Structural evidence of T cell xeno-reactivity in the absence of molecular mimicry

The T cell receptor (TCR), from a xeno-reactive murine cytotoxic T lymphocy te clone AHIII12.2, recognizes murine H-2D(b) complexed with peptide p1027 (FAPGVFPYM), as well as human HLA-A2.1 complexed with peptide p1049 (ALWGFF PVL). A commonly proposed model (the molecular mimicry model) used to expla in TCR cross-reactivity suggests that the molecular surfaces of the recogni zed complexes are similar in shape, charge, or both, in spite of the primar y sequence differences. To examine the mechanism of xeno-reactivity of AHII I12.2, we have determined the crystal structures of A2/p1049 and D-b/p1027 to 2.5 Angstrom and 2.8 Angstrom resolution, respectively. The crystal stru ctures show that the TCR footprint regions of the two class I complexes are significantly different in shape and charge. We propose that rather than s imple molecular mimicry, unpredictable arrays of common and differential co ntacts on the two class I complexes are used for their recognition by the s ame TCR.