Post-sepsis immunosuppression depends on NKT cell regulation of mTOR/IFN-γ in NK cells

• Published in: The Journal of clinical investigation Vol. 130; no. 6; pp. 3238 - 3252
• Main Authors: Kim, Edy Y, Ner-Gaon, Hadas, Varon, Jack, Cullen, Aidan M, Guo, Jingyu, Choi, Jiyoung, Barragan-Bradford, Diana, Higuera, Angelica, Pinilla-Vera, Mayra, Short, Samuel Ap, Arciniegas-Rubio, Antonio, Tamura, Tomoyoshi, Leaf, David E, Baron, Rebecca M, Shay, Tal, Brenner, Michael B
• Format: Journal Article
• Language: English
• Published: United States American Society for Clinical Investigation 01.06.2020
• Subjects: Animals; Antigens; Antigens, CD1d - genetics; Antigens, CD1d - immunology; Biomedical research; Candida; Candida - immunology; Candidemia; Candidiasis - genetics; Candidiasis - immunology; Candidiasis - pathology; CD1d antigen; Cell activation; Clinical trials; Clonal deletion; Cytokines; Endotoxemia; Female; Humans; Hypotension; Hypotheses; Immune Tolerance; Immunosuppression; Infections; Inflammation; Interferon-gamma - genetics; Interferon-gamma - immunology; Killer Cells, Natural - immunology; Killer Cells, Natural - pathology; Lymphocytes; Lymphocytes T; Macrophages; Male; Mice; Mice, Knockout; Mortality; Natural killer cells; Natural Killer T-Cells - immunology; Natural Killer T-Cells - pathology; Phagocytosis; Plasma; Rapamycin; Secondary infection; Sepsis; Sepsis - genetics; Sepsis - immunology; Sepsis - pathology; Signal Transduction - genetics; Signal Transduction - immunology; T cell receptors; TOR protein; TOR Serine-Threonine Kinases - genetics; TOR Serine-Threonine Kinases - immunology; γ-Interferon; Infectious disease; NK T cells; Immunology; Fungal infections; Macrophages
• ISSN: 0021-9738; 1558-8238
• DOI: 10.1172/JCI128075

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 IFN-γ typically helps microbial clearance, we found that increased plasma IFN-γ in early clinical sepsis was associated with the later development of secondary Candida infection. Consistent with this observation, we found that exogenous IFN-γ suppressed macrophage phagocytosis of zymosan in vivo, and antibody blockade of IFN-γ after endotoxemia improved survival of secondary candidemia. Transcriptomic analysis of innate lymphocytes during endotoxemia suggested that NKT cells drove IFN-γ production by NK cells via mTORC1. Activation of invariant NKT (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 an NKT cell/mTOR/IFN-γ axis in immunosuppression following endotoxemia or sepsis. In summary, in vivo iNKT cells activated mTORC1 in NK cells to produce IFN-γ, which worsened macrophage phagocytosis, clearance of secondary Candida infection, and mortality.