This review describes the ways in which cells of the innate immune system have a role in both the pathogenesis and the prevention of the autoimmune disease type 1 diabetes.
Epidemiological studies have highlighted a role for both genetic and environmental factors in the development of diabetes.
An overview is provided of the ways in which infectious agents have the potential to modulate type 1 diabetes through their effects on the crosstalk between the innate and adaptive arms of the immune response.
The development of type 1 diabetes involves a complex interaction between pancreatic β-cells and cells of both the innate and adaptive immune systems. Analyses of the interactions between natural killer (NK) cells, NKT cells, different dendritic cell populations and T cells have highlighted how these different cell populations can influence the onset of autoimmunity. There is evidence that infection can have either a potentiating or inhibitory role in the development of type 1 diabetes. Interactions between pathogens and cells of the innate immune system, and how this can influence whether T cell activation or tolerance occurs, have been under close scrutiny in recent years. This Review focuses on the nature of this crosstalk between the innate and the adaptive immune responses and how pathogens influence the process.
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Banting, F. G. & Best, C. H. The internal secretion of the pancreas. J. Lab. Clin. Med. 7, 465–480 (1922).
Redondo, M. J., Fain, P. R. & Eisenbarth, G. S. Genetics of type 1A diabetes. Recent Prog. Horm. Res. 56, 69–89 (2001).
Kyvik, K. O., Green, A. & Beck-Nielsen, H. Concordance rates of insulin dependent diabetes mellitus: a population based study of young Danish twins. BMJ 311, 913–917 (1995).
Redondo, M. J., Jeffrey, J., Fain, P. R., Eisenbarth, G. S. & Orban, T. Concordance for islet autoimmunity among monozygotic twins. N. Engl. J. Med. 359, 2849–2850 (2008).
Dunne, D. W. & Cooke, A. A worm's eye view of the immune system: consequences for evolution of human autoimmune disease. Nature Rev. Immunol. 5, 420–426 (2005).
Turley, S., Poirot, L., Hattori, M., Benoist, C. & Mathis, D. Physiological β cell death triggers priming of self-reactive T cells by dendritic cells in a type-1 diabetes model. J. Exp. Med. 198, 1527–1537 (2003). This study reveals the role of physiological β-cell apoptosis in young NOD mice, which induces the presentation of islet antigen by DCs and subsequent islet antigen-specific T cell priming in the draining lymph nodes.
Barrett, J. C. et al. Genome-wide association study and meta-analysis find that over 40 loci affect risk of type 1 diabetes. Nature Genet. 41, 703–707 (2009).
Reimann, M. et al. An update on preventive and regenerative therapies in diabetes mellitus. Pharmacol. Ther. 121, 317–331 (2009).
Hyoty, H. et al. Decline of mumps antibodies in type 1 (insulin-dependent) diabetic children and a plateau in the rising incidence of type 1 diabetes after introduction of the mumps–measles–rubella vaccine in Finland. Childhood Diabetes in Finland Study Group. Diabetologia 36, 1303–1308 (1993).
von Herrath, M. G., Fujinami, R. S. & Whitton, J. L. Microorganisms and autoimmunity: making the barren field fertile? Nature Rev. Microbiol. 1, 151–157 (2003).
Sibley, R. K., Sutherland, D. E., Goetz, F. & Michael, A. F. Recurrent diabetes mellitus in the pancreas iso- and allograft. A light and electron microscopic and immunohistochemical analysis of four cases. Lab. Invest. 53, 132–144 (1985).
Phillips, J. M. et al. Type 1 diabetes development requires both CD4+ and CD8+ T cells and can be reversed by non-depleting antibodies targeting both T cell populations. Rev. Diabet. Stud. 6, 97–103 (2009).
Chatenoud, L., Thervet, E., Primo, J. & Bach, J. F. Anti-CD3 antibody induces long-term remission of overt autoimmunity in nonobese diabetic mice. Proc. Natl Acad. Sci. USA 91, 123–127 (1994).
Chatenoud, L. Immune therapy for type 1 diabetes mellitus—what is unique about anti-CD3 antibodies? Nature Rev. Endocrinol. 6, 149–157 (2010).
Eizirik, D. L., Colli, M. L. & Ortis, F. The role of inflammation in insulitis and β cell loss in type 1 diabetes. Nature Rev. Endocrinol. 5, 219–226 (2009).
Wildin, R. S. & Freitas, A. IPEX and FOXP3: clinical and research perspectives. J. Autoimmun. 25, S56–S62 (2005).
