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Mariuzza, Roy A Yin, Yiyuan Digital Repository at the University of Maryland University of Maryland (College Park, Md.) Molecular and Cell Biology 2011-02-19T06:59:49Z 2011-02-19T06:59:49Z 2010 http://hdl.handle.net/1903/11181 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 self-peptide 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 CDR3 β 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. Structural basis for escaping negative selection by T cell receptor with high affinity for self antigen Dissertation Molecular Biology Biochemistry Biophysics MHC class II multiple sclerosis negative selection T cell recepter X-ray crystallography open.access