Virus-induced autoimmune diabetes: most beta-cells die through inflammatory cytokines and not perforin from autoreactive (anti-viral) cytotoxic T-lymphocytes.

Abstract

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

Tipping the balance between necrosis and apoptosis in human and murine cells treated with interferon and dsRNA

“…63 Such virusinduced diabetes is suggested to occur due to inflammatory cytokines, and not perforin from autoreactive (antiviral) cytotoxic T-lymphocytes. 64 The cytokines interleukin-1, TNF and IFN are cytotoxic to b-cells by inducing formation of oxygen-free radicals, nitric oxide, and peroxynitrite in the bcells themselves. 64,65 The effect of IFNs is intensified by dsRNA that can inhibit b-cell function and induce islet damage by its own.…”

“…64 The cytokines interleukin-1, TNF and IFN are cytotoxic to b-cells by inducing formation of oxygen-free radicals, nitric oxide, and peroxynitrite in the bcells themselves. 64,65 The effect of IFNs is intensified by dsRNA that can inhibit b-cell function and induce islet damage by its own. 54,66 Interestingly, insulin-dependent diabetes mellitus was reported to occur also after treatment of viral hepatitis patients with exogenous IFNs.…”

γ-Interferon Signaling in Pancreatic β-Cells Is Persistent but Can Be Terminated by Overexpression of Suppressor of Cytokine Signaling-1

“…In vitro, combinations of these cytokines result in ␤-cell damage (6 -11). In vivo, we have shown that ␤-cells unresponsive to IFN-␥ are protected from destruction in the lymphocytic choriomeningitis virus-induced transgenic mouse model of diabetes (12). On the other hand, we have described that IFN-␥ is a key regulator of class I MHC expression but is not required for ␤-cell destruction in the nonobese diabetic (NOD) mouse model (13,14).…”

CTLA-4 Differentially Regulates T Cell Responses to Endogenous Tissue Protein Versus Exogenous Immunogen

“…To compare the same numbers of 3A9/wild-type and 3A9/ CTLA-4 Ϫ/Ϫ cells, we used high-speed cell sorting to isolate 3A9 T cells from the pancreatic LNs of mice that had received 3A9/ wild-type or 3A9/CTLA-4 Ϫ/Ϫ cells and had been immunized (HEL/alum s.c.), and analyzed their responsiveness in vitro. We were particularly interested in the ability of the T cells to produce IFN-␥ because most studies have indicated a key role for this cytokine (12)(13)(14) and its receptor (15)(16)(17) in the pathogenesis of diabetes. Despite the striking difference in the ability of wild-type and CTLA-4 Ϫ/Ϫ 3A9 T cells to induce diabetes in RIP-HEL mice, when isolated from the pancreatic LN and analyzed on a per cell basis, both cell types showed comparable proliferative responses to HEL peptide and comparable levels of IFN-␥ production (Fig.…”