Salomon, B. et al. B7/CD28 costimulation is essential for the homeostasis of the CD4+CD25+ immunoregulatory T cells that control autoimmune diabetes. Immunity 12, 431–440 (2000).
Tang, Q. & Bluestone, J. A. The Foxp3+ regulatory T cell: a jack of all trades, master of regulation. Nature Immunol. 9, 239–244 (2008).
Hu, C. Y. et al. Treatment with CD20-specific antibody prevents and reverses autoimmune diabetes in mice. J. Clin. Invest. 117, 3857–3867 (2007).
Serreze, D. V. et al. B lymphocytes are essential for the initiation of T cell-mediated autoimmune diabetes: analysis of a new “speed congenic” stock of NOD.Igμnull mice. J. Exp. Med. 184, 2049–2053 (1996).
Pescovitz, M. D. et al. Rituximab, B-lymphocyte depletion, and preservation of β-cell function. N. Engl. J. Med. 361, 2143–2152 (2009).
Martin, S. et al. Development of type 1 diabetes despite severe hereditary B-lymphocyte deficiency. N. Engl. J. Med. 345, 1036–1040 (2001).
Xiu, Y. et al. B lymphocyte depletion by CD20 monoclonal antibody prevents diabetes in nonobese diabetic mice despite isotype-specific differences in FcγR effector functions. J. Immunol. 180, 2863–2875 (2008).
Hutchings, P. et al. Transfer of diabetes in mice prevented by blockade of adhesion-promoting receptor on macrophages. Nature 348, 639–642 (1990). The role of macrophages in the pathogenesis of T1D was first shown by blocking macrophage adhesion with a specific monoclonal antibody. This treatment prevented insulitis and T1D in NOD mice.
Jun, H. S., Yoon, C. S., Zbytnuik, L., van Rooijen, N. & Yoon, J. W. The role of macrophages in T cell-mediated autoimmune diabetes in nonobese diabetic mice. J. Exp. Med. 189, 347–358 (1999).
Alleva, D. G., Pavlovich, R. P., Grant, C., Kaser, S. B. & Beller, D. I. Aberrant macrophage cytokine production is a conserved feature among autoimmune-prone mouse strains: elevated interleukin (IL)-12 and an imbalance in tumor necrosis factor-α and IL-10 define a unique cytokine profile in macrophages from young nonobese diabetic mice. Diabetes 49, 1106–1115 (2000).
Martin, A. P. et al. Increased expression of CCL2 in insulin-producing cells of transgenic mice promotes mobilization of myeloid cells from the bone marrow, marked insulitis, and diabetes. Diabetes 57, 3025–3033 (2008).
Yang, L. J. Big mac attack: does it play a direct role for monocytes/macrophages in type 1 diabetes? Diabetes 57, 2922–2923 (2008).
Arnush, M., Scarim, A. L., Heitmeier, M. R., Kelly, C. B. & Corbett, J. A. Potential role of resident islet macrophage activation in the initiation of autoimmune diabetes. J. Immunol. 160, 2684–2691 (1998).
Dahlen, E., Dawe, K., Ohlsson, L. & Hedlund, G. Dendritic cells and macrophages are the first and major producers of TNF-α in pancreatic islets in the nonobese diabetic mouse. J. Immunol. 160, 3585–3593 (1998).
Cantor, J. & Haskins, K. Recruitment and activation of macrophages by pathogenic CD4 T cells in type 1 diabetes: evidence for involvement of CCR8 and CCL1. J. Immunol. 179, 5760–5767 (2007).
Uno, S. et al. Macrophages and dendritic cells infiltrating islets with or without β cells produce tumour necrosis factor-α in patients with recent-onset type 1 diabetes. Diabetologia 50, 596–601 (2007).
Dotta, F. et al. Coxsackie B4 virus infection of β cells and natural killer cell insulitis in recent-onset type 1 diabetic patients. Proc. Natl Acad. Sci. USA 104, 5115–5120 (2007). This report describes the isolation of coxsackie virus B4 in the pancreas of patients with T1D, which was associated with lower β-cell function and with NK cell infiltrates.
Flodstrom, M. et al. Target cell defense prevents the development of diabetes after viral infection. Nature Immunol. 3, 373–382 (2002).
Poirot, L., Benoist, C. & Mathis, D. Natural killer cells distinguish innocuous and destructive forms of pancreatic islet autoimmunity. Proc. Natl Acad. Sci. USA 101, 8102–8107 (2004).
