Staphylococcal superantigens trigger rapid human IL-17A production by a novel population of memory T cells (HUM1P.268)

Abstract

Abstract Toxic shock syndrome (TSS) is a life-threatening illness characterized by fever, hypotensive shock and multi-organ failure within hours of onset. TSS is caused by exposure to bacterial toxins known as superantigens (SAgs), which are produced by common Gram-positive bacteria such as Staphylococcus aureus. During infection, SAgs can activate of up to 20% of all T cells, resulting in massive and rapid release of pro-inflammatory cytokines, systemic intravascular coagulation, organ damage and death. However, the exact cellular mechanisms underlying the rapidity of this potentially fatal inflammatory reaction are far from clearly understood. In our preliminary experiments, human peripheral blood mononuclear cells (PBMCs) stimulated with SAgs in vitro showed immediate up-regulation (up to 2000-fold) of mRNA for the pro-inflammatory cytokine IL-17A. SAg-stimulated PBMCs also produced substantial amounts of IL-17A protein within hours of activation. The cells responsible for the rapid production of IL-17A were identified as a subset of memory T cells exhibiting a novel phenotype. Furthermore, neutralizing IL-17A at the onset significantly reduced both morbidity and mortality in a humanized mouse model of TSS. Our results reveal a critical role for memory T cells in TSS and define a novel contribution by IL-17A to the initiation and pathogenesis of the syndrome.