Molecular Requirements for MHC Class II α-Chain Engagement and Allelic Discrimination by the Bacterial Superantigen Streptococcal Pyrogenic Exotoxin C

Superantigens (SAgs) are microbial toxins that bind to both TCR β-chain variable domains (Vβs) and MHC class II molecules, resulting in the activation of T cells in a Vβ-specific manner. It is now well established that different isoforms of MHC II molecules can play a significant role in the immune response to bacterial SAgs. In this work, using directed mutational studies in conjunction with functional analyses, we provide a complete functional map of the low-affinity MHC II α-chain binding interface of the SAg streptococcal pyrogenic exotoxin C (SpeC) and identify a functional epitope in the β-barrel domain that is required for the activation of T cells. Using cell lines that exclusively express individual MHC II isoforms, our studies provide a molecular basis for the selectivity of SpeC-MHC II recognition, and provide one mechanism by how SAgs are capable of distinguishing between different MHC II alleles.