Crystal structure of an autoimmune TCR with optimal binding to its self-antigen - an alternative strategy for escaping negative selection (93.32)

Abstract

Abstract The failure to eliminate self-reactive T cells during thymic selection is a prerequisite for autoimmunity. To escape deletion, autoreactive T cell receptors (TCRs) usually form relatively unstable complexes with their self-peptide/MHC ligands. As shown previously, these TCRs adopt suboptimal binding topologies as opposed to anti-microbial TCRs. In other cases, escape can be mediated by weak binding between self-peptides and MHC. Here, we determined the crystal structure, to 2.7 Å resolution, of a human MHC class II-restricted autoimmune TCR (3C8) bound to its self-antigen, MBP 114-126/HLA-DR4. TCR 3C8, which was originally isolated from a multiple sclerosis patient, has demonstrated pathogenic potential in humanized transgenic mice. The MBP self-peptide binds HLA-DR4 with unusually low affinity. The structure showed a loose accommodation of MBP in the peptide binding groove. By contrast, 3C8 binds to MBP/HLA-DR4 at the high end of the affinity range for TCR-peptide/MHC interactions. Moreover, 3C8 engages its self-ligand via a docking mode that closely resembles the optimal binding topology of anti-foreign TCRs, but is distinct from that of other autoreactive TCRs. Thus, the 3C8-MBP/HLA-DR4 complex reveals the structural basis for an alternative strategy by which autoreactive T cells escape negative selection, yet still retain the ability to become sufficiently activated in the periphery to be pathogenic.