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Diabetes ; 66(3): 722-734, 2017 03.
Artigo em Inglês | MEDLINE | ID: mdl-27920090

RESUMO

Type 1 diabetes results from chronic autoimmune destruction of insulin-producing ß-cells within pancreatic islets. Although insulin is a critical self-antigen in animal models of autoimmune diabetes, due to extremely limited access to pancreas samples, little is known about human antigenic targets for islet-infiltrating T cells. Here we show that proinsulin peptides are targeted by islet-infiltrating T cells from patients with type 1 diabetes. We identified hundreds of T cells from inflamed pancreatic islets of three young organ donors with type 1 diabetes with a short disease duration with high-risk HLA genes using a direct T-cell receptor (TCR) sequencing approach without long-term cell culture. Among 85 selected CD4 TCRs tested for reactivity to preproinsulin peptides presented by diabetes-susceptible HLA-DQ and HLA-DR molecules, one T cell recognized C-peptide amino acids 19-35, and two clones from separate donors responded to insulin B-chain amino acids 9-23 (B:9-23), which are known to be a critical self-antigen-driving disease progress in animal models of autoimmune diabetes. These B:9-23-specific T cells from islets responded to whole proinsulin and islets, whereas previously identified B:9-23 responsive clones from peripheral blood did not, highlighting the importance of proinsulin-specific T cells in the islet microenvironment.


Assuntos
Autoantígenos/imunologia , Linfócitos T CD4-Positivos/imunologia , Diabetes Mellitus Tipo 1/imunologia , Insulina/imunologia , Ilhotas Pancreáticas/imunologia , Fragmentos de Peptídeos/imunologia , Proinsulina/imunologia , Precursores de Proteínas/imunologia , Receptores de Antígenos de Linfócitos T/imunologia , Adolescente , Peptídeo C/imunologia , Criança , Feminino , Antígenos HLA-DQ/imunologia , Antígenos HLA-DR/imunologia , Humanos , Células Secretoras de Insulina , Ilhotas Pancreáticas/citologia , Ilhotas Pancreáticas/patologia , Receptores de Antígenos de Linfócitos T/genética , Adulto Jovem
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