Nat. Immunol. 3, 196–200 (2002).

  33. 33

    Asselin-Paturel, C. et al. Mouse type I IFN-producing cells are immature APCs with plasmacytoid morphology. Nat. Immunol. 2, 1144–1150 (2001).

  34. 34

    Ishikawa, R. & Biron, C.A. IFN induction and associated changes in splenic leukocyte distribution. J. Immunol. 150, 3713–3727 (1993).

  35. 35

    Ou, R., Zhou, S., Huang, L. & Moskophidis, D. Critical role for α /β and γ interferons in persistence of lymphocytic choriomeningitis virus by clonal exhaustion of cytotoxic T cells. J. Virol. 75, 8407–8423 (2001).

  36. 36

    Malmgaard, L., Salazar-Mather, T.P., Lewis, C.A. & Biron, C.A. Promotion of α /β interferon induction during in vivo viral infection through α /β interferon receptor/STAT1 system-dependent and -independent pathways. J. Virol. 76, 4520–4525 (2002).

  37. 37

    Betterle, C. et al. Autoimmunity against pancreatic islets and other tissues before and after interferon-alpha therapy in patients with hepatitis C virus chronic infection. Diabetes Care 23, 1177–1181 (2000).

  38. 38

    Serreze, D.V., Hamaguchi, K. & Leiter, E.H. Immunostimulation circumvents diabetes in NOD/Lt mice. J. Autoimmun. 2, 759–776 (1989).

  39. 39

    Sobel, D.O. et al. Poly I:C induces development of diabetes mellitus in BB rat. Diabetes 41, 515–520 (1992).

  40. 40

    Ewel, C.H., Sobel, D.O., Zeligs, B.J. & Bellanti, J.A. Poly I:C accelerates development of diabetes mellitus in diabetes-prone BB rat. Diabetes 41, 1016–1021 (1992).

  41. 41

    Sobel, D.O. et al. Low dose poly I:C prevents diabetes in the diabetes prone BB rat. J. Autoimmun. 11, 343–352 (1998).

  42. 42

    Langenkamp, A., Messi, M., Lanzavecchia, A. & Sallusto, F. Kinetics of dendritic cell activation: impact on priming of TH1, TH2 and nonpolarized T cells. Nat. Immunol. 1, 311–316 (2000).

  43. 43

    Kobayashi, K. et al. IRAK-M is a negative regulator of Toll-like receptor signaling. Cell 110, 191–202 (2002).

  44. 44

    Kawai, T., Adachi, O., Ogawa, T., Takeda, K. & Akira, S. Unresponsiveness of MyD88-deficient mice to endotoxin. Immunity 11, 115–122 (1999).

  45. 45

    O'Neill, L.A. The interleukin-1 receptor/Toll-like receptor superfamily: signal transduction during inflammation and host defense. Sci. STKE 2000, RE1 (2000).

  46. 46

    Akira, S. The role of IL-18 in innate immunity. Curr. Opin. Immunol. 12, 59–63 (2000).

  47. 47

    Pien, G.C., Nguyen, K.B., Malmgaard, L., Satoskar, A.R. & Biron, C.A. A unique mechanism for innate cytokine promotion of T cell responses to viral infections. J. Immunol. 169, 5827–5837 (2002).

  48. 48

    Battegay, M. et al. Quantification of lymphocytic choriomeningitis virus with an immunological focus assay in 24- or 96-well plates. J. Virol. Methods 33, 191–198 (1991). Published errata appear in J. Virol. Methods 35, 115 (1991) and 38, 263 (1992).

  49. 49

    Honda, K. et al. Selective contribution of IFN-α /β signaling to the maturation of dendritic cells induced by double-stranded RNA or viral infection. Proc. Natl. Acad. Sci. USA 100, 10872–10877 (2003).

  50. 50

    Junt, T. et al. Antiviral immune responses in the absence of organized lymphoid T cell zones in plt/plt mice. J. Immunol. 168, 6032–6040 (2002).

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Acknowledgements

We thank A. Aguzzi, M. Heikenwälder and C. Sigurdson for ideas, discussions and critical comments. Additionally, we thank K. Tschannen for technical support and A. Nowotny and S. Behnke for histological analysis. This study was supported by the Swiss National Science Foundation and Deutsche Forschungsgemeinschaft (DFG) LA1419/1-1.

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Correspondence to Karl S Lang.

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Supplementary information

Supplementary Fig. 1

Kinetics of MHC I up-regulation after Toll-like receptor stimulation (PDF 183 kb)

Supplementary Fig. 2

Source of IFN-α (PDF 275 kb)

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Lang, K., Recher, M., Junt, T. et al. Toll-like receptor engagement converts T-cell autoreactivity into overt autoimmune disease. Nat Med 11, 138–145 (2005) doi:10.1038/nm1176

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