Assessment of thymic output in the context of genetics, environmental exposures, and progression to type 1 diabetes

About This Grant

Project Summary Type 1 Diabetes is rising in incidence and is most commonly diagnosed before the age of 10, predisposing patients to lifelong complications. The window for intervention is narrowing as the overall mean age at diagnosis is decreasing with time. Although we can identify genetic risk for T1D using polygenic risk scores, disease prevalence among those without known genetic risk is also increasing over time, suggesting that environmental factors may contribute to the autoimmune process. Our current understanding of the involvement and interplay of genetics and environment has relied on intensive population screening efforts, including The Environmental Determinants of Diabetes in the Young (TEDDY) study supported by the NIH. The major inflection point for T1D disease progression is seroconversion (development of autoantibody positivity). Though valuable in prediction, these tests are not administered in pediatric clinics. Population level screening for this relatively low-occurrence event is laborious and costly, as time from seroconversion to disease development can range from months to years, depending on genetics, age at seroconversion, the specificity of the first-appearing autoantibody, as well as the autoantibody titer. Decades of research support autoantibodies as predictive tools for estimating likelihood of T1D over time, yet the field still lacks understanding of the early initiating events pushing T cells to enact pancreatic beta cell loss. We have defined key features of accelerated immune aging in T1D via flow cytometry. However, although peripheral T cell phenotype and function have been extensively studied in T1D, it remains unclear how thymic function is impacted during the progression to diabetes. The thymus is exquisitely responsive to environmental stimuli, including stress, nutritional changes, viral infection and inflammation, all noted as major contributors to T1D. We hypothesize that the observation of accelerated aging and exhaustion in T1D is reflective of a smaller, inflammatory- skewed naïve T cell pool, reduced thymic output, and peripheral expansion of memory T cells in response to environmental insults. This provides an opportunity for a T cell-specific biomarker of disease progression. The objective of this proposal is to inform on peripheral T cell phenotype and thymic output as a function of age, environmental exposures and risk for T1D. This approach emphasizes sample sparing assays and novel analysis of existing data. We expect that this project will provide robust biomolecular signatures, producing a novel, clinically relevant biomarker in the pathogenesis of T1D.