Proinsulin-Specific, HLA-DQ8, and HLA-DQ8-Transdimer–Restricted CD4+ T Cells Infiltrate Islets in Type 1 Diabetes
-
- Vimukthi Pathiraja
- Immunology and Diabetes Unit, St. Vincent’s Institute of Medical Research, Fitzroy, Victoria, Australia
-
- Janine P. Kuehlich
- Immunology and Diabetes Unit, St. Vincent’s Institute of Medical Research, Fitzroy, Victoria, Australia
-
- Peter D. Campbell
- Immunology and Diabetes Unit, St. Vincent’s Institute of Medical Research, Fitzroy, Victoria, Australia
-
- Balasubramanian Krishnamurthy
- Immunology and Diabetes Unit, St. Vincent’s Institute of Medical Research, Fitzroy, Victoria, Australia
-
- Thomas Loudovaris
- Immunology and Diabetes Unit, St. Vincent’s Institute of Medical Research, Fitzroy, Victoria, Australia
-
- P. Toby H. Coates
- Department of Medicine, University of Adelaide, Adelaide, South Australia, Australia
-
- Thomas C. Brodnicki
- Immunology and Diabetes Unit, St. Vincent’s Institute of Medical Research, Fitzroy, Victoria, Australia
-
- Philip J. O’Connell
- National Pancreas Transplant Unit, University of Sydney at Westmead Hospital, Sydney, New South Wales, Australia
-
- Katherine Kedzierska
- Department of Microbiology and Immunology, University of Melbourne at the Peter Doherty Institute for Infection and Immunity, Parkville, Victoria, Australia
-
- Christine Rodda
- University of Melbourne, NorthWest Academic Centre, Sunshine Hospital, St. Albans, Victoria, Australia
-
- Philip Bergman
- Department of Paediatrics, Monash University, Clayton, Victoria, Australia
-
- Erin Hill
- Department of Paediatrics, Monash University, Clayton, Victoria, Australia
-
- Anthony W. Purcell
- Department of Biochemistry and Molecular Biology, Monash University, Clayton, Victoria, Australia
-
- Nadine L. Dudek
- Department of Biochemistry and Molecular Biology, Monash University, Clayton, Victoria, Australia
-
- Helen E. Thomas
- Immunology and Diabetes Unit, St. Vincent’s Institute of Medical Research, Fitzroy, Victoria, Australia
-
- Thomas W.H. Kay
- Immunology and Diabetes Unit, St. Vincent’s Institute of Medical Research, Fitzroy, Victoria, Australia
-
- Stuart I. Mannering
- Immunology and Diabetes Unit, St. Vincent’s Institute of Medical Research, Fitzroy, Victoria, Australia
抄録
<jats:p>Type 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.</jats:p>
収録刊行物
-
- Diabetes
-
Diabetes 64 (1), 172-182, 2014-08-25
American Diabetes Association