Journal
IMMUNITY
Volume 47, Issue 1, Pages 135-+Publisher
CELL PRESS
DOI: 10.1016/j.immuni.2017.06.021
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Funding
- National Health and Medical Research Council of Australia (NHMRC)
- Sylvia and Charles Viertel Foundation
- Victorian State Government Operational Infrastructure Support
- Australian Government NHMRC Independent Research Institute Infrastructure Support scheme
- Societe Francaise d'Anesthesie Reanimation
- Fondation des Gueules Cassees
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Lung infections cause prolonged immune alterations and elevated susceptibility to secondary pneumonia. We found that, after resolution of primary viral or bacterial pneumonia, dendritic cells (DC), and macrophages exhibited poor antigen-presentation capacity and secretion of immunogenic cytokines. Development of these paralyzed'' DCs and macrophages depended on the immunosuppressive microenvironment established upon resolution of primary infection, which involved regulatory T (Treg) cells and the cytokine TGF-beta. Paralyzed DCs secreted TGF-beta and induced local Treg cell accumulation. They also expressed lower amounts of IRF4, a transcription factor associated with increased antigen-presentation capacity, and higher amounts of Blimp1, a transcription factor associated with tolerogenic functions, than DCs present during primary infection. Blimp1 expression in DC of humans suffering sepsis or trauma correlated with severity and complicated outcomes. Our findings describe mechanisms underlying sepsis-and trauma-induced immunosuppression, reveal prognostic markers of susceptibility to secondary infections and identify potential targets for therapeutic intervention.
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