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The T cell receptor (TCR), from a xeno-reactive murine cytotoxic T lymphocyte
clone AHIII12.2, recognizes murine H-2Db complexed with peptide p1027
(FAPGVFPYM), as well as human HLA-A2.1 complexed with peptide p1049 (ALWGFFPVL).
A commonly proposed model (the molecular mimicry model) used to explain TCR
cross-reactivity suggests that the molecular surfaces of the recognized
complexes are similar in shape, charge, or both, in spite of the primary
sequence differences. To examine the mechanism of xeno-reactivity of AHIII12.2,
we have determined the crystal structures of A2/p1049 and Db/p1027 to 2.5 A and
2.8 A resolution, respectively. The crystal structures show that the TCR
footprint regions of the two class I complexes are significantly different in
shape and charge. We propose that rather than simple molecular mimicry,
unpredictable arrays of common and differential contacts on the two class I
complexes are used for their recognition by the same TCR.
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