T cell-mediated immunity requires T cell receptor (TCR) cross-reactivity, the mechanisms behind which remain incompletely elucidated. The αβ TCR A6 recognizes both the Tax (LLFGYPVYV) and Tel1p (MLWGYLQYV) peptides presented by the human class I MHC molecule HLA-A2. Here we found that although the two ligands are ideal structural mimics, they form substantially different interfaces with A6, with conformational differences in the peptide, the TCR, and unexpectedly, the MHC molecule. The differences between the Tax and Tel1p ternary complexes could not be predicted from the free peptide-MHC structures and are inconsistent with a traditional induced-fit mechanism. Instead, the differences were attributable to peptide and MHC molecular motion present in Tel1p-HLA-A2 but absent in Tax-HLA-A2. Differential "tuning" of the dynamic properties of HLA-A2 by the Tax and Tel1p peptides thus facilitates cross-recognition and impacts how structural diversity can be presented to and accommodated by receptors of the immune system.
Bibliographical noteFunding Information:
We thank F. Insaidoo for helpful discussion, A. Wojnarowicz for technical assistance, and P. Kamat for use of a FluoroCube 5000U instrument. Supported by grants R01GM06079 from NIGMS (NIH) and MCB0448298 from NSF. Results shown in this report are derived from work performed at the Structural Biology Center and Lilly Research Laboratories Collaborative Access Teams (SBC-CAT and LRL-CAT) at the Advanced Photon Source, Argonne National Laboratory. Argonne is operated by UChicago Argonne, LLC, for the U.S. Department of Energy under contract DE-AC02-06CH11357. Use of the LRL-CAT facilities at Sector 31 of the Advanced Photon Source was provided by Eli Lilly & Company, who operates the facility. K.H.P. was supported by the Notre Dame CBBI training program, funded by T32GM075762 from NIGMS (NIH).