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

• DOI: 10.1038/s41385-022-00487-x
• Publication Date: 2022-02-15T11:03:01Z
• Authors: Jonas Ahlers; Andrej Mantei; Laura Lozza; Manuela Stäber; Frederik Heinrich; Petra Bacher; Thordis Hohnstein; Lutz Menzel; Simge G. Yüz; Daniel Alvarez-Simon; Anne Rieke Bicken...; Carl Weidinger; Nadine Mockel-Ten...; Anja A. Kühl; Britta Siegmund; Jochen Maul; Christian Neumann; Alexander Scheffold
• Keywords: Mice, Knockout; STAT3 Transcription Factor; 0301 basic medicine; Cancer Research; Th1 Cells; Inflammatory Bowel Diseases; Article; Interleukin-10; 3. Good health; Mice; 03 medical and health sciences; Crohn Disease; Proto-Oncogene Proteins c-maf; Integrative Biomedicine [Topic 3]; Animals; Humans

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.