The T cell receptor beta-chain second complementarity determining region loop (CDR2beta governs T cell activation and Vbeta specificity by bacterial superantigens

• Published in: The Journal of biological chemistry 2011-02, Vol.286 (6), p.4871
• Main Authors: Nur-ur Rahman, A K M, Bonsor, Daniel A, Herfst, Christine A, Pollard, Fraser, Peirce, Michael, Wyatt, Aaron W, Kasper, Katherine J, Madrenas, Joaquín, Sundberg, Eric J, McCormick, John K
• Format: Article
• Language: English
• Subjects: Bacterial Proteins - chemistry; Bacterial Proteins - genetics; Bacterial Proteins - immunology; Bacterial Toxins - chemistry; Bacterial Toxins - genetics; Bacterial Toxins - immunology; Cell Line; Complementarity Determining Regions - chemistry; Complementarity Determining Regions - genetics; Complementarity Determining Regions - immunology; Crystallography, X-Ray; Enterotoxins - chemistry; Enterotoxins - genetics; Enterotoxins - immunology; Exotoxins - chemistry; Exotoxins - genetics; Exotoxins - immunology; Humans; Lymphocyte Activation; Mutagenesis; Protein Structure, Quaternary; Protein Structure, Tertiary; Receptors, Antigen, T-Cell, alpha-beta - chemistry; Receptors, Antigen, T-Cell, alpha-beta - genetics; Receptors, Antigen, T-Cell, alpha-beta - immunology; Superantigens - chemistry; Superantigens - genetics; Superantigens - immunology; T-Lymphocytes - chemistry; T-Lymphocytes - immunology
• ISSN: 1083-351X
• DOI: 10.1074/jbc.M110.189068

Superantigens (SAgs) are microbial toxins defined by their ability to activate T lymphocytes in a T cell receptor (TCR) β-chain variable domain (Vβ)-specific manner. Although existing structural information indicates that diverse bacterial SAgs all uniformly engage the Vβ second complementarity determining region (CDR2β) loop, the molecular rules that dictate SAg-mediated T cell activation and Vβ specificity are not fully understood. Herein we report the crystal structure of human Vβ2.1 (hVβ2.1) in complex with the toxic shock syndrome toxin-1 (TSST-1) SAg, and mutagenesis of hVβ2.1 indicates that the non-canonical length of CDR2β 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 Vβ-specificity exhibited by this SAg. Furthermore, domain swapping experiments with SAgs, which use distinct domains to engage both CDR2β and FR3/4β revealed that the CDR2β contacts dictate T lymphocyte Vβ-specificity. These findings demonstrate that the TCR CDR2β loop is the critical determinant for functional recognition and Vβ-specificity by diverse bacterial SAgs.