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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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 6

Selective activation of iNKT cells by the glycolipid antigen αGalCer drives immunosuppression via mTOR.

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Selective activation of iNKT cells by the glycolipid antigen αGalCer dri...
(A) Flow cytometry plots and MFI of phosphorylated S6 kinase (p-S6) in splenic cell subsets from WT mice 3 hours after αGalCer i.v. (or vehicle) (n = 6 per group). (B) Mice were treated with rapamycin i.p. (or vehicle), then 3 hours later with αGalCer i.p. (or vehicle). Three hours after αGalCer (or vehicle), mice were given brefeldin A i.p., and 6 hours later, IFN-γ was assessed by flow cytometry. Plots and percentage IFN-γ+ are shown (n = 5 per group). (C) In vivo phagocytosis assay. WT mice received αGalCer i.p. (or vehicle), then 3 and 15 hours later were treated with rapamycin i.p. (or vehicle). At 18 hours after αGalCer, opsonized zymosan-FITC was administered. Flow cytometry plots for splenic Ly6c+ macrophages are shown. (D and E) Percentage of zymosan+ macrophages in the spleen (n = 6) (D) and kidney (naive, n = 4–8; αGalCer, n = 9–11) (E) is shown. (F) In vivo phagocytosis assay. WT mice were treated with αGalCer and then rapamycin as in C. At 18 hours after αGalCer, mice were infected with Candida i.v. In vivo phagocytosis assay of opsonized zymosan-FITC was assessed at day 1 after Candida infection in kidney (n = 6). In bar graphs, mean ± SEM is shown. (A–E) Unpaired t test. (F) Kruskal-Wallis test. *P < 0.05; **P ≤ 0.01; ***P < 0.001.