T cell receptor recognition of hybrid insulin peptides bound to HLA-DQ8
| العنوان: | T cell receptor recognition of hybrid insulin peptides bound to HLA-DQ8 |
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| المؤلفون: | Goodluck Onwukwe, Mai T. Tran, Jamie Rossjohn, Jia Jia Lim, Eleonora Tresoldi, Nicole L. La Gruta, Claerwen M. Jones, Pouya Faridi, Pushpak Bhattacharjee, Anthony W. Purcell, Fergus J. Cameron, Hugh H. Reid, Yi Tian Ting, Stuart I. Mannering |
| المصدر: | Nature Communications, Vol 12, Iss 1, Pp 1-13 (2021) Nature Communications |
| بيانات النشر: | Nature Portfolio, 2021. |
| سنة النشر: | 2021 |
| مصطلحات موضوعية: | CD4-Positive T-Lymphocytes, endocrine system, Science, Receptors, Antigen, T-Cell, General Physics and Astronomy, Autoimmunity, Peptide, Article, General Biochemistry, Genetics and Molecular Biology, Epitope, Tetramer, HLA-DQ Antigens, medicine, Humans, Insulin, Amino Acid Sequence, Receptor, X-ray crystallography, Proinsulin, chemistry.chemical_classification, Multidisciplinary, Pancreatic islets, T-cell receptor, nutritional and metabolic diseases, food and beverages, General Chemistry, Cell biology, Diabetes Mellitus, Type 1, medicine.anatomical_structure, chemistry, RNA splicing, Peptides, Protein Binding |
| الوصف: | HLA-DQ8, a genetic risk factor in type I diabetes (T1D), presents hybrid insulin peptides (HIPs) to autoreactive CD4+ T cells. The abundance of spliced peptides binding to HLA-DQ8 and how they are subsequently recognised by the autoreactive T cell repertoire is unknown. Here we report, the HIP (GQVELGGGNAVEVLK), derived from splicing of insulin and islet amyloid polypeptides, generates a preferred peptide-binding motif for HLA-DQ8. HLA-DQ8-HIP tetramer+ T cells from the peripheral blood of a T1D patient are characterised by repeated TRBV5 usage, which matches the TCR bias of CD4+ T cells reactive to the HIP peptide isolated from the pancreatic islets of a patient with T1D. The crystal structure of three TRBV5+ TCR-HLA-DQ8-HIP complexes shows that the TRBV5-encoded TCR β-chain forms a common landing pad on the HLA-DQ8 molecule. The N- and C-termini of the HIP is recognised predominantly by the TCR α-chain and TCR β-chain, respectively, in all three TCR ternary complexes. Accordingly, TRBV5 + TCR recognition of HIP peptides might occur via a ‘polarised’ mechanism, whereby each chain within the αβTCR heterodimer recognises distinct origins of the spliced peptide presented by HLA-DQ8. Epitopes formed by fusion of more than one self peptide, such as proinsulin and other β cell proteins, can result in the formation of non-self hybrid peptides that can potentially trigger autoimmune responses. Here the authors show how TRBV5 + T cell receptors are geared towards recognition of HLA-DQ8 bound hybrid peptides in patients with type 1 diabetes. |
| اللغة: | English |
| تدمد: | 2041-1723 |
| URL الوصول: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::b60d011244d03b6c452fee4a14906f90 https://doaj.org/article/6cfc61766a5b4c9d973ece4ad2e9ab57 |
| Rights: | OPEN |
| رقم الانضمام: | edsair.doi.dedup.....b60d011244d03b6c452fee4a14906f90 |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 20411723 |
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