Abstract
SummaryStreptococcal pyrogenic exotoxin (Spe) A expression is epidemiologically linked to streptococcal tonsillo‐pharyngitis and outbreaks of scarlet fever, although the mechanisms by which superantigens confer advantage to Streptococcus pyogenes are unclear. S. pyogenes is an exclusively human pathogen. As the leucocyte profile of tonsil is unique, the impact of SpeA production on human tonsil cell function was investigated. Human tonsil cells from routine tonsillectomy were co‐incubated with purified streptococcal superantigens or culture supernatants from isogenic streptococcal isolates, differing only in superantigen production. Tonsil cell proliferation was quantified by tritiated thymidine incorporation, and cell surface characteristics assessed by flow cytometry. Soluble mediators including immunoglobulin were measured using enzyme‐linked immunosorbent assay. Tonsil T cells proliferated in response to SpeA and demonstrated typical release of proinflammatory cytokines. When cultured in the absence of superantigen, tonsil preparations released large quantities of immunoglobulin over 7 days. In contrast, marked B cell apoptosis and abrogation of total immunoglobulin (Ig)A, IgM, and IgG production occurred in the presence of SpeA and other superantigens. In SpeA‐stimulated cultures, T follicular helper (Tfh) cells showed a reduction in C‐X‐C chemokine receptor (CXCR)5 (CD185) expression, but up‐regulation of OX40 (CD134) and inducible T cell co‐stimulator (ICOS) (CD278) expression. The phenotypical change in the Tfh population was associated with impaired chemotactic response to CXCL13. SpeA and other superantigens cause dysregulated tonsil immune function, driving T cells from Tfh to a proliferating phenotype, with resultant loss of B cells and immunoglobulin production, providing superantigen‐producing bacteria with a probable survival advantage.
Highlights
Introduction he human pathogenStreptococcus pyogenes can produce up to 11 diferent secreted superantigens that contribute to the features of cytokine-induced toxic shock during lethal, invasive infections such as necrotizing fasciitis [1]
Using the phage-encoded toxin streptococcal pyrogenic exotoxin A (SpeA), which has been implicated in the emergence of severe S. pyogenes infections in recent decades, as a paradigm of a streptococcal superantigen [7] we set out to conduct a systematic examination of responses to superantigen using both human tonsil histocultures and cultured cell suspensions
To establish that fresh human tonsil cell suspensions were responsive to streptococcal superantigens, cells were exposed to puriied superantigens SpeA and streptococcal mitogenic exotoxin Z (SmeZ)), and proliferation assessed by tritiated thymidine incorporation
Summary
Introduction he human pathogenStreptococcus pyogenes can produce up to 11 diferent secreted superantigens that contribute to the features of cytokine-induced toxic shock during lethal, invasive infections such as necrotizing fasciitis [1]. When secreted in the vicinity of host leucocytes, streptococcal superantigens bind host major histocompatibility complex II (MHC-II) outside the antigen groove and ligate a variably discrete repertoire of T cell receptor variable β chain (TCR-Vβ) subunits, thereby leading to mass activation and proliferation of all target populations of T. Using the phage-encoded toxin SpeA, which has been implicated in the emergence of severe S. pyogenes infections in recent decades, as a paradigm of a streptococcal superantigen [7] we set out to conduct a systematic examination of responses to superantigen using both human tonsil histocultures and cultured cell suspensions
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