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.
Highlights
The anti-inflammatory cytokine Interleukin (IL-) 10 plays a key role in the establishment of immune tolerance and prevention of immunopathology by limiting immune responses against harmless antigens and constraining excessive immunity against pathogens.[1,2] In particular, IL-10 is essential for the regulation of intestinal immune homeostasis by assuring balanced immune control of the microbiota.[3]
Advances have been made to unravel the molecular control of IL-10 in murine CD4+ T cells,[2,52,53] the respective extra- and intracellular mediators governing IL-10 expression in human effector CD4+ T cells are less well understood
Downstream of Notch/STAT3, we identified the transcriptional regulators Blimp-1 and c-Maf to jointly control IL-10 expression, establishing a novel universal anti-inflammatory pathway in human CD4+ T cells
Summary
The anti-inflammatory cytokine Interleukin (IL-) 10 plays a key role in the establishment of immune tolerance and prevention of immunopathology by limiting immune responses against harmless antigens and constraining excessive immunity against pathogens.[1,2] In particular, IL-10 is essential for the regulation of intestinal immune homeostasis by assuring balanced immune control of the microbiota.[3]. (STAT4) for Th1 cells, IL-4 (STAT6) for Th2 cells as well as IL-6, IL-21 (STAT3) and TGF-ß for Th17 cells.[17,18,19,20,21] In addition, IL-27 (STAT1/3) has been shown to promote IL-10 expression by murine CD4+ T cells.[22,23,24,25,26,27] In humans, type I interferon (IFN) (STAT1/3), which generally supports Th1 immunity, appears to co-stimulate CD4+ T cell-derived IL-10 production.[28,29,30,31] In summary, all these IL-10 inducing signals predominantly drive inflammatory effector CD4+ Th cell programming.
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