Cure of prediabetic mice by viral infections involves lymphocyte recruitment along an IP-10 gradient (original) (raw)
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F1000 - Post-publication peer review of the biomedical literature, 2009
Type 1 diabetes (T1D) is an autoimmune disease that is caused by the destruction of insulin-producing β cells. Viral infections induce immune responses that can damage β cells and promote T1D or on the other hand prevent the development of the disease. However, the opposing roles of viral infections in T1D are not understood mechanistically. We report here that viruses that do not inflict damage on β cells provided protection from T1D by triggering immunoregulatory mechanisms. Infection of prediabetic NOD mice with Coxsackie virus B3 or lymphocytic choriomeningitis virus (LCMV) delayed diabetes onset and reduced disease incidence. Delayed T1D onset was due to transient upregulation of programmed cell death-1 ligand 1 (PD-L1) on lymphoid cells, which prevented the expansion of diabetogenic CD8 + T cells expressing programmed cell death-1 (PD-1). Reduced T1D incidence was caused by increased numbers of invigorated CD4 + CD25 + Tregs, which produced TGF-β and maintained long-term tolerance. Full protection from T1D resulted from synergy between PD-L1 and CD4 + CD25 + Tregs. Our results provide what we believe to be novel mechanistic insight into the role of viruses in T1D and should be valuable for prospective studies in humans.
Journal of Autoimmunity, 2009
Recent studies suggest a beneficial role for blocking CD103 signaling in preventing islet allograft rejection and thus Type 1 diabetes (T1D) in non-obese diabetic mice (NOD). However, antibody blockade approaches generally raise anti-microbial safety issues, necessitating additional studies to address the possible adverse effects of antibody therapy. Here we report that CD103 had no significant impact on the development of primary and memory CD8 + or CD4 + responses after acute lymphocytic choriomeningitis virus (LCMV) infection. In addition, CD103 was found to be dispensable for T1D progression in a rapid, CD8-mediated virally-induced T1D model (the rat insulin promoter-[RIP]-LCMV), suggesting that its previous efficacy in the NOD mouse model may not be related to its effect on the generation, memory conversion and/or effector function of CD8 + or CD4 + T cells. While the data does not preclude a role for CD103 in T1D in its entirety, the current study does provide much evidence to suggest that CD103 blockade may prove to be a safe intervention for autoimmunity and allo-transplantation. While in cases of rapid microbial (CD8)-driven T1D CD103 antibody blockade may not limit disease progression or severity, in mucosally-driven cases of T1D anti-CD103 antibody treatment may provide a new and safe therapeutic avenue.
Target cell defense prevents the development of diabetes after viral infection
Nature Immunology, 2002
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.
Innate Immune Pathways in Virus-Induced Autoimmune Diabetes
Annals of The New York Academy of Sciences, 2008
We recently hypothesized that Toll-like receptor-induced innate upregulation by Kilham rat virus (KRV) in the BioBreeding diabetes-resistant (BBDR) rat model plays a key role in the mechanism of diabetes induction. To address this hypothesis, we analyzed innate immune signaling pathways upregulated by KRV in vitro and in vivo. We demonstrate that KRV activates the signal transducer and activator of transcription (STAT)-1 in spleen cells in vitro and that this activation can be blocked by TLR9 inhibition. We also show that KRV upregulates STAT-1 in pancreatic lymph nodes early after virus infection. Our data may implicate TLR9-induced STAT-1 signaling pathways in KRVinduced innate immune activation in the BBDR rat and raise the possibility that these pathways are involved in mediating autoimmune diabetes.
