Local Modulation of Antigen-Presenting Cell Development after Resolution of Pneumonia Induces Long-Term Susceptibility to Secondary Infections

Publication date: 18 July 2017
Source:Immunity, Volume 47, Issue 1
Author(s): Antoine Roquilly, Hamish E.G. McWilliam, Cedric Jacqueline, Zehua Tian, Raphael Cinotti, Marie Rimbert, Linda Wakim, Irina Caminschi, Mireille H. Lahoud, Gabrielle T. Belz, Axel Kallies, Justine D. Mintern, Karim Asehnoune, Jose A. Villadangos
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-β. Paralyzed DCs secreted TGF-β 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.

Graphical abstract

Teaser

Following a severe primary infection, the risk of developing pneumonia increases due to acquired immune defects collectively known as sepsis-induced immunosuppression. Roquilly et al. show that resolution of the primary infection changed the local environment, leading to the development of DCs and macrophages that are functionally impaired in terms of T cell activation, and instead exhibit tolerogenic properties that contribute to immune suppression.


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