Alba, A. et al. Natural killer cells are required for accelerated type 1 diabetes driven by interferon-β. Clin. Exp. Immunol. 151, 467–475 (2008).
Brauner, H. et al. Distinct phenotype and function of NK cells in the pancreas of nonobese diabetic mice. J. Immunol. 184, 2272–2280 (2010).
Feuerer, M., Shen, Y., Littman, D. R., Benoist, C. & Mathis, D. How punctual ablation of regulatory T cells unleashes an autoimmune lesion within the pancreatic islets. Immunity 31, 654–664 (2009). This report shows that T Reg cell depletion enhances T1D development, which is associated with an increased frequency of activated NK cells in the pancreas.
Gur, C. et al. The activating receptor NKp46 is essential for the development of type 1 diabetes. Nature Immunol. 11, 121–128 (2010). This study highlights a role for NKp46, an activating receptor on NK cells, in the development of T1D and provides evidence for a direct interaction between NK cells and β-cells.
Ogasawara, K. et al. NKG2D blockade prevents autoimmune diabetes in NOD mice. Immunity 20, 757–767 (2004).
Lacy, P. E., Davie, J. M. & Finke, E. H. Prolongation of islet allograft survival following in vitro culture (24 degrees C) and a single injection of ALS. Science 204, 312–313 (1979).
Faustman, D. L. et al. Prevention of rejection of murine islet allografts by pretreatment with anti-dendritic cell antibody. Proc. Natl Acad. Sci. USA 81, 3864–3868 (1984).
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).
Marleau, A. M., Summers, K. L. & Singh, B. Differential contributions of APC subsets to T cell activation in nonobese diabetic mice. J. Immunol. 180, 5235–5249 (2008).
Kim, H. S. et al. Toll-like receptor 2 senses β-cell death and contributes to the initiation of autoimmune diabetes. Immunity 27, 321–333 (2007).
Wen, L. et al. Innate immunity and intestinal microbiota in the development of type 1 diabetes. Nature 455, 1109–1113 (2008). This study based on the analysis of MYD88-deficient NOD mice suggests that the gut microbiota have a crucial role in the prevention of T1D.
Poligone, B., Weaver, D. J. Jr, Sen, P., Baldwin, A. S. Jr & Tisch, R. Elevated NF-κB activation in nonobese diabetic mouse dendritic cells results in enhanced APC function. J. Immunol. 168, 188–196 (2002).
Steptoe, R. J., Ritchie, J. M. & Harrison, L. C. Increased generation of dendritic cells from myeloid progenitors in autoimmune-prone nonobese diabetic mice. J. Immunol. 168, 5032–5041 (2002).
Lande, R. & Gilliet, M. Plasmacytoid dendritic cells: key players in the initiation and regulation of immune responses. Ann. NY Acad. Sci. 1183, 89–103 (2010).
Stewart, T. A. et al. Induction of type I diabetes by interferon-α in transgenic mice. Science 260, 1942–1946 (1993).
Huang, Y., Blatt, L. M. & Taylor, M. W. Type 1 interferon as an antiinflammatory agent: inhibition of lipopolysaccharide-induced interleukin-1β and induction of interleukin-1 receptor antagonist. J. Interferon Cytokine Res. 15, 317–321 (1995).
Li, Q. et al. Interferon-α initiates type 1 diabetes in nonobese diabetic mice. Proc. Natl Acad. Sci. USA 105, 12439–12444 (2008).
Van Belle, T. L., Juntti, T., Liao, J. & von Herrath, M. G. Pre-existing autoimmunity determines type 1 diabetes outcome after Flt3-ligand treatment. J. Autoimmun. 34, 445–452 (2009).
Vuckovic, S. et al. Decreased blood dendritic cell counts in type 1 diabetic children. Clin. Immunol. 123, 281–288 (2007).
Chen, X. et al. Type 1 diabetes patients have significantly lower frequency of plasmacytoid dendritic cells in the peripheral blood. Clin. Immunol. 129, 413–418 (2008).
Allen, J. S. et al. Plasmacytoid dendritic cells are proportionally expanded at diagnosis of type 1 diabetes and enhance islet autoantigen presentation to T-cells through immune complex capture. Diabetes 58, 138–145 (2009).
Ohnmacht, C. et al. Constitutive ablation of dendritic cells breaks self-tolerance of CD4 T cells and results in spontaneous fatal autoimmunity. J. Exp. Med. 206, 549–559 (2009).
Ueno, H. et al. Dendritic cell subsets in health and disease. Immunol. Rev. 219, 118–142 (2007).
