Structure of a TCR with high affinity for self-antigen reveals basis for escape from negative selection.

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TitleStructure of a TCR with high affinity for self-antigen reveals basis for escape from negative selection.
Publication TypeJournal Article
Year of Publication2011
AuthorsYin, Y, Li, Y, Kerzic, MC, Martin, R, Mariuzza, RA
JournalEMBO J
Volume30
Issue6
Pagination1137-48
Date Published2011 Mar 16
ISSN1460-2075
KeywordsAutoantigens, Crystallography, X-Ray, HLA-DR4 Antigen, Humans, Models, Molecular, Myelin Basic Protein, Protein Binding, Protein Conformation, Protein Structure, Quaternary, Receptors, Antigen, T-Cell, Surface Plasmon Resonance
Abstract

The failure to eliminate self-reactive T cells during negative selection is a prerequisite for autoimmunity. To escape deletion, autoreactive T-cell receptors (TCRs) may form unstable complexes with self-peptide-MHC by adopting suboptimal binding topologies compared with anti-microbial TCRs. Alternatively, escape can occur by weak binding between self-peptides and MHC. We determined the structure of a human autoimmune TCR (MS2-3C8) bound to a self-peptide from myelin basic protein (MBP) and the multiple sclerosis-associated MHC molecule HLA-DR4. MBP is loosely accommodated in the HLA-DR4-binding groove, accounting for its low affinity. Conversely, MS2-3C8 binds MBP-DR4 as tightly as the most avid anti-microbial TCRs. MS2-3C8 engages self-antigen via a docking mode that resembles the optimal topology of anti-foreign TCRs, but is distinct from that of other autoreactive TCRs. Combined with a unique CDR3β conformation, this docking mode compensates for the weak binding of MBP to HLA-DR4 by maximizing interactions between MS2-3C8 and MBP. Thus, the MS2-3C8-MBP-DR4 complex reveals the basis for an alternative strategy whereby autoreactive T cells escape negative selection, yet retain the ability to initiate autoimmunity.

DOI10.1038/emboj.2011.21
Alternate JournalEMBO J.
PubMed ID21297580
PubMed Central IDPMC3061028
Grant ListAI036900 / AI / NIAID NIH HHS / United States
AI073654 / AI / NIAID NIH HHS / United States
P30 EB009998 / EB / NIBIB NIH HHS / United States