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Proinsulin-specific, HLA-DQ8, and HLA-DQ8-transdimer-restricted CD4+ T cells infiltrate islets in type 1 diabetes.
- Source :
-
Diabetes [Diabetes] 2015 Jan; Vol. 64 (1), pp. 172-82. Date of Electronic Publication: 2014 Aug 25. - Publication Year :
- 2015
-
Abstract
- 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.<br /> (© 2015 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered.)
- Subjects :
- Autoimmunity immunology
CD4-Positive T-Lymphocytes cytology
Cells, Cultured
Diabetes Mellitus, Type 1 genetics
Dimerization
Epitope Mapping
HLA-DP Antigens chemistry
HLA-DP Antigens genetics
HLA-DP Antigens immunology
HLA-DQ Antigens chemistry
HLA-DQ Antigens genetics
HLA-DR Antigens chemistry
HLA-DR Antigens genetics
HLA-DR Antigens immunology
Heterozygote
Humans
Insulin-Secreting Cells cytology
Insulin-Secreting Cells immunology
CD4-Positive T-Lymphocytes immunology
Diabetes Mellitus, Type 1 immunology
HLA-DQ Antigens immunology
Islets of Langerhans immunology
Proinsulin immunology
Subjects
Details
- Language :
- English
- ISSN :
- 1939-327X
- Volume :
- 64
- Issue :
- 1
- Database :
- MEDLINE
- Journal :
- Diabetes
- Publication Type :
- Academic Journal
- Accession number :
- 25157096
- Full Text :
- https://doi.org/10.2337/db14-0858