T helper type 2‐polarized invariant natural killer T cells reduce disease severity in acute intra‐abdominal sepsis

Summary 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 ( iNK T ) 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 iNK T cells in their peripheral blood (as a percentage of their circulating T cells) compared to non‐septic patients. We therefore investigated the role of iNK T cells in a mouse model of intra‐abdominal sepsis ( IAS ). Our data show that iNK T cells are pathogenic in IAS , and that T helper type 2 ( T h2) polarization of iNK T cells using the synthetic glycolipid OCH significantly reduces 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 proinflammatory cytokines within the spleen, notably interleukin ( IL) ‐17. Finally, we show that treatment of sepsis with OCH in mice is accompanied by significantly reduced apoptosis of splenic T and B lymphocytes and macrophages, but not natural killer cells. We propose that modulation of iNK T cell responses towards a Th 2 phenotype may be an effective therapeutic strategy in early sepsis.