Proinsulin C-peptide is an autoantigen in people with type 1 diabetes

Significance Type 1 diabetes (T1D) is an incurable autoimmune disease caused by T cell-mediated destruction of insulin-producing beta cells. The beta-cell antigens recognized by human CD4 + T cells in T1D are poorly defined. Here, we show that C-peptide, derived from proinsulin, is recognized by CD4 + T cells from the blood of >60% of people with recent onset T1D. The majority of C-peptide–derived epitopes were recognized when presented by high-risk T1D HLA alleles. For some T cells, full-length C-peptide was a more potent stimulator than shorter peptides. Hence, our data suggests that full-length C-peptide may be uniquely antigenic in human T1D. C-peptide may be useful in assays to monitor changes in T cell autoimmunity and antigen-specific therapies for T1D.