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


  • J. Ahlers
  • A. Mantei
  • L. Lozza
  • M. Stäber
  • F. Heinrich
  • P. Bacher
  • T. Hohnstein
  • L. Menzel
  • S.G. Yüz
  • D. Alvarez-Simon
  • A.R. Bickenbach
  • C. Weidinger
  • N. Mockel-Tenbrinck
  • A.A. Kühl
  • B. Siegmund
  • J. Maul
  • C. Neumann
  • A. Scheffold


  • Mucosal Immunology


  • Mucosal Immunol 15 (3): 480-490


  • 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.