Enhancing antigen-based therapy for T1D by T cell coreceptor tuning

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SUMMARY/ABSTRACT Currently no cure exists for Type 1 diabetes (T1D). Due to immune-mediated destruction of the insulin- producing  cells, treatment of T1D is limited to daily exogenous insulin administration. Needed are immunotherapies that effectively suppress  cell autoimmunity longterm in order to prevent and treat T1D. One approach is the administration of cell autoantigens to induce differentiation of adaptive regulatory CD4+ T cells (aTreg). The approach is appealing since autoimmunity can be selectively targeted while leaving acquired immunity unperturbed. A major hurdle, however, is inducing a sufficiently sized and subset diverse aTreg pool, while avoiding expansion of pathogenic effector T cells (Teff). The size and nature of the aTreg pool is particularly important at late preclinical T1D stages and at the onset of clinical diabetes, when a high frequency of diabetogenic CD4+ and CD8+ Teff is found. This R21 outlines a novel approach to enhance the efficacy of antigen therapy by “tuning” the function of CD4. CD4 binding to MHCII activates a signaling cascade that contributes to overall TCR signaling strength. We hypothesize that modulating CD4 function and TCR signaling strength, results in increased and selective induction of aTreg by antigen vaccination. In our model, differentiation of aTreg subsets is determined by varying the level of coreceptor tuning (CoT). We will employ nondepleting CD4 antibody to achieve CoT. Key objectives of this R21 are to gain initial insight into the mechanism(s) by which CoT selectively promotes aTreg differentiation (Aim 1), and determine the therapeutic efficacy of this combinatorial approach (Aim 2). If successful, combined CoT and self-antigen vaccination is expected to be applicable not only for the prevention and treatment of T1D, but also for other T cell-mediated autoimmune diseases and pathologies.