Pharmacological inhibition of RORC2 enhances human Th17‐Treg stability and function. Issue 9 (10th June 2020)

• Record Type: Journal Article
• Authors: Boardman, Dominic A.; Garcia, Rosa V.; Ivison, Sabine M.; Bressler, Brian; Dhar, TG Murali; Zhao, Qihong; Levings, Megan K.
• Is Part Of: European journal of immunology. Volume 50:Issue 9(2020)
• Page Start: 1400
• Page End: 1411
• Publication Date: 2020-06-10
• Subjects: IL‐10 -- Inflammatory bowel disease -- RORC2 -- Regulatory T cell -- Th17; Immunology -- Periodicals; 616.079
• DOI: 10.1002/eji.201948435
• Languages: English
• ISSNs: 0014-2980

Abstract

Abstract: Inflammatory bowel diseases (IBD) are chronic conditions that result from uncontrolled intestinal inflammation. Pathogenic Th17 cells, characterized by production of IL‐17A in the absence of IL‐10, are thought to contribute to this inflammation, but in humans, antibody‐mediated blockade of IL‐17A is an ineffective IBD therapy whereas IL‐23 blockade is effective. Here, we investigated the effects of pharmacological inhibition of RORC2, the Th17 cell lineage‐defining transcription factor, on in vivo‐differentiated human Th17 cells and Th17‐like Tregs (Th17‐Tregs). BMS‐336, a small molecule RORC2 inverse agonist, inhibited expression of RORC2‐regulated genes in peripheral Th17 cells (CD4 + CD25 – CD127 + CXCR3 – CCR4 + CCR6 + ) in a dose–dependent manner, with similar inhibitory effects on laminar propria mononuclear cells from IBD and non‐IBD subjects. Exposure of peripheral Th17‐Tregs (CD4 + CD25 hi CD127 lo CXCR3 – CCR4 + CCR6 + ) to BMS‐336 also inhibited IL‐17A production and prevented inflammatory cytokine‐induced destabilization, as evidenced by preserved FOXP3 expression and epigenetic status of the Treg‐specific demethylation region. In parallel, RORC2 inhibition increased the production of IL‐10 in Th17‐Tregs, resulting in enhanced suppression of inflammatory cytokines from myeloid cells. Thus, via its ability to simultaneously inhibit Th17 cells and enhance the stability and function of Th17‐Tregs, pharmacological inhibition of RORC2 is a promising approach to suppress inflammation and promote immune regulation in IBD. Abstract : Th17‐Tregs are immunosuppressive FOXP3 + RORC2 + cells that inhibit Th17 cells and reduce inflammatory bowel disease progression. Inhibition of RORC2 in Th17‐Tregs enhances IL‐10 secretion which, in turn, improves their suppression of innate immune cells. In an inflammatory environment, RORC2 inhibition stabilizes Th17‐Tregs by preserving FOXP3 expression.