Nasopharyngeal infection by<i>Streptococcus pyogenes</i>requires superantigen-responsive Vβ-specific T cells

Abstract

The globally prominent pathogen <i>Streptococcus pyogenes</i> secretes potent immunomodulatory proteins known as superantigens (SAgs), which engage lateral surfaces of major histocompatibility class II molecules and T-cell receptor (TCR) β-chain variable domains (Vβs). These interactions result in the activation of numerous Vβ-specific T cells, which is the defining activity of a SAg. Although streptococcal SAgs are known virulence factors in scarlet fever and toxic shock syndrome, mechanisms by how SAgs contribute to the life cycle of <i>S. pyogenes</i> remain poorly understood. Herein, we demonstrate that passive immunization against the Vβ8-targeting SAg streptococcal pyrogenic exotoxin A (SpeA), or active immunization with either wild-type or a nonfunctional SpeA mutant, protects mice from nasopharyngeal infection; however, only passive immunization, or vaccination with inactive SpeA, resulted in high-titer SpeA-specific antibodies in vivo. Mice vaccinated with wild-type SpeA rendered Vβ8⁺ T cells poorly responsive, which prevented infection. This phenotype was reproduced with staphylococcal enterotoxin B, a heterologous SAg that also targets Vβ8⁺ T cells, and rendered mice resistant to infection. Furthermore, antibody-mediated depletion of T cells prevented nasopharyngeal infection by <i>S. pyogenes</i>, but not by <i>Streptococcus pneumoniae</i>, a bacterium that does not produce SAgs. Remarkably, these observations suggest that <i>S. pyogenes</i> uses SAgs to manipulate Vβ-specific T cells to establish nasopharyngeal infection.