Structure of a human autoimmune TCR bound to a myelin basic protein self-peptide and a multiple sclerosis-associated MHC class II molecule

• Published in: The EMBO journal Vol. 24; no. 17; pp. 2968 - 2979
• Main Authors: Li, Yili, Huang, Yuping, Lue, Jessica, Quandt, Jacqueline A, Martin, Roland, Mariuzza, Roy A
• Format: Journal Article
• Language: English
• Published: Chichester, UK John Wiley & Sons, Ltd 07.09.2005; Blackwell Publishing Ltd
• Subjects: Autoimmunity; Central nervous system; complex; Dimerization; HLA-DR2 Antigen - chemistry; Humans; Hydrogen Bonding; MHC class II; Models, Molecular; multiple sclerosis; Multiple Sclerosis - immunology; Myelin Basic Protein - chemistry; Peptide Fragments - chemistry; Peptides; Peptides - chemistry; Protein Conformation; Receptors, Antigen, T-Cell - chemistry; Surface Plasmon Resonance; T-cell receptor
• ISSN: 0261-4189; 1460-2075
• DOI: 10.1038/sj.emboj.7600771

Multiple sclerosis is mediated by T‐cell responses to central nervous system antigens such as myelin basic protein (MBP). To investigate self‐peptide/major histocompatibility complex (MHC) recognition and T‐cell receptor (TCR) degeneracy, we determined the crystal structure, at 2.8 Å resolution, of an autoimmune TCR (3A6) bound to an MBP self‐peptide and the multiple sclerosis‐associated MHC class II molecule, human leukocyte antigen (HLA)‐DR2a. The complex reveals that 3A6 primarily recognizes the N‐terminal portion of MBP, in contrast with antimicrobial and alloreactive TCRs, which focus on the peptide center. Moreover, this binding mode, which may be frequent among autoimmune TCRs, is compatible with a wide range of orientation angles of TCR to peptide/MHC. The interface is characterized by a scarcity of hydrogen bonds between TCR and peptide, and TCR‐induced conformational changes in MBP/HLA‐DR2a, which likely explain the low observed affinity. Degeneracy of 3A6, manifested by recognition of superagonist peptides bearing substitutions at nearly all TCR‐contacting positions, results from the few specific interactions between 3A6 and MBP, allowing optimization of interface complementarity through variations in the peptide.