A study of T cell antigens relevant to autoimmune diabetes in mice and humans
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Type 1 diabetes (T1D) is an autoimmune disease caused by the T cell mediated attack on pancreatic beta cells, leading to insulin deficiency. Many factors, both genetic and environmental in origin, contribute to the development of the disease in humans and in the well-studied model of the disease, the non-obese diabetic (NOD) mouse. Loss of tolerance to self-antigens is thought to play a crucial role in the development of autoimmune diabetes, and knowledge of disease-relevant antigenic epitopes and their role during progression to type 1 diabetes (T1D) is critical for the development of therapeutics. Our aims were to, (1) identify novel epitopes derived from the beta cell antigens islet-specific glucose-6-phosphatase catalytic subunit-related protein (IGRP) and insulin; and (2) study the immunological basis for the genetic association between low thymic insulin expression and T1D. First, we wanted to determine whether IGRP, the most frequently targeted CD8 T-cell antigen in nonobese diabetic (NOD) mice, is targeted in humans. We collected blood from patients and controls and tested the samples for reactivity to IGRP peptides. Using IFNgamma ELISPOT, we found that 65% of patients and zero controls have T-cell reactivity to at least one IGRP epitope. We then used HLA-A*0201-transgenic NOD mice and identified two novel insulin epitopes frequently targeted by CD8 T-cells during disease progression. These epitopes are excellent candidates for translation to humans. Second, we studied the specificity of the islet-infiltrating T-cell repertoire in NOD mice lacking thymic insulin expression (NOD.Ins24 -/-). We found that NOD.Ins2-/- mice have a much greater proportion of insulin-specific CD8 and CD4 T-cells in the islet infiltrate. In addition, novel insulin-derived epitopes are targeted by CD8 T-cells in these mice. Further, we found that NOD.Ins24-/- mice have lower percentages of regulatory T-cells in the islet. These findings, showing that multiple T cell compartments are affected in NOD.Ins2-/- mice, are the first to directly demonstrate that lack of thymic autoantigen expression can lead to increased autoreactivity and accelerated T1D development. These findings contribute to the understanding of the biology underlying development of diabetes in NOD mice and T1D patients, as well as to other T cell-mediated autoimmune diseases.