Kared, H. et al. Treatment with granulocyte colony-stimulating factor prevents diabetes in NOD mice by recruiting plasmacytoid dendritic cells and functional CD4+CD25+ regulatory T-cells. Diabetes 54, 78–84 (2005).
Chilton, P. M. et al. Flt3-ligand treatment prevents diabetes in NOD mice. Diabetes 53, 1995–2002 (2004).
O'Keeffe, M. et al. Fms-like tyrosine kinase 3 ligand administration overcomes a genetically determined dendritic cell deficiency in NOD mice and protects against diabetes development. Int. Immunol. 17, 307–314 (2005).
Darrasse-Jeze, G. et al. Feedback control of regulatory T cell homeostasis by dendritic cells in vivo. J. Exp. Med. 206, 1853–1862 (2009). This study describes a feedback regulatory loop between T Reg cells and DCs. Increasing DC frequency increases T Reg cell frequency thereby preventing T1D.
Saxena, V., Ondr, J. K., Magnusen, A. F., Munn, D. H. & Katz, J. D. The countervailing actions of myeloid and plasmacytoid dendritic cells control autoimmune diabetes in the nonobese diabetic mouse. J. Immunol. 179, 5041–5053 (2007). This article shows the contrasting roles of DC subsets in the development of T1D: cDCs promote T1D, whereas pDCs are protective and induce IDO production in the pancreatic islets.
Grohmann, U. et al. A defect in tryptophan catabolism impairs tolerance in nonobese diabetic mice. J. Exp. Med. 198, 153–160 (2003).
Alexander, A. M. et al. Indoleamine 2, 3-dioxygenase expression in transplanted NOD Islets prolongs graft survival after adoptive transfer of diabetogenic splenocytes. Diabetes 51, 356–365 (2002).
Diana, J. et al. NKT Cell-plasmacytoid dendritic cell cooperation via OX40 controls viral infection in a tissue-specific manner. Immunity 30, 289–299 (2009). This study describes the cooperation between iNKT cells and pDCs in the pancreas to control viral replication and dampen local T cell responses.
Carnaud, C., Gombert, J., Donnars, O., Garchon, H. & Herbelin, A. Protection against diabetes and improved NK/NKT cell performance in NOD.NK1.1 mice congenic at the NK complex. J. Immunol. 166, 2404–2411 (2001).
Ogasawara, K. et al. Impairment of NK cell function by NKG2D modulation in NOD mice. Immunity 18, 41–51 (2003).
Rodacki, M. et al. Altered natural killer cells in type 1 diabetic patients. Diabetes 56, 177–185 (2007).
Lee, I. F., Qin, H., Trudeau, J., Dutz, J. & Tan, R. Regulation of autoimmune diabetes by complete Freund's adjuvant is mediated by NK cells. J. Immunol. 172, 937–942 (2004).
Beilke, J. N., Kuhl, N. R., Van Kaer, L. & Gill, R. G. NK cells promote islet allograft tolerance via a perforin-dependent mechanism. Nature Med. 11, 1059–1065 (2005).
Novak, J., Griseri, T., Beaudoin, L. & Lehuen, A. Regulation of type 1 diabetes by NKT cells. Int. Rev. Immunol. 26, 49–72 (2007).
Hammond, K. J. et al. α/β-T cell receptor (TCR)+CD4−CD8− (NKT) thymocytes prevent insulin-dependent diabetes mellitus in nonobese diabetic (NOD)/Lt mice by the influence of interleukin (IL)-4 and/or IL-10. J. Exp. Med. 187, 1047–1056 (1998).
Lehuen, A. et al. Overexpression of natural killer T cells protects Vα14–Jα281 transgenic nonobese diabetic mice against diabetes. J. Exp. Med. 188, 1831–1839 (1998). References 73 and 74 are the first reports describing the role of iNKT cells in preventing T1D.
Sharif, S. et al. Activation of natural killer T cells by α-galactosylceramide treatment prevents the onset and recurrence of autoimmune type 1 diabetes. Nature Med. 7, 1057–1062 (2001).
Hong, S. et al. The natural killer T-cell ligand α-galactosylceramide prevents autoimmune diabetes in non-obese diabetic mice. Nature Med. 7, 1052–1056 (2001).
Mizuno, M. et al. Synthetic glycolipid OCH prevents insulitis and diabetes in NOD mice. J. Autoimmun 23, 293–300 (2004).
Forestier, C. et al. Improved outcomes in NOD mice treated with a novel Th2 cytokine-biasing NKT cell activator. J. Immunol. 178, 1415–1425 (2007).
