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

The Journal of Clinical Investigation
Edy Y KimMichael B Brenner

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 v...Continue Reading

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Citations

Oct 11, 2020·GeroScience·Ramasamy SelvaraniArlan Richardson
Nov 8, 2020·Biochemical and Biophysical Research Communications·Yanyan LuBen Lu
Jan 31, 2021·The Journal of Immunology : Official Journal of the American Association of Immunologists·Isaac J JensenVladimir P Badovinac
Mar 7, 2021·International Journal of Molecular Sciences·Ting SuYutaka Furutani
Apr 26, 2021·Clinical Immunology : the Official Journal of the Clinical Immunology Society·Margaret R DunneThomas R Rogers
Jul 22, 2021·Critical Care Explorations·Maheetha BharadwajEdy Y Kim

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Methods Mentioned

BETA
dissection
RNA-Seq
flow cytometry
PCR
ELISA

Software Mentioned

FlowJo
HISAT
CuffQuant
GSEA
Tuxedo
MATLAB
CuffLinks
CuffNorm
kmeans
FACSDiva

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