Autoreactive T cells specific for insulin B:11-23 recognize a low-affinity peptide register in human subjects with autoimmune diabetes

Previous studies in type 1 diabetes (T1D) in the nonobese diabetic mouse demonstrated that a crucial insulin epitope (B:9-23) is presented to diabetogenic CD4 T cells by IA(g7) in a weakly bound register. The importance of antigenic peptides with low-affinity HLA binding in human autoimmune disease...

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Vydáno v:Proceedings of the National Academy of Sciences - PNAS Ročník 111; číslo 41; s. 14840
Hlavní autoři: Yang, Junbao, Chow, I-Ting, Sosinowski, Tomasz, Torres-Chinn, Nadia, Greenbaum, Carla J, James, Eddie A, Kappler, John W, Davidson, Howard W, Kwok, William W
Médium: Journal Article
Jazyk:angličtina
Vydáno: United States 14.10.2014
Témata:
Amino Acid Sequence
Animals
Case-Control Studies
CD4-Positive T-Lymphocytes - immunology
Cell Proliferation
Cell Separation
Clone Cells
Diabetes Mellitus, Type 1 - immunology
HLA-DQ Antigens
Humans
Insulin - chemistry
Insulin - immunology
Lymphocyte Activation - immunology
Mice
Molecular Sequence Data
Peptides - chemistry
Peptides - immunology
antigen presentation
MHCII tetramers
self-antigen
ISSN:1091-6490, 1091-6490
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Popis
Shrnutí:Previous studies in type 1 diabetes (T1D) in the nonobese diabetic mouse demonstrated that a crucial insulin epitope (B:9-23) is presented to diabetogenic CD4 T cells by IA(g7) in a weakly bound register. The importance of antigenic peptides with low-affinity HLA binding in human autoimmune disease remains less clear. The objective of this study was to investigate T-cell responses to a low-affinity self-epitope in subjects with T1D. HLA-DQ8 tetramers loaded with a modified insulin peptide designed to improve binding the low-affinity register were used to visualize T-cell responses following in vitro stimulation. Positive responses were only detectable in T1D patients. Because the immunogenic register of B:9-23 presented by DQ8 has not been conclusively demonstrated, T-cell assays using substituted peptides and DQ8 constructs engineered to express and present B:9-23 in fixed binding registers were used to determine the immunogenic register of this peptide. Tetramer-positive T-cell clones isolated from T1D subjects that responded to stimulation by B:11-23 peptide and denatured insulin protein were conclusively shown to recognize B:11-23 bound to HLA-DQ8 in the low-affinity register 3. These T cells also responded to homologous peptides derived from microbial antigens, suggesting that their initial priming could occur via molecular mimicry. These results are in accord with prior observations from the nonobese diabetic mouse model, suggesting a mechanism shared by mouse and man through which T cells that recognize a weakly bound peptide can circumvent tolerance mechanisms and play a role in the initiation of autoimmune diseases, such as T1D.
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ISSN:1091-6490
1091-6490
DOI:10.1073/pnas.1416864111