Laloux, V., Beaudoin, L., Jeske, D., Carnaud, C. & Lehuen, A. NK T cell-induced protection against diabetes in Vα14-Jα281 transgenic nonobese diabetic mice is associated with a Th2 shift circumscribed regionally to the islets and functionally to islet autoantigen. J. Immunol. 166, 3749–3756 (2001).
Beaudoin, L., Laloux, V., Novak, J., Lucas, B. & Lehuen, A. NKT cells inhibit the onset of diabetes by impairing the development of pathogenic T cells specific for pancreatic β cells. Immunity 17, 725–736 (2002).
Chen, Y. G. et al. Activated NKT cells inhibit autoimmune diabetes through tolerogenic recruitment of dendritic cells to pancreatic lymph nodes. J. Immunol. 174, 1196–1204 (2005).
Duarte, N. et al. Prevention of diabetes in nonobese diabetic mice mediated by CD1d-restricted nonclassical NKT cells. J. Immunol. 173, 3112–3118 (2004).
Jordan, M. A., Fletcher, J. M., Pellicci, D. & Baxter, A. G. Slamf1, the NKT cell control gene Nkt1. J. Immunol. 178, 1618–1627 (2007).
Oikawa, Y. et al. High frequency of Vα24+ Vβ11+ T-cells observed in type 1 diabetes. Diabetes Care 25, 1818–1823 (2002).
Kukreja, A. et al. Multiple immuno-regulatory defects in type-1 diabetes. J. Clin. Invest. 109, 131–140 (2002).
Kato, H. et al. Differential roles of MDA5 and RIG-I helicases in the recognition of RNA viruses. Nature 441, 101–105 (2006).
Nejentsev, S., Walker, N., Riches, D., Egholm, M. & Todd, J. A. Rare variants of IFIH1, a gene implicated in antiviral responses, protect against type 1 diabetes. Science 324, 387–389 (2009).
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).
Baek, H. S. & Yoon, J. W. Direct involvement of macrophages in destruction of β-cells leading to development of diabetes in virus-infected mice. Diabetes 40, 1586–1597 (1991).
Lee, Y. S., Li, N., Shin, S. & Jun, H. S. Role of nitric oxide in the pathogenesis of encephalomyocarditis virus-induced diabetes in mice. J. Virol. 83, 8004–8011 (2009).
Shibasaki, S. et al. Expression of Toll-like receptors in the pancreas of recent-onset fulminant type 1 diabetes. Endocr. J. 23, 211–219 (2009).
Atkinson, M. A. et al. Cellular immunity to a determinant common to glutamate decarboxylase and coxsackie virus in insulin-dependent diabetes. J. Clin. Invest. 94, 2125–2129 (1994).
Honeyman, M. C., Stone, N. L., Falk, B. A., Nepom, G. & Harrison, L. C. Evidence for molecular mimicry between human T cell epitopes in rotavirus and pancreatic islet autoantigens. J. Immunol. 184, 2204–2210 (2010).
Ou, D., Mitchell, L. A., Metzger, D. L., Gillam, S. & Tingle, A. J. Cross-reactive rubella virus and glutamic acid decarboxylase (65 and 67) protein determinants recognised by T cells of patients with type I diabetes mellitus. Diabetologia 43, 750–762 (2000).
Pak, C. Y., Cha, C. Y., Rajotte, R. V., McArthur, R. G. & Yoon, J. W. Human pancreatic islet cell specific 38 kilodalton autoantigen identified by cytomegalovirus-induced monoclonal islet cell autoantibody. Diabetologia 33, 569–572 (1990).
Oldstone, M. B., Nerenberg, M., Southern, P., Price, J. & Lewicki, H. Virus infection triggers insulin-dependent diabetes mellitus in a transgenic model: role of anti-self (virus) immune response. Cell 65, 319–331 (1991).
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).
Seewaldt, S. et al. Virus-induced autoimmune diabetes: most β-cells die through inflammatory cytokines and not perforin from autoreactive (anti-viral) cytotoxic T-lymphocytes. Diabetes 49, 1801–1809 (2000).
Christen, U. et al. A dual role for TNF-α in type 1 diabetes: islet-specific expression abrogates the ongoing autoimmune process when induced late but not early during pathogenesis. J. Immunol. 166, 7023–7032 (2001).
