Date of this Version
J Immunol. 2011 March 1; 186(5): 2950–2958. doi:10.4049/jimmunol.1003150.
Molecular mimicry between foreign and self antigens is a mechanism of T cell receptor cross reactivity and is thought to contribute to the development of autoimmunity. The αβ TCR A6 recognizes the foreign antigen Tax from the virus HTLV-1 when presented by the class I MHC HLA-A2. In a possible link with the autoimmune disease HAM/TSP, A6 also recognizes a self peptide from the neuronal protein HuD in the context of HLA-A2. We found here that the complexes of the HuD and Tax epitopes with HLA-A2 are close but imperfect structural mimics, and that in contrast with other recent structures of TCRs with self antigens, A6 engages the HuD antigen with the same traditional binding mode used to engage Tax. Although peptide and MHC conformational changes are needed for recognition of HuD but not Tax and the difference of a single hydroxyl triggers an altered TCR loop conformation, TCR affinity towards HuD is still within the range believed to result in negative selection. Probing further, we found that the HuD/ HLA-A2 complex is only weakly stable. Overall, these findings help clarify how molecular mimicry can drive self/non-self cross-reactivity and illustrate how low peptide/MHC stability can permit the survival of T cells expressing self-reactive TCRs that nonetheless bind with a traditional binding mode.