Diabetes, 2000
Autoimmune diabetes is caused by selective loss of insulin-producing pancreatic -cells. The main factors directly implicated in -cell death are autoreactive, cytotoxic (islet-antigen specific) T-lymphocytes (CTL), and inflammatory cytokines. In this study, we have used an antigen-specific model of virally induced autoimmune diabetes to demonstrate that even high numbers of autoreactive CTL are unable to lyse -cells by perforin unless major histocompatibility complex class I is upregulated on islets. This requires the presence of inflammatory cytokines induced by viral infection of the exocrine pancreas but not of the -cells. Unexpectedly, we found that the resulting perforin-mediated killing of -cells by autoreactive CTL is not sufficient to lead to clinically overt diabetes in vivo, and it is not an absolute prerequisite for the development of insulitis, as shown by studies in perforin-deficient transgenic mice. In turn, destruction of -cells also requires a direct effect of ␥-interferon (IFN-␥), which is likely to be in synergy with other cytokines, as shown in double transgenic mice that express a mutated IFN-␥ receptor on their -cells in addition to the viral (target) antigen and do not develop diabetes. Thus, destruction of most -cells occurs as cytokine-mediated death and requires IFN-␥ in addition to perforin. Understanding these kinetics could be of high conceptual importance for the design of suitable interventions in prediabetic individuals at risk to develop type 1 diabetes. Diabetes
Diabetes, 2013
Cytotoxic T lymphocytes (CTLs) constitute a major effector population in pancreatic islets from patients suffering from type 1 diabetes (T1D) and thus represent attractive targets for intervention. Some studies have suggested that blocking the interaction between the chemokine CXCL10 and its receptor CXCR3 on activated CTLs potently inhibits their recruitment and prevents b-cell death. Since recent studies on human pancreata from T1D patients have indicated that both ligand and receptor are abundantly present, we reevaluated whether their interaction constitutes a pivotal node within the chemokine network associated with T1D. Our present data in a viral mouse model challenge the notion that specific blockade of the CXCL10/CXCR3 chemokine axis halts T1D onset and progression. Diabetes 62: [2492][2493][2494][2495][2496][2497][2498][2499] 2013 T he mechanisms governing autoreactive T-cell homing to pancreatic islets in type 1 diabetes (T1D) are poorly characterized, which in turn has impeded the rational design of therapies at this crucial intersection. Interest in targeting chemokines was sparked by a study that identified b-cells as a key source of CXCL10 in the viral rat insulin promoter (RIP)lymphocytic choriomeningitis virus (LCMV) diabetes model, which in turn would serve to attract CXCR3expressing T cells (1). In CXCR3-deficient mice, diabetes onset was markedly delayed. It was subsequently reported in the same model that among CXCR3 ligands, which include CXCL9, -10, and -11, only CXCL10 exerted dominant effects on T-cell recruitment .
European Journal of Immunology, 1990
In order to gain insight into the interaction between autoimmunity and viral infection in the onset of insulin-dependent diabetes, non-obese diabetic (NOD) mice which spontaneously develop autoimmune diabetes were inoculated with the diabetogenic variant of the encephalomyocarditis virus (EMCV-D) before the onset of the disease. The pre-diabetic period was divided into two phases: the early phase (days 88 to 116) during which development of spontaneous diabetes is rare and the late phase (day 123 to 200) during which the incidence of spontaneous diabetes is high. As controls ICR mice of common ancestry were also inoculated. During the early phase diabetes was observed in 4/10 inoculated, 0/13 control NOD and 7/13 inoculated ICR males vs. 6/12 inoculated, 1/11 control NOD and 0/15 inoculated ICR females. However, in NOD female, virus-induced diabetes prevalence was variable from one experiment to another. In parallel the flow cytometric analysis showed a high percentage of L3T4+ T lymphocytes in the pancreas of inoculated female NOD mice 10 days after the infection. At this time a large proportion of both L3T4+ and Ly-2+ cells expressed the interleukin 2 receptor. During the late phase no new case of diabetes occurred in inoculated NOD mice but one case was observed in control NOD males and five in control NOD females. This prevention of autoimmune diabetes was constantly found in other experiments. Insulitis was milder in inoculated NOD mice of both sexes than in control NOD. Adoptive transfer of diabetes into irradiated 8-week-old males by splenocytes from 28-week-old females was successful in five out seven attempts with control splenocytes and in zero out of six attempts with splenocytes from inoculated mice. This immunosuppression was specific as the ability of lymphocytes to respond to soluble or allogeneic antigens was preserved. In the early phase EMCV-D precipitated the onset of diabetes in females NOD mice by amplifying L3T4+ T lymphocyte-mediated immune mechanisms. During the late phase viral infection had lessened immune processes in animals which had resisted or recovered from virus-induced diabetes.