Christen, U., McGavern, D. B., Luster, A. D., von Herrath, M. G. & Oldstone, M. B. Among CXCR3 chemokines, IFN-γ-inducible protein of 10 kDa (CXC chemokine ligand (CXCL) 10) but not monokine induced by IFN-γ (CXCL9) imprints a pattern for the subsequent development of autoimmune disease. J. Immunol. 171, 6838–6845 (2003).
Horwitz, M. S. et al. Diabetes induced by coxsackie virus: initiation by bystander damage and not molecular mimicry. Nature Med. 4, 781–785 (1998). This report describes the role of bystander activation of T cells leading to T1D onset following coxsackie virus B4 infection.
Katz, J. D., Wang, B., Haskins, K., Benoist, C. & Mathis, D. Following a diabetogenic T cell from genesis through pathogenesis. Cell 74, 1089–1100 (1993).
Stadinski, B. D. et al. Chromogranin A is an autoantigen in type 1 diabetes. Nature Immunol. 11, 225–231 (2010).
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).
Drescher, K. M., Kono, K., Bopegamage, S., Carson, S. D. & Tracy, S. Coxsackievirus B3 infection and type 1 diabetes development in NOD mice: insulitis determines susceptibility of pancreatic islets to virus infection. Virology 329, 381–394 (2004).
Horwitz, M. S., Ilic, A., Fine, C., Rodriguez, E. & Sarvetnick, N. Presented antigen from damaged pancreatic β cells activates autoreactive T cells in virus-mediated autoimmune diabetes. J. Clin. Invest. 109, 79–87 (2002).
Horwitz, M. S., Ilic, A., Fine, C., Balasa, B. & Sarvetnick, N. Coxsackieviral-mediated diabetes: induction requires antigen-presenting cells and is accompanied by phagocytosis of β cells. Clin. Immunol. 110, 134–144 (2004).
Graham, K. L. et al. Rotavirus infection of infant and young adult nonobese diabetic mice involves extraintestinal spread and delays diabetes onset. J. Virol. 81, 6446–6458 (2007).
Graham, K. L. et al. Rotavirus infection accelerates type 1 diabetes in mice with established insulitis. J. Virol. 82, 6139–6149 (2008).
Serreze, D. V. et al. Diabetes acceleration or prevention by a coxsackievirus B4 infection: critical requirements for both interleukin-4 and γ interferon. J. Virol. 79, 1045–1052 (2005).
Filippi, C. M., Estes, E. A., Oldham, J. E. & von Herrath, M. G. Immunoregulatory mechanisms triggered by viral infections protect from type 1 diabetes in mice. J. Clin. Invest. 119, 1515–1523 (2009).
Ansari, M. J. et al. The programmed death-1 (PD-1) pathway regulates autoimmune diabetes in nonobese diabetic (NOD) mice. J. Exp. Med. 198, 63–69 (2003).
Diana, J. & Lehuen, A. NKT cells: Friend or foe during viral infections? Eur. J. Immunol. 39, 3283–3291 (2009).
Serreze, D. V., Hamaguchi, K. & Leiter, E. H. Immunostimulation circumvents diabetes in NOD/Lt mice. J. Autoimmun. 2, 759–776 (1989).
Lee, B. J. et al. Limited effect of CpG ODN in preventing type 1 diabetes in NOD mice. Yonsei Med. J. 46, 341–346 (2005).
Quintana, F. J., Rotem, A., Carmi, P. & Cohen, I. R. Vaccination with empty plasmid DNA or CpG oligonucleotide inhibits diabetes in nonobese diabetic mice: modulation of spontaneous 60-kDa heat shock protein autoimmunity. J. Immunol. 165, 6148–6155 (2000).
Fallarino, F. et al. IDO mediates TLR9-driven protection from experimental autoimmune diabetes. J. Immunol. 183, 6303–6312 (2009).
Wen, L., Peng, J., Li, Z. & Wong, F. S. The effect of innate immunity on autoimmune diabetes and the expression of Toll-like receptors on pancreatic islets. J. Immunol. 172, 3173–3180 (2004).
Bras, A. & Aguas, A. P. Diabetes-prone NOD mice are resistant to Mycobacterium avium and the infection prevents autoimmune disease. Immunology 89, 20–25 (1996).
Baxter, A. G., Healey, D. & Cooke, A. Mycobacteria precipitate autoimmune rheumatic disease in NOD mice via an adjuvant-like activity. Scand. J. Immunol. 39, 602–606 (1994).
Harada, M., Kishimoto, Y. & Makino, S. Prevention of overt diabetes and insulitis in NOD mice by a single BCG vaccination. Diabetes Res. Clin. Pract. 8, 85–89 (1990).
