Post-sepsis immunosuppression depends on NKT cell regulation of mTOR/IFN-γ in NK cells
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
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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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 4

Selective activation of iNKT cells with glycolipid antigen (αGalCer) drives IFN-γ production and immunosuppression.

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Selective activation of iNKT cells with glycolipid antigen (αGalCer) dri...
(A) WT mice (n = 6–7 per group except n = 4 for γδ T cells) were treated with vehicle or αGalCer i.p., followed 3 hours later by brefeldin A i.p. IFN-γ was assessed by flow cytometry 6 hours later. (B) Percent IFN-γ+ in splenic cell subsets from A. (C) In vivo phagocytosis. WT mice were treated with vehicle (naive) or αGalCer 1 μg i.p., then 18 hours later with opsonized zymosan-FITC i.v. Flow cytometry plots for percentage zymosan-FITC+ Ly6c+ macrophages are shown. (D) Percent zymosan-FITC+ splenic and kidney cell subsets from C (naive, n = 4–5; αGalCer, n = 4–6). (E) Survival curves for WT mice treated with αGalCer i.p. only; vehicle and then Candida i.v. only; or αGalCer 1 μg i.p., followed 18 hours later (day –1) or 3 days later (day –3) by Candida i.v. (n = 7 per group). (F) Candida CFU in kidney of WT mice treated with αGalCer (or vehicle) followed 18 hours later by Candida i.v. (n = 5 per group). (G) Survival curves for WT or IFN-γ–KO mice treated with αGalCer i.p., followed 18 hours later by Candida i.v. (n = 12 per group). (H) Candida CFU in kidney (n = 5 per group). In bar graphs, mean ± SEM is shown. (B, D, F, and H) Unpaired t tests. (E and G) Log-rank test. *P < 0.05; **P < 0.01; ***P < 0.001; ****P < 0.0001.