TNF and CD28 signaling play unique but complementary roles in the systemic recruitment of innate immune cells after Staphylococcus aureus enterotoxin A inhalation. Mus musculus

Staphylococcus aureus enterotoxins cause debilitating systemic inflammatory responses, but how they spread systemically and trigger cascading inflammation is unclear. Here, we showed in mice that after inhalation, Staphylococcus aureus enterotoxin A rapidly entered the bloodstream and induced T cells to orchestrate systemic recruitment of inflammatory monocytes and neutrophils. To study the mechanism used by specific T cells that mediate this process, a systems approach revealed inducible and non-inducible pathways as potential targets. It was found that TNF induced neutrophil entry into the peripheral blood, while CD28 signaling, but not TNF, was needed for chemotaxis of inflammatory monocytes into blood and lymphoid tissue. However, both pathways triggered local recruitment of neutrophils into lymph nodes. Thus, our findings revealed a dual mechanism of monocyte and neutrophil recruitment by T cells relying on overlapping and non-overlapping roles for the non-inducible costimulatory receptor CD28 and the inflammatory cytokine TNF. During sepsis, there might be clinical value in inhibiting CD28 signaling to decrease T cell-mediated inflammation and recruitment of innate cells while retaining bioactive TNF to foster neutrophil circulation. Overall design: The purpose of this analysis was to determine changes in gene expression in SEA-specific Vβ3+ T cells and bystander T Vβ14+ cells 40 min after SEA or vehicle inhalation.The samples were collected from three independent experiments with total n=3 per group. Three groups of samples were prepared: vehicle Vβ3+ T cells, SEA Vβ3+ T cells, and SEA Vβ14+ T cells.