Colorado PROFILES, The Colorado Clinical and Translational Sciences Institute (CCTSI)
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Analysis of diabetogenic human T cell receptors

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Our demonstration that the islet-specific zinc transporter ZnT8 is a major target of autoantibodies in newly diabetic subjects was arguably the most significant new diabetes biomarker discovered in over a decade. We now have evidence that ZnT8 is also a major target of autoreactive T-cells. The holy grail of type 1 diabetes (T1D) research is the development of autoantigen-specific therapies that can prevent or arrest disease progression in humans. To date attention has focused mainly on (pro)insulin, HSP60 and GAD65 as potential targets;we propose that ZnT8 is also a highly attractive therapeutic target, and has several potential advantages over those currently under investigation. Firstly, unlike GAD65 and HSP60, ZnT8 is essentially islet specific. Secondly, unlike insulin it does not have systemic bioactivity. Thirdly, unlike (pro)insulin, in many individuals ZnT8 appears to be a late target of autoimmunity, which will likely result in those persons having a larger precursor pool of ZnT8-specific than proinsulin-specific nave T-cells that can be induced to adopt an immunoregulatory phenotype at the onset of clinical disease. A necessary first step in exploiting the considerable therapeutic potential of ZnT8 is to gain a greater understanding of spontaneous autoimmunity to this key autoantigen in humans. Specifically, to define the major epitopes within ZnT8 that are restricted to MHC class II glycoproteins that are associated with diabetes susceptibility, and characterize at the molecular level the T cell receptors (TCRs) that recognize the complexes between them. These are the major goals of our proposal, which will have 2 specific aims. Firstly, to identify the naturally processed epitopes from ZnT8 presented by high-risk HLA alleles, conduct a comprehensive analysis of the cytokine and chemokine profiles of T-cells recognizing them, and map their key MHC contact residues. Secondly, to clone and sequence TCRs from both pro-inflammatory and regulatory ZnT8-specific T-cells, reconstitute them in TCR negative Jurkat thymomas, and determine the key contact residues of the cognate epitope peptides, with the goal of creating altered peptide ligands that can differentially promote the differentiation/expansion of potentially protective T-cells. We believe that this study will provide new insight into diabetogenesis in general, and the role of ZnT8 in particular. We also anticipate that it will confirm the existence of naturally occurring ZnT8-specific regulatory Tcells in humans, and provide important new clues into the optimal design of drugs and protocols that can ultimately be translated to the clinic.
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