Sepsis is characterized by a severe systemic inflammatory response to infection that is associated with high morbidity and mortality despite optimal care. Invariant natural killer T (iNKT) cells are potent regulatory lymphocytes that can produce pro- and/or anti-inflammatory cytokines, thus shaping the course and nature of immune responses; however, little is known about their role in sepsis. We demonstrate here that patients with sepsis/severe sepsis have significantly elevated proportions of circulating iNKT cells in their peripheral blood, as compared to non-septic patients. We therefore investigated iNKT cells in mice with intra-abdominal sepsis (IAS). Our data show that iNKT cells are pathogenic in IAS, and that T helper (Th)2-type polarization of iNKT cells using the synthetic glycolipid OCH significantly reduced mortality from IAS. This reduction in mortality is associated with the systemic elevation of the anti-inflammatory cytokine interleukin (IL)-13, and reduction of several pro-inflammatory cytokines within the spleen, notably IL-17. Finally, we show that administration of OCH in septic mice is associated with significantly reduced apoptosis of splenic T and B lymphocytes, as well as macrophages, but not natural killer cells. We propose that modulation of iNKT cell responses towards a Th2 phenotype may be an effective therapeutic strategy in sepsis
