Post-sepsis immunosuppression depends on NKT cell regulation of mTOR/IFN-γ in NK cells
| Autor: | Rebecca M. Baron, Edy Y. Kim, Tomoyoshi Tamura, Hadas Ner-Gaon, Samuel A.P. Short, David E. Leaf, Tal Shay, Aidan M. Cullen, Diana Barragan-Bradford, Jiyoung Choi, Jingyu Guo, Jack Varon, Angelica Higuera, Mayra Pinilla-Vera, Antonio J. Arciniegas-Rubio, Michael B. Brenner |
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| Jazyk: | angličtina |
| Rok vydání: | 2020 |
| Předmět: |
0301 basic medicine
Male medicine.medical_treatment Secondary infection Inflammation mTORC1 Sepsis 03 medical and health sciences Interferon-gamma Mice 0302 clinical medicine Antigen medicine Immune Tolerance Animals Humans PI3K/AKT/mTOR pathway Candida Mice Knockout business.industry TOR Serine-Threonine Kinases Candidiasis Immunosuppression General Medicine medicine.disease Natural killer T cell Killer Cells Natural 030104 developmental biology 030220 oncology & carcinogenesis Immunology Natural Killer T-Cells Female medicine.symptom Antigens CD1d business Research Article Signal Transduction |
| Zdroj: | J Clin Invest |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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