Post-sepsis immunosuppression depends on NKT cell regulation of mTOR/IFN-γ in NK cells
Edy Y. Kim, … , Tal Shay, Michael B. Brenner
Edy Y. Kim, … , Tal Shay, Michael B. Brenner
Published March 10, 2020
Citation Information: J Clin Invest. 2020;130(6):3238-3252. https://doi.org/10.1172/JCI128075.
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Research Article Immunology Infectious disease

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

Abstract

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.

Authors

Edy Y. Kim, Hadas Ner-Gaon, Jack Varon, Aidan M. Cullen, Jingyu Guo, Jiyoung Choi, Diana Barragan-Bradford, Angelica Higuera, Mayra Pinilla-Vera, Samuel A.P. Short, Antonio Arciniegas-Rubio, Tomoyoshi Tamura, David E. Leaf, Rebecca M. Baron, Tal Shay, Michael B. Brenner

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Figure 7

NKT cells and mTORC1 drive post-sepsis immunosuppression and susceptibility to secondary candidemia.

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NKT cells and mTORC1 drive post-sepsis immunosuppression and susceptibil...
(A) Survival curves for WT mice treated with αGalCer i.p. or LPS i.v. followed by rapamycin i.p. or vehicle at 3 and 15 hours later (n = 6 per group). (B and C) Survival curves for WT mice after administration of αGalCer i.p. (B) or LPS i.v. (C). At 3 and 15 hours after these primary challenges, mice were treated with rapamycin i.p. (or vehicle). At 18 hours after primary challenge, mice received secondary infection with Candida i.v. (n = 13–15 per group). (D) Survival curves for WT mice and CD1d-KO mice infected with cecal slurry peritonitis i.p. A subset of WT mice (WT + rapamycin) were treated at 3 and 15 hours after cecal slurry with rapamycin i.p. (n = 6–12). (E) Survival curves for WT mice and CD1d-KO mice infected with cecal slurry peritonitis i.p. followed 18 hours later with secondary Candida i.v. (n = 10–13). (F) Survival curves for WT mice infected with cecal slurry peritonitis i.p. and then treated 3 and 15 hours later with rapamycin i.p. or vehicle. Eighteen hours after cecal slurry, mice received secondary infection with Candida i.v. (n = 19). (A–F) Log-rank test. *P < 0.05; ****P < 0.0001.