Post-sepsis immunosuppression depends on NKT cell regulation of mTOR/IFNgamma in NK cells.

As treatment of the early, inflammatory phase of sepsis improves, post-sepsis immunosuppression and secondary infection have increased in importance. How early inflammation drives immunosuppression remains unclear. Although IFNgamma typically helps microbial clearance, we found that increased plasma IFNgamma in early clinical sepsis was associated with the later development of secondary Candida infection. Consistent with this observation, we found that exogenous IFNgamma suppressed macrophage phagocytosis of zymosan in vivo, and antibody blockade of IFNgamma after endotoxemia improved survival of secondary candidemia. Transcriptomic analysis of innate lymphocytes during endotoxemia suggested that NKT cells drove IFNgamma production by NK cells via mTORC1. Activation of iNKT cells with glycolipid antigen drove immunosuppression. Deletion of iNKT cells in Cd1d-/- mice or inhibition of mTOR by rapamycin reduced immunosuppression and susceptibility to secondary Candida infection. Thus, although rapamycin is typically an immunosuppressive medication, in the context of sepsis, rapamycin has the opposite effect. These results implicated a NKT cell-mTOR-IFNgamma axis in immunosuppression following endotoxemia or sepsis. In summary, in vivo iNKT cells activated mTORC1 in NK cells to produce IFNgamma , which worsened macrophage phagocytosis, clearance of secondary Candida infection and mortality.