TY - JOUR
T1 - Post-sepsis immunosuppression depends on NKT cell regulation of mTOR/IFN-γ in NK cells
AU - Kim, Edy Y.
AU - Ner-Gaon, Hadas
AU - Varon, Jack
AU - Cullen, Aidan M.
AU - Guo, Jingyu
AU - Choi, Jiyoung
AU - Barragan-Bradford, Diana
AU - Higuera, Angelica
AU - Pinilla-Vera, Mayra
AU - Short, Samuel A.P.
AU - Arciniegas-Rubio, Antonio
AU - Tamura, Tomoyoshi
AU - Leaf, David E.
AU - Baron, Rebecca M.
AU - Shay, Tal
AU - Brenner, Michael B.
N1 - Publisher Copyright: © 2020, American Society for Clinical Investigation.
PY - 2020/6/1
Y1 - 2020/6/1
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85083873956&partnerID=8YFLogxK
U2 - https://doi.org/10.1172/JCI128075
DO - https://doi.org/10.1172/JCI128075
M3 - Article
C2 - 32154791
SN - 0021-9738
VL - 130
SP - 3238
EP - 3252
JO - Journal of Clinical Investigation
JF - Journal of Clinical Investigation
IS - 6
ER -