HLA class II mediates type 1 diabetes risk by anti-insulin repertoire selection

Type 1 diabetes (T1D) is a common autoimmune disorder characterized by the destruction of insulin-secreting pancreatic β cells [1], in which polymorphism of the human leukocyte antigen (HLA) class II region is the major genetic risk factor [2, 3, 4]. However, how variation in class II molecules alters T1D risk remains a longstanding question. Here we show how T1D risk due to HLA class II haplotype combinations [5] correlates with the frequency of negatively charged sequences in the CDR3β region of CD4 + T cell receptor (TCR) repertoires purified from peripheral blood. These sequences are known to be common in receptors that bind insulin B:9–23 [6], the primary autoantigen in T1D. We also show the same effect in circulating activated CD4 + T cells from newly-diagnosed T1D cases, and in islet-infiltrating T cells from patients with active T1D. Furthermore, we demonstrate that the proportion of insulin-reactive CD4 + T cells present in islets is predicted by the frequency of these negatively charged CDR3β amino acid sequences. Our results suggest diagnostic uses of T cell repertoire profiling in early detection of insulin autoimmunity, and inform ongoing efforts to improve tolerance induction to insulin and prevention of T1D [7].