RESUMO
Superantigens (SAgs) are microbial toxins defined by their ability to activate T lymphocytes in a T cell receptor (TCR) ß-chain variable domain (Vß)-specific manner. Although existing structural information indicates that diverse bacterial SAgs all uniformly engage the Vß second complementarity determining region (CDR2ß) loop, the molecular rules that dictate SAg-mediated T cell activation and Vß specificity are not fully understood. Herein we report the crystal structure of human Vß2.1 (hVß2.1) in complex with the toxic shock syndrome toxin-1 (TSST-1) SAg, and mutagenesis of hVß2.1 indicates that the non-canonical length of CDR2ß is a critical determinant for recognition by TSST-1 as well as the distantly related SAg streptococcal pyrogenic exotoxin C. Frame work (FR) region 3 is uniquely critical for TSST-1 function explaining the fine Vß-specificity exhibited by this SAg. Furthermore, domain swapping experiments with SAgs, which use distinct domains to engage both CDR2ß and FR3/4ß revealed that the CDR2ß contacts dictate T lymphocyte Vß-specificity. These findings demonstrate that the TCR CDR2ß loop is the critical determinant for functional recognition and Vß-specificity by diverse bacterial SAgs.
