title: Structure of a TCR with high affinity for self-antigen reveals basis for escape from negative selection.
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.
authors.affiliation: Institute for Bioscience and Biotechnology Research, University of Maryland, WM Keck Laboratory for Structural Biology, Rockville, MD, USA.
authors.forename: Yiyuan
authors.initials: Y
authors.lastname: Yin
authors.forename: Yili
authors.initials: Y
authors.lastname: Li
authors.forename: Melissa C
authors.initials: MC
authors.lastname: Kerzic
authors.forename: Roland
authors.initials: R
authors.lastname: Martin
authors.forename: Roy A
authors.initials: RA
authors.lastname: Mariuzza
mesh_terms: D001324:Autoantigens / Q000276:immunology* / Q000378:metabolism*; D018360:Crystallography, X-Ray; D015804:HLA-DR4 Antigen / Q000276:immunology / Q000378:metabolism; D006801:Humans; D008958:Models, Molecular; D004676:Myelin Basic Protein / Q000276:immunology / Q000378:metabolism; D011485:Protein Binding; D011487:Protein Conformation; D020836:Protein Structure, Quaternary; D011948:Receptors, Antigen, T-Cell / Q000737:chemistry* / Q000276:immunology / Q000378:metabolism*; D020349:Surface Plasmon Resonance
chemical_list: D001324:Autoantigens; D015804:HLA-DR4 Antigen; D004676:Myelin Basic Protein; D011948:Receptors, Antigen, T-Cell