Type I Natural Killer T Cells Suppress Infection-Induced Cytokine Storm Through an IL-22-STAT3 Axis

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 an intradermal murine Francisella tularensis LVS model of infection-induced cytokine storm, we demonstrate that type I NKT cells act as dominant suppressors of systemic hyperinflammation, whereas type II-enriched NKT cells confer limited 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 type I NKT cell immunoregulatory axis that restrains pathological macrophage cytokine responses during severe bacterial infection.