Proinsulin-specific, HLA-DQ8, and HLA-DQ8-transdimer-restricted CD4+ T cells infiltrate islets in type 1 diabetes.
Diabetes
; 64(1): 172-82, 2015 Jan.
Article
em En
| MEDLINE
| ID: mdl-25157096
ABSTRACT
Type 1 diabetes (T1D) develops when insulin-secreting ß-cells, found in the pancreatic islets of Langerhans, are destroyed by infiltrating T cells. How human T cells recognize ß-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 ß-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.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Proinsulina
/
Linfócitos T CD4-Positivos
/
Antígenos HLA-DQ
/
Ilhotas Pancreáticas
/
Diabetes Mellitus Tipo 1
Limite:
Humans
Idioma:
En
Revista:
Diabetes
Ano de publicação:
2015
Tipo de documento:
Article