Expression of type I interferon by splenic macrophages suppresses adaptive immunity during sepsis.
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.
Institutes of Molecular Medicine and Experimental Immunology (IMMEI), University of Bonn, Bonn, Germany.
Timo
T
Schwandt
Beatrix
B
Schumak
Gerrit H
GH
Gielen
Frank
F
Jüngerkes
Patricia
P
Schmidbauer
Katrin
K
Klocke
Andrea
A
Staratschek-Jox
Niko
N
van Rooijen
Georg
G
Kraal
Isis
I
Ludwig-Portugall
Lars
L
Franken
Sven
S
Wehner
Jörg C
JC
Kalff
Olaf
O
Weber
Carsten
C
Kirschning
Christoph
C
Coch
Ulrich
U
Kalinke
Jörg
J
Wenzel
Christian
C
Kurts
Rainer
R
Zawatzky
Bernhard
B
Holzmann
Laura
L
Layland
Joachim L
JL
Schultze
Sven
S
Burgdorf
Joke M M
JM
den Haan
Percy A
PA
Knolle
Andreas
A
Limmer
D056704:Adaptive Immunity; D000818:Animals; D003713:Dendritic Cells / Q000378:metabolism; D007370:Interferon Type I / Q000378:metabolism*; D008264:Macrophages / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D053594:Myeloid Differentiation Factor 88 / Q000378:metabolism; D018805:Sepsis / Q000276:immunology* / Q000378:metabolism; D015398:Signal Transduction; D013154:Spleen / Q000378:metabolism*; D051197:Toll-Like Receptor 4 / Q000378:metabolism
D007370:Interferon Type I; D053594:Myeloid Differentiation Factor 88; D051197:Toll-Like Receptor 4