The mammalian immune system contains multiple intricately regulated networks of opposing stimulatory and inhibitory signals that together allow protective pathogen-specific immunity to be rapidly mobilized during infection while simultaneously quenching self-reative immune responses that can result in autoimmunity. Interestingly while the molecules that comprise these immune stimulatory or inhibitory networks are now being defined, the biological basis for how and why organ specific autoimmune disease occurs and the signals that cause breakdown in immune tolerance to self-antigens during autoimmunity remains largely unknown. In the well-characterized Non-obese diabetes (NOD) model of type I diabetes, immune tolerace that prevents the onset of islet cell desctuction is mediated in large part by T cell suppression through program cell death ligand-1 (PDL-1). Simarily PDL-1-medated suppression maintains T cell exhaustion in numerous models of chronic infection. However in sharp contrast, our recent studies using primary Listeria monocytogenes infeciton indicate that these PDL-1-mediated suppressive signals are re-programmed into T cell stimulation signals during acute infection conditions. These results combined with the epidemiological observation that most cases of type 1 diabetes are triggered by non-specific infectious illness suggest that acute infection through re-programming the normally suppressive effects of PDL-1 to self-antigen may trigger autoimmune diabetes. Accordingly in this application, we propose to examine the mechanistic basis for how acute infection reverses PDL-1 mediated T cell suppression and test the consequences of reversing PDL-1 function in a mouse model of autoimmune diabetes.
Aim 1 of this application will explore roles of specific inflammatory cytokines in reprogramming PDL-1 function using mice with individual or combined defects in specific cytokine or cytokine receptors.
Aim 2 of this application will examine the specific immune cell type(s) that PDL-1 acts on to confer either T cell stimulatory or inhibitory effects using cells isolated from PDL-1 deficient mice. Lastly, experiments outlined in aim 3 will directly test how acute infection, and the role of specific cytokines and immune cells described in the first two aims, reverses PDL-1 mediated tolerance using diabetes susceptible NOD mice. The results of these experiments will provide a mechansitic explanation for how autoimmunity is triggered in susceptible individuals, and more importantly elucide the specific immune cytokines and cells involved in this process allowing more rational prevention and immunotherapies for type 1 diabetes.
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