Unusual features of self-peptide/MHC binding by autoimmune T cell receptors.
Structural studies on T cell receptors (TCRs) specific for foreign antigens demonstrated a remarkably similar topology characterized by a central, diagonal TCR binding mode that maximizes interactions with the MHC bound peptide. However, three recent structures involving autoimmune TCRs demonstrated unusual interactions with self-peptide/MHC complexes. Two TCRs from multiple sclerosis patients bind with unconventional topologies, and both TCRs are shifted toward the peptide N terminus and the MHC class II beta chain helix. A TCR from the experimental autoimmune encephalomyelitis (EAE) model binds in a conventional orientation, but the structure is unusual because the self-peptide only partially fills the binding site. For all three TCRs, interaction with the MHC bound self-peptide is suboptimal, and only two or three TCR loops contact the peptide. Optimal TCR binding modes confer a competitive advantage for antimicrobial T cells during an infection, whereas altered binding properties may permit survival of a subset of autoreactive T cells during thymic selection.
Nicholson
Melissa J
MJ
Department of Cancer Immunology and AIDS, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts 02115, USA.
Hahn
Michael
M
Wucherpfennig
Kai W
KW
D000818:Animals; D001324:Autoantigens / Q000737:chemistry* / Q000276:immunology* / Q000378:metabolism; D001327:Autoimmune Diseases / Q000276:immunology*; D022801:Complementarity Determining Regions / Q000737:chemistry / Q000276:immunology / Q000378:metabolism; D006801:Humans; D051379:Mice; D008958:Models, Molecular; D011948:Receptors, Antigen, T-Cell / Q000737:chemistry* / Q000276:immunology* / Q000378:metabolism
D001324:Autoantigens; D022801:Complementarity Determining Regions; D011948:Receptors, Antigen, T-Cell