期刊
JOURNAL OF EXPERIMENTAL MEDICINE
卷 208, 期 1, 页码 91-102出版社
ROCKEFELLER UNIV PRESS
DOI: 10.1084/jem.20100725
关键词
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资金
- National Institutes of Health [P01 AI045757, R01 AI064177]
- National Multiple Sclerosis Society
- Cancer Research Institute
- Offices of Biological and Environmental Research and of Basic Energy Sciences of the US Department of Energy
- National Center for Research Resources of the National Institutes of Health
Self-reactive T cells that escape elimination in the thymus can cause autoimmune pathology, and it is therefore important to understand the structural mechanisms of self-antigen recognition. We report the crystal structure of a T cell receptor (TCR) from a patient with relapsing-remitting multiple sclerosis that engages its self-peptide-major histocompatibility complex (pMHC) ligand in an unusual manner. The TCR is bound in a highly tilted orientation that prevents interaction of the TCR-alpha chain with the MHC class II beta chain helix. In this structure, only a single germline-encoded TCR loop engages the MHC protein, whereas in most other TCR-pMHC structures all four germline-encoded TCR loops bind to the MHC helices. The tilted binding mode also prevents peptide contacts by the short complementarity-determining region (CDR) 3 beta loop, and interactions that contribute to peptide side chain specificity are focused on the CDR3 alpha loop. This structure is the first example in which only a single germline-encoded TCR loop contacts the MHC helices. Furthermore, the reduced interaction surface with the peptide may facilitate TCR cross-reactivity. The structural alterations in the trimolecular complex are distinct from previously characterized self-reactive TCRs, indicating that there are multiple unusual ways for self-reactive TCRs to bind their pMHC ligand.
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