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.
Jonas AhlersAndrej ManteiLaura LozzaManuela StäberFrederik HeinrichPetra BacherThordis HohnsteinLutz MenzelSimge G YüzDaniel Alvarez-SimonAnne Rieke BickenbachCarl WeidingerNadine Mockel-TenbrinckAnja A KühlBritta SiegmundJochen MaulChristian NeumannAlexander ScheffoldPublished in: Mucosal immunology (2022)
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.
Keyphrases
- cell proliferation
- endothelial cells
- poor prognosis
- end stage renal disease
- transcription factor
- ejection fraction
- induced pluripotent stem cells
- chronic kidney disease
- pluripotent stem cells
- oxidative stress
- prognostic factors
- anti inflammatory
- dendritic cells
- high glucose
- regulatory t cells
- stem cells
- immune response
- mesenchymal stem cells
- long non coding rna
- binding protein
- peritoneal dialysis
- deep learning
- big data
- blood brain barrier
- electronic health record
- patient reported
- drug induced
- brain injury