PT Journal
AU Ahlers, J
   Mantei, A
   Lozza, L
   Stäber, M
   Heinrich, F
   Bacher, P
   Hohnstein, T
   Menzel, L
   Yüz, SG
   Alvarez-Simon, D
   Bickenbach, AR
   Weidinger, C
   Mockel-Tenbrinck, N
   Kühl, AA
   Siegmund, B
   Maul, J
   Neumann, C
   Scheffold, GA
TI A Notch/STAT3-driven Blimp-1/c-Maf-dependent molecular switch induces IL-10 expression in human CD4+ T cells and is defective in Crohn´s disease patients
SO Mucosal immunology : official journal of the Society for Mucosal Immunology
JI Mucosal Immunology
PY 2022
BP 480
EP 490
VL 15
IS 3
PU Elsevier BV
DI 10.1038/s41385-022-00487-x
WP https://macau.uni-kiel.de/receive/macau_mods_00004920
LA en
DE Th1 Cells; Animals; Mice, Knockout; Humans; Mice; Inflammatory Bowel Diseases; Crohn Disease; Interleukin-10; STAT3 Transcription Factor; Proto-Oncogene Proteins c-maf
SN 1933-0219
AB Immunosuppressive Interleukin (IL)-10 production by pro-inflammatory CD4+ T cells is a central self-regulatory function to limit aberrant inflammation. Still, the molecular mediators controlling IL-10 expression in human CD4+ T cells are largely undefined. Here, we identify a Notch/STAT3 signaling-module as a universal molecular switch to induce IL-10 expression across human naïve and major effector CD4+ T cell subsets. IL-10 induction was transient, jointly controlled by the transcription factors Blimp-1/c-Maf and accompanied by upregulation of several co-inhibitory receptors, including LAG-3, CD49b, PD-1, TIM-3 and TIGIT. Consistent with a protective role of IL-10 in inflammatory bowel diseases (IBD), effector CD4+ T cells from Crohn's disease patients were defective in Notch/STAT3-induced IL-10 production and skewed towards an inflammatory Th1/17 cell phenotype. Collectively, our data identify a Notch/STAT3-Blimp-1/c-Maf axis as a common anti-inflammatory pathway in human CD4+ T cells, which is defective in IBD and thus may represent an attractive therapeutic target.
PI New York, NY
ER