Retinoid-Related Orphan Receptor RORγt in CD4+ T-Cell–Mediated Intestinal Homeostasis and Inflammation

Abstract

Retinoic aciderelated orphan receptor (ROR)-gt, the master transcription factor of the Th17 subset of CD4 þ Th cells, is a promising target for treating a host of autoimmune diseases. RORgt plays a vital role in the pathogenesis of inflammatory bowel diseasesdCrohn disease and ulcerative colitisdcaused by untoward reactivity of the immune system to the components of the intestinal microbiome. The mammalian intestinal tract is a highly complex and compartmentalized organ with specialized functions, and is a privileged site for the generation of both peripherally induced regulatory CD4 þ T cells (Tregs) and effector Th17 cells. As Th17 cells can be proinflammatory in nature, the equilibrium between effector Th17 and Treg cells is crucial for balancing intestinal homeostasis and inflammation. Recent findings suggest that RORgt, in addition to Th17 cells, is also expressed in peripherally induced, colonic regulatory CD4 þ T cells. Therefore, RORgt is expressed in both effector and regulatory subsets of CD4 þ T cells in the intestine. The present review discusses the role of RORgt in cellular and molecular differentiation of Th17 and Treg, and examines how targeting RORgt in inflammatory bowel disease therapy could influence the development of these two diverse subsets of immune cells with opposing functions.

The Effect of a Novel Serine Protease Inhibitor on Inflammation and Intestinal Permeability in a Murine Colitis Transfer Model

“…RORγt mRNA expression was however decreased in T cell transfer colitis mice, but significantly increased upon UAMC-00050 treatment. This latter phenomenon may be due to the fact that nonpathogenic Th17 cells might lose RORγt expression during colitis, converting them into the pathogenic Th1-like Th17 cells as recently proposed ( Mickael et al, 2020 ). Furthermore, RORγt is also present in Treg cells ( Mickael et al, 2020 ), which thereby demonstrates the therapeutic effect of increased RORγt expression levels.…”

“…This latter phenomenon may be due to the fact that nonpathogenic Th17 cells might lose RORγt expression during colitis, converting them into the pathogenic Th1-like Th17 cells as recently proposed ( Mickael et al, 2020 ). Furthermore, RORγt is also present in Treg cells ( Mickael et al, 2020 ), which thereby demonstrates the therapeutic effect of increased RORγt expression levels. The above findings suggest a role for Th1, Th17 and Treg cell subsets in the mechanism of action by which UAMC-00050 ameliorates intestinal inflammation.…”

“…Besides, IL-10 and IL-17 have been linked to epithelial proliferation and repair ( Andrews et al, 2018 ). Furthermore, the transcription factors Tbet, GATA-3 and RORγt influence naïve T cell development towards Th1, Th2 and Th17/Treg cells, respectively ( Zhu and Paul, 2010 ; Mickael et al, 2020 ). In this study, mRNA expression levels of Tbet and GATA-3 were significantly increased in T cell transfer colitis mice (colitis + vehicle group) which could be normalized after treatment with UAMC-00050 (colitis + UAMC-00050 group).…”

Paradoxical Augmentation of Experimental Spondyloarthritis by RORC Inhibition in HLA-B27 Transgenic Rats

“…The RORγt+ Tregs subset might be involved in these unanticipated effects. The function of these regulatory cells was thought to be controlled partly by RORγt ( 45 ). Kleinewietfeld et al showed that a low molecular weight RORγt inhibitor could influence the frequencies of regulatory T-cells (Tregs) beside the Th17 response.…”

Treatment of Intestinal Inflammation With Epicutaneous Immunotherapy Requires TGF-β and IL-10 but Not Foxp3+ Tregs

“…Importantly, gut-homing Foxp3 Tregs are required for intestinal tolerance in the lamina propria. IL-10 is an important cytokine produced by a large number of Tregs in the gut and helps to inhibit immune responses and maintain immune tolerance (17). Its importance in the intestinal immune milieu is apparent in both mice and humans as IL-10 deficient mice develop spontaneous inflammation of the colon, and humans with mutations in IL-10 or IL-10 receptor (IL-10R) also develop colitis at an early age (18).…”