Torres, C. M.; Setzu, N. R.; Rodriguez, B.; Sanchez Guillen, A.; Gutierrez, A.; Rodriguez, L.; Molina-Limon, N.; Rodriguez, L.; Devora, C.; Sanchez Guillen, M.; Spencer, C. T.

Severe infections can trigger systemic inflammatory response syndrome (SIRS), wherein excessive cytokine release generates a cytokine storm causing tissue damage, multi-organ failure, and death. Natural killer T (NKT) cells are innate-like lymphocytes that respond rapidly to infection and can either amplify or suppress inflammation. Distinct NKT subsets may have opposing roles in acute infection, but their specific contributions to hyperinflammation remain unclear. Using a murine model of the cytokine storm, we demonstrate that type I NKT cells act as dominant suppressors of infection-induced hyperinflammation, whereas type II NKT cells confer minimal protection. This immunoregulation occurs via secreted mediators rather than direct cytotoxicity or cell-cell contact. Notably, we identify IL-22 as a key type I NKT cell effector that suppresses pro-inflammatory cytokine levels. These findings define a novel IL-22-dependent immunoregulatory axis wherein type I NKT cells limit pathological inflammation, providing insight for therapies targeting cytokine storms.