TNF‐α impairs peripheral tolerance towards β‐cells, and local costimulation by B7.1 enhances the effector function of diabetogenic T cells

Abstract

Maintenance of peripheral tolerance and inactivation of autoreactive T cells is based on a delicate balance between pro-inflammatory and protective cytokines that is poorly understood. We have here addressed how the local expression of the inflammatory cytokine TNF- § can impair peripheral tolerance and lead to autoreactivity. After transplantation of pancreata that are immunogenic due to g -cell expression of B7.1 and TNF- § , into thymectomized and euthymic syngeneic mice, we found that only euthymic mice rejected the grafts. This result suggests that under normal circumstances autoreactive T cells are functionally inactivated, and initiation of an autoreactive response requires de-novo generation of T cells. By contrast, thymectomized mice expressing TNF- § on the endogenous islets rejected the grafts, showing that expression of TNF- § prevents functional silencing of the autoreactive T cells. Thus, this study provides a mechanism by which TNF- § and possibly chronic inflammatory responses may promote autoimmune diseases. Furthermore, we have investigated whether B7.1 can enhance T cell responses of already activated T cells leading to islet rejection. By transplantation of wild-type and B7.1-expressing islets into overtly diabetic mice we found that only the wild-type islets could restore normoglycemia, suggesting that costimulation by B7.1 is required in the expansion or effector phase of the response.

Genetic differentiation of Poly I:C from B:9-23 peptide induced experimental autoimmune diabetes

“…As expected, mice with transgenic expression of B7.1 molecule and viral glycoprotein on beta cells together with glycoprotein-specific transgenic T cells develop insulitis and diabetes while mice with a combination of only two-thirds of the above transgenes do not develop diabetes [26]. Islet B7.1 expression may directly influence the threshold for autoimmune T-cell killing through enhancement of effector function of diabetogenic T cells, namely cytotoxic T lymphocytes [27][28][29]. B:9-23 peptide induced aggressive intra islet insulitis regardless of the age of onset and destruction was restricted to beta cells.…”

CD40 expression on human pancreatic duct cells: role in nuclear factor-kappa B activation and production of pro-inflammatory cytokines

“…However, the role of TNF-α in Type 1 diabetes is still controversial. Previous studies in animal models for Type 1 diabetes have clearly demonstrated that TNF-α could participate in the development of diabetes, while other studies have highlighted the role of TNF-α in silencing the autoimmune process, suggesting a dual role of TNF-α in the development of the disease based on the timing of TNF-α expression [47,48,49,50,51,52,53].…”

IL-6 and TNF-α Synergistically Inhibit Allograft Acceptance

“…8 Indeed, TNF-␣, like IL-6, promotes T cell proliferation 9 and also impairs peripheral tolerance of islets. 10 It is likely that there are redundant pathways between inflammatory cytokines in immune regulation, 11 but it is not clear whether IL-6 and TNF-␣ cooperate in preventing transplant tolerance.…”