Sadelain, M. W., Qin, H. Y., Lauzon, J. & Singh, B. Prevention of type I diabetes in NOD mice by adjuvant immunotherapy. Diabetes 39, 583–589 (1990).
Zaccone, P. et al. Salmonella typhimurium infection halts development of type 1 diabetes in NOD mice. Eur. J. Immunol. 34, 3246–3256 (2004).
Raine, T., Zaccone, P., Mastroeni, P. & Cooke, A. Salmonella typhimurium infection in nonobese diabetic mice generates immunomodulatory dendritic cells able to prevent type 1 diabetes. J. Immunol. 177, 2224–2233 (2006).
Sarkar, S. A. et al. Induction of indoleamine 2, 3-dioxygenase by interferon-γ in human islets. Diabetes 56, 72–79 (2007).
Sai, P. & Rivereau, A. S. Prevention of diabetes in the nonobese diabetic mouse by oral immunological treatments. Comparative efficiency of human insulin and two bacterial antigens, lipopolysacharide from Escherichia coli and glycoprotein extract from Klebsiella pneumoniae. Diabetes Metab. 22, 341–348 (1996).
Karumuthil-Melethil, S., Perez, N., Li, R. & Vasu, C. Induction of innate immune response through TLR2 and dectin 1 prevents type 1 diabetes. J. Immunol. 181, 8323–8334 (2008).
Zaccone, P. et al. Immune modulation by Schistosoma mansoni antigens in NOD mice: effects on both innate and adaptive immune systems. J. Biomed. Biotechnol. 2010, 795210 (2010).
Zaccone, P. et al. Schistosoma mansoni egg antigens induce Treg that participate in diabetes prevention in NOD mice. Eur. J. Immunol. 39, 1098–1107 (2009). These data show the importance of T Reg cells in the prevention of T1D in NOD mice by S. mansoni SEA through the induction of both indirect (DC mediated) and direct functional changes in diabetogenic CD4+ T cells.
Cooke, A. et al. Infection with Schistosoma mansoni prevents insulin dependent diabetes mellitus in non-obese diabetic mice. Parasite Immunol. 21, 169–176 (1999).
Zaccone, P. et al. Schistosoma mansoni antigens modulate the activity of the innate immune response and prevent onset of type 1 diabetes. Eur. J. Immunol. 33, 1439–1449 (2003).
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).
Tirabassi, R. S. et al. Infection with viruses from several families triggers autoimmune diabetes in LEW*1WR1 rats: prevention of diabetes by maternal immunization. Diabetes 59, 110–118 (2010).
Zipris, D. et al. Infections that induce autoimmune diabetes in BBDR rats modulate CD4+CD25+ T cell populations. J. Immunol. 170, 3592–3602 (2003).
Oldstone, M. B. Viruses as therapeutic agents. I. Treatment of nonobese insulin-dependent diabetes mice with virus prevents insulin-dependent diabetes mellitus while maintaining general immune competence. J. Exp. Med. 171, 2077–2089 (1990). This paper documents the ability of LCMV infection to prevent T1D in NOD mice without the general ablation of T cell function.
Takei, I. et al. Suppression of development of diabetes in NOD mice by lactate dehydrogenase virus infection. J. Autoimmun. 5, 665–673 (1992).
Wilberz, S., Partke, H. J., Dagnaes-Hansen, F. & Herberg, L. Persistent MHV (mouse hepatitis virus) infection reduces the incidence of diabetes mellitus in non-obese diabetic mice. Diabetologia 34, 2–5 (1991).
Smith, K. A., Efstathiou, S. & Cooke, A. Murine gammaherpesvirus-68 infection alters self-antigen presentation and type 1 diabetes onset in NOD mice. J. Immunol. 179, 7325–7333 (2007).
Martins, T. C. & Aguas, A. P. A role for CD45RBlow CD38+ T cells and costimulatory pathways of T-cell activation in protection of non-obese diabetic (NOD) mice from diabetes. Immunology 96, 600–605 (1999).
Toyota, T., Satoh, J., Oya, K., Shintani, S. & Okano, T. Streptococcal preparation (OK-432) inhibits development of type I diabetes in NOD mice. Diabetes 35, 496–499 (1986).
Alyanakian, M. A. et al. Transforming growth factor-beta and natural killer T-cells are involved in the protective effect of a bacterial extract on type 1 diabetes. Diabetes 55, 179–185 (2006).
