Proinsulin-specific, HLA-DQ8, and HLA-DQ8-transdimer-restricted CD4(+) T cells infiltrate islets in type 1 diabetes

This article contains Supplementary Data online at http://diabetes.diabetesjournals.org/lookup/suppl/doi:10.2337/db14-0858/-/DC1Type 1 diabetes (T1D) develops when insulin-secreting β-cells, found in the pancreatic islets of Langerhans, are destroyed by infiltrating T cells. How human T cells recognize β-cell-derived antigens remains unclear. Genetic studies have shown that HLA and insulin alleles are the most strongly associated with risk of T1D. These long-standing observations implicate CD4(+) T-cell responses against (pro)insulin in the pathogenesis of T1D. To dissect the autoimmune T-cell response against human β-cells, we isolated and characterized 53 CD4(+) T-cell clones from within the residual pancreatic islets of a deceased organ donor who had T1D. These 53 clones expressed 47 unique clonotypes, 8 of which encoded proinsulin-specific T-cell receptors. On an individual clone basis, 14 of 53 CD4(+) T-cell clones (26%) recognized 6 distinct but overlapping epitopes in the C-peptide of proinsulin. These clones recognized C-peptide epitopes presented by HLA-DQ8 and, notably, HLA-DQ8 transdimers that form in HLA-DQ2/-DQ8 heterozygous individuals. Responses to these epitopes were detected in the peripheral blood mononuclear cells of some people with recent-onset T1D but not in HLA-matched control subjects. Hence, proinsulin-specific, HLA-DQ8, and HLA-DQ8-transdimer-restricted CD4(+) T cells are strongly implicated in the autoimmune pathogenesis of human T1D.Vimukthi Pathiraja, Janine P. Kuehlich, Peter D. Campbell, Balasubramanian Krishnamurthy, Thomas Loudovaris, P. Toby H. Coates, Thomas C. Brodnicki, Philip J. O, Connell, Katherine Kedzierska, Christine Rodda, Philip Bergman, Erin Hill, Anthony W. Purcell, Nadine L. Dudek, Helen E. Thomas, Thomas W.H. Kay, and Stuart I. Mannerin