TY - JOUR
T1 - Expression of type I interferon by splenic macrophages suppresses adaptive immunity during sepsis
AU - Schwandt, Timo
AU - Schumak, Beatrix
AU - Gielen, Gerrit H.
AU - Jüngerkes, Frank
AU - Schmidbauer, Patricia
AU - Klocke, Katrin
AU - Staratschek-Jox, Andrea
AU - van Rooijen, Niko
AU - Kraal, Georg
AU - Ludwig-Portugall, Isis
AU - Franken, Lars
AU - Wehner, Sven
AU - Kalff, Jörg C.
AU - Weber, Olaf
AU - Kirschning, Carsten
AU - Coch, Christoph
AU - Kalinke, Ulrich
AU - Wenzel, Jörg
AU - Kurts, Christian
AU - Zawatzky, Rainer
AU - Holzmann, Bernhard
AU - Layland, Laura
AU - Schultze, Joachim L.
AU - Burgdorf, Sven
AU - den Haan, Joke M. M.
AU - Knolle, Percy A.
AU - Limmer, Andreas
PY - 2012
Y1 - 2012
N2 - Early during Gram-negative sepsis, excessive release of pro-inflammatory cytokines can cause septic shock that is often followed by a state of immune paralysis characterized by the failure to mount adaptive immunity towards secondary microbial infections. Especially, the early mechanisms responsible for such immune hypo-responsiveness are unclear. Here, we show that TLR4 is the key immune sensing receptor to initiate paralysis of T-cell immunity after bacterial sepsis. Downstream of TLR4, signalling through TRIF but not MyD88 impaired the development of specific T-cell immunity against secondary infections. We identified type I interferon (IFN) released from splenic macrophages as the critical factor causing T-cell immune paralysis. Early during sepsis, type I IFN acted selectively on dendritic cells (DCs) by impairing antigen presentation and secretion of pro-inflammatory cytokines. Our results reveal a novel immune regulatory role for type I IFN in the initiation of septic immune paralysis, which is distinct from its well-known immune stimulatory effects. Moreover, we identify potential molecular targets for therapeutic intervention to overcome impairment of T-cell immunity after sepsis
AB - Early during Gram-negative sepsis, excessive release of pro-inflammatory cytokines can cause septic shock that is often followed by a state of immune paralysis characterized by the failure to mount adaptive immunity towards secondary microbial infections. Especially, the early mechanisms responsible for such immune hypo-responsiveness are unclear. Here, we show that TLR4 is the key immune sensing receptor to initiate paralysis of T-cell immunity after bacterial sepsis. Downstream of TLR4, signalling through TRIF but not MyD88 impaired the development of specific T-cell immunity against secondary infections. We identified type I interferon (IFN) released from splenic macrophages as the critical factor causing T-cell immune paralysis. Early during sepsis, type I IFN acted selectively on dendritic cells (DCs) by impairing antigen presentation and secretion of pro-inflammatory cytokines. Our results reveal a novel immune regulatory role for type I IFN in the initiation of septic immune paralysis, which is distinct from its well-known immune stimulatory effects. Moreover, we identify potential molecular targets for therapeutic intervention to overcome impairment of T-cell immunity after sepsis
U2 - https://doi.org/10.1038/emboj.2011.380
DO - https://doi.org/10.1038/emboj.2011.380
M3 - Article
C2 - 22036947
SN - 0261-4189
VL - 31
SP - 201
EP - 213
JO - EMBO Journal
JF - EMBO Journal
IS - 1
ER -