Saunders, K. A., Raine, T., Cooke, A. & Lawrence, C. E. Inhibition of autoimmune type 1 diabetes by gastrointestinal helminth infection. Infect. Immun. 75, 397–407 (2007).
Hubner, M. P., Stocker, J. T. & Mitre, E. Inhibition of type 1 diabetes in filaria-infected non-obese diabetic mice is associated with a T helper type 2 shift and induction of FoxP3+ regulatory T cells. Immunology 127, 512–522 (2009).
Imai, S., Tezuka, H. & Fujita, K. A factor of inducing IgE from a filarial parasite prevents insulin-dependent diabetes mellitus in nonobese diabetic mice. Biochem. Biophys. Res. Commun. 286, 1051–1058 (2001).
We apologize to all the authors whose work we could not cite owing to space constrictions. The Cooke laboratory is supported by The Wellcome Trust, Medical Research Council (MRC) and Diabetes UK. P.Z. is supported by the MRC. The Lehuen laboratory is supported by the Institut National de la Santé et de la Recherche Médicale (INSERM), Agence Nationale de la Recherche (ANR-GENOPAT) and the European Foundation for the Study of Diabetes (EFSD).
The authors declare no competing financial interests.
- Non-obese diabetic (NOD) mice
Mice that spontaneously develop type 1 diabetes as a result of islet antigen-specific T cell-mediated destruction of pancreatic β-cells.
- X-linked agammaglobulinaemia
A human immunodeficiency that is caused by mutations in the gene encoding Bruton's tyrosine kinase (BTK) (which is located on the X chromosome).These mutations result in a block in B cell maturation and in poor antibody production. A naturally occurring mouse mutant of BTK, X-linked immune deficiency, is associated with less severe disease.
- Non-obese resistant (NOR) mice
NOR mice have the identical T cell developmental background as NOD mice, but they do not spontaneously develop type 1 diabetes.
- BDC2.5 TCR-transgenic NOD mice
T cells in these mice express a TCR specific for a pancreatic antigen but, interestingly, these mice have a decreased incidence of type 1 diabetes and develop a non-invasive insulitis. These mice are used as donors of islet antigen-specific CD4+ T cells and manipulation of these mice, such as injection of blocking CTLA4-specific antibody and infection with coxsackie virus B4, induces rapid type 1 diabetes.
- RIP–LCMV transgenic model
A transgenic mouse model of type 1 diabetes in which peptides derived from lymphocytic choriomeningitis (LCMV) are expressed in the pancreas under the control of the rat insulin promoter (RIP). Infection of the mice with LCMV leads to the development of type 1 diabetes as a result of infiltrating CD8+ effector T cells.
A component of cytolytic granules that participates in the permeabilization of plasma membranes, allowing granzymes and other cytotoxic components to enter target cells.
- Peripheral tolerance
The lack of self responsiveness of mature lymphocytes in the periphery to specific antigens. These mechanisms control potentially self-reactive lymphocytes that have escaped central tolerance. Peripheral tolerance is associated with the suppression of production of self-reactive antibodies by B cells and inhibition of self-reactive effector cells, such as cytotoxic T lymphocytes.
- T cell anergy
A state of T cell unresponsiveness to antigen-specific stimulation. It can be induced by stimulation with a large amount of specific antigen in the absence of the engagement of co-stimulatory molecules.
- Indoleamine 2,3-dioxygenase
(IDO). An intracellular haem-containing enzyme that catalyses the oxidative catabolism of tryptophan. IDO suppresses T cell responses and promotes immune tolerance in mammalian pregnancy, tumour resistance, chronic infection, autoimmunity and allergic inflammation.
- Invariant NKT (iNKT) cells
Lymphocytes that express a particular variable gene segment, Vα14 (in mice) and Vα24 (in humans), precisely rearranged to a particular Jα (joining) gene segment to yield T cell receptor α-chains that have an invariant sequence. Typically, these cells co-express cell surface markers that are encoded by the NK locus, and they are activated by recognition of CD1d, particularly when α-galactosylceramide is bound in the groove of CD1d.
- Molecular mimicry
Resemblance between epitopes contained in microbial and host proteins, leading to cross-reactivity of T cells in the host.
An infiltration of lymphocytes into pancreatic islets during the progression of type 1 diabetes. Insulitis can be innocuous or destructive.
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Lehuen, A., Diana, J., Zaccone, P. et al. Immune cell crosstalk in type 1 diabetes. Nat Rev Immunol 10, 501–513 (2010). https://doi.org/10.1038/nri2787
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