Zn-T8 is a novel autoantigen in type 1 diabetes (T1D). The role of Zn-T8 as a target in MHC class II-mediatedislet autoimmunity has remained largely unexplored. To our knowledge, there are no reports on the Zn-T8-specific CD4+ T cell responses in the preclinical phase of diabetes progression. We propose to determine therole of Zn-T8-specific T cell responses in T1D by investigating these responses in islet autoantibody positivefamily members of T1D patients stratified by a distinct disease risk using PBMC samples from TrialNet NaturalHistory Study. Our hypothesis is that CD4+ and CD8+ T cell responses to Zn-T8 are associated withprogression to T1D. Specifically we expect that Zn-T8 specific T cells in the high risk individuals display amemory phenotype associated with recent activation. We also expect that in the high risk individuals bothCD4+ and CD8+ T cell responses are more robust and targeted to multiple epitopes. The comparison betweenhigh and low risk subjects is expected to reveal a potential regulatory phenotype in the latter, which coulddiscriminate the subjects who are unlikely to progress to the disease despite of the same MHC class IIgenotypes. Furthermore, we predict that there will be differences in the Zn-T8 epitope utilization and/or T cellreactivity when subjects are stratified by SLC30A8 polymorphism. The overall goal of the project is to providea novel insight to T cell-mediated autoimmunity in T1D which could be applied for monitoring the diseaseprogression and the immunological outcomes of therapies in clinical trials. Furthermore, improved knowledgeof the mechanisms of autoimmune process leading to T1D will contribute to discovery of new therapeutictargets.
Incidence of type 1 diabetes has multiplied across the world during the past decades especiallyin the young children. This is increasing public health burden and warrants a more urgent andfocused approach to early prediction of the disease progression in those at risk. Our proposedstudy is relevant for understanding the pathogenesis of the disease progression and preventionof type 1 diabetes.