Toxic shock syndrome (TSS) is caused by staphylococcal and streptococcal superantigens (SAgs) that provoke a swift hyperinflammatory response typified by a cytokine storm. The precipitous decline in the host's clinical status and the lack of targeted therapies for TSS emphasize the need to identify key players of the storm's initial wave. Using a humanized mouse model of TSS and human cells, we herein demonstrate that SAgs elicit in vitro and in vivo IL-17A responses within hours. SAg-triggered human IL-17A production was characterized by remarkably high mRNA stability for this cytokine. A distinct subpopulation of CD4 effector memory T (T) cells that secrete IL-17A, but not IFN-γ, was responsible for early IL-17A production. We found mouse "T-17" cells to be enriched within the intestinal epithelium and among lamina propria lymphocytes. Furthermore, interfering with IL-17A receptor signaling in human PBMCs attenuated the expression of numerous inflammatory mediators implicated in the TSS-associated cytokine storm. IL-17A receptor blockade also abrogated the secondary effect of SAg-stimulated PBMCs on human dermal fibroblasts as judged by C/EBP δ expression. Finally, the early IL-17A response to SAgs was pathogenic because in vivo neutralization of IL-17A in humanized mice ameliorated hepatic and intestinal damage and reduced mortality. Together, our findings identify CD4 T cells as a key effector of TSS and reveal a novel role for IL-17A in TSS immunopathogenesis. Our work thus elucidates a pathogenic, as opposed to protective, role for IL-17A during Gram-positive bacterial infections. Accordingly, the IL-17-IL-17R axis may provide an attractive target for the management of SAg-mediated illnesses.

Toxic shock syndrome (TSS) and other superantigen-mediated illnesses are associated with 'systemic' immunosuppression that jeopardizes the host's ability to fight pathogens. Here, we define a novel mechanism of 'local' immunosuppression that may benefit the host. Systemic exposure to staphylococcal enterotoxin B (SEB) rapidly and selectively recruited CD11b(+)Gr-1(high)Ly-6C(+) granulocytic myeloid-derived suppressor cells (MDSCs) to the liver of HLA-DR4 transgenic mice. Hepatic MDSCs inhibited SEB-triggered T cell proliferation in a reactive oxygen species-dependent manner, and ex vivo-generated human MDSCs also similarly attenuated the proliferative response of autologous T cells to SEB. We propose a role for MDSCs in mitigating excessive tissue injury during TSS.

Toxic shock syndrome (TSS) is a life-threatening illness characterized by high-grade fever, erythematous rash, hypotensive shock, and multi-organ dysfunction within hours of onset. It is caused by exposure to bacterial exotoxins known as superantigens (SAgs), which are produced by the common bacterium Staphylococcus aureus. During infection, SAgs activate up to 20% of T cells inducing a severe systemic inflammatory response that can lead to vascular leakage, multiple organ damage and death. However, the role of IL-17A, a potent inflammatory cytokine, in this potentially fatal reaction remains virtually unexplored. We have found that human peripheral blood mononuclear cells (PBMCs) stimulated with SAgs in vitro immediately up-regulate IL-17A mRNA (up to 12,000-fold) and produce substantial amounts of IL-17A protein within hours. Utilizing the cutting-edge RNA-Flow Cytometry technique, we identified a subset of memory T cells that was responsible for the rapid IL-17A response. We also investigated the effect of IL-17A signaling on downstream inflammatory cytokine and chemokine gene expression via IL-17A receptor blockade. Lastly, we used HLA-DR4 transgenic mice to demonstrate rapid IL-17A production in response to SAgs, similar to human PBMCs. Neutralizing IL-17A in this model greatly reduced tissue damage, morbidity and mortality. Taken together, our results reveal a novel role for memory T cells in TSS and define a previously unrecognized contribution by IL-17A to the initiation and pathogenesis of the syndrome.

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.