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.

ABSTRACT: 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.

SUBMITTER: Ahlers J 

PROVIDER: S-EPMC9038525 | biostudies-literature | 2022 Mar

REPOSITORIES: biostudies-literature