Title: Proinsulin-Specific, HLA-DQ8, and HLA-DQ8-Transdimer-Restricted CD4(+) T Cells Infiltrate Islets in Type 1 Diabetes
Authors: Pathiraja, V
Kuehlich, JP
Campbell, PD
Krishnamurthy, B
Loudovaris, T
Coates, PTH
Brodnicki, TC
O’Connell, PJ
Kedzierska, K
Rodda, C
Bergman, P
Hill, E
Purcell, AW
Dudek, NL
Thomas, HE
Kay, TWH
Mannering, SI
Issue Year: 2015
Series DIABETES: 64(1): 172-182
Abstract Type 1 diabetes (T1D) develops when insulin-secreting beta-cells, found in the pancreatic islets of Langerhans, are destroyed by infiltrating T cells. How human T cells recognize beta-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 beta-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.
URI: https://publications.svi.edu.au/publications/1807
Other Identifiers 10.2337/db14-0858
Publication type Article
Grant ID GNT1061961; GNT1037321; GNT1042735
Find it online http://diabetes.diabetesjournals.org/content/64/1/172.long