Structural Basis for Escaping Negative Selection by T Cell Receptor with High Affinity for Self Antigen

Title of Dissertation: STRUCTURAL BASIS FOR ESCAPING NEGATIVE SELECTION BY T CELL RECEPTOR WITH HIGH AFFINITY FOR SELF ANTIGEN Yiyuan Yin, Doctor of Philosophy, 2010 Directed By: Professor Roy A. Mariuzza Department of Cell Biology and Molecular Genetics The failure to eliminate self-reactive T cells is a prerequisite for autoimmunity. To escape thymic deletion, autoreactive T cell receptors (TCRs) may form relatively unstable complexes with self-peptide–MHC. These TCRs adopt suboptimal docking topologies in striking contrast to the classical topology of 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 selfpeptide from myelin basic protein (MBP) and the multiple sclerosis-associated MHC molecule HLA-DR4. MS2-3C8 is encephalitogenic in humanized transgenic mice. The structure showed loose accommodation of MBP in the HLA-DR4 binding groove, accounting for its low affinity. By contrast, MS2-3C8 binds MBP–DR4 as tightly as the most avid anti-microbial TCRs. Structurally, MS2-3C8 engages self-antigen via a docking mode that closely resembles the optimal topology of anti-microbial 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 HLADR4 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. STRUCTURAL BASIS FOR ESCAPING NEGATIVE SELECTION BY T CELL RECEPTOR WITH HIGH AFFINITY FOR SELF ANTIGEN