Notch regulates IL-10 production by T helper 1 cells.
T helper 1 (Th1) cells mediate powerful cellular immune responses. However, if unbalanced, Th1 immunity eventually may cause pathology. Recently, it has been shown that IL-10, an antiinflammatory cytokine strongly antagonizing Th1-mediated effects, can be produced by Th1 cells and is indeed essential for self-regulation of Th1 immunity. Here, we show that Notch induces IL-10 production in newly developing and already established Th1 cells via a signal transducer and activator of transcription 4 (STAT4)-dependent process. Notch signaling in the presence of the cytokines IL-12 or IL-27 induces Th1 cells to produce large amounts of IL-10 without diminishing IFN-gamma production. Notch-modified Th1 cells completely lose their inflammatory capacity and instead are able to actively suppress a Th1 cell-induced delayed-type hypersensitivity (DTH) reaction in an IL-10-dependent fashion. IL-10 production can be elicited by active forms of all four mammalian Notch receptors but was found to be specific for the Delta-like family of Notch ligands. Dendritic cells (DC) selectively acquire Delta-like 4 expression upon stimulation with various Toll-like receptor (TLR) ligands and concomitantly induce IL-10 production by Th1 cells in vitro and in vivo. This effect can be selectively reversed by pharmacological inhibitors of Notch signaling (gamma-secretase inhibitor). Our data suggest that Notch regulates IL-10 production in Th1 cells by a STAT4-dependent process that converts proinflammatory Th1 cells into T cells with regulatory activity. This pathway may provide unique opportunities for therapeutic intervention in Th1-driven immune diseases and for Th1-associated vaccination strategies.
Rutz
Sascha
S
Deutsches Rheuma-Forschungszentrum Berlin, Charitéplatz 1, 10117 Berlin, Germany.
Janke
Marko
M
Kassner
Nadine
N
Hohnstein
Thordis
T
Krueger
Manuela
M
Scheffold
Alexander
A
D000818:Animals; D002454:Cell Differentiation; D016207:Cytokines; D006968:Hypersensitivity, Delayed; D016753:Interleukin-10 / Q000096:biosynthesis*; D018664:Interleukin-12 / Q000502:physiology*; D007378:Interleukins / Q000502:physiology*; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D051880:Receptors, Notch / Q000502:physiology*; D050797:STAT4 Transcription Factor / Q000502:physiology*; D015398:Signal Transduction / Q000276:immunology; D050378:T-Lymphocytes, Regulatory / Q000166:cytology; D018417:Th1 Cells / Q000166:cytology / Q000276:immunology / Q000378:metabolism*
D016207:Cytokines; C486767:Il27 protein, mouse; D007378:Interleukins; D051880:Receptors, Notch; D050797:STAT4 Transcription Factor; C494091:Stat4 protein, mouse; D016753:Interleukin-10; D018664:Interleukin-12