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

Retinoic acid-related orphan receptor (ROR)-γt, the master transcription factor of the Th17 subset of CD4⁺ Th cells, is a promising target for treating a host of autoimmune diseases. RORγt plays a vital role in the pathogenesis of inflammatory bowel diseases-Crohn disease and ulcerative colitis-caused 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⁺ 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 RORγt, in addition to Th17 cells, is also expressed in peripherally induced, colonic regulatory CD4⁺ T cells. Therefore, RORγt is expressed in both effector and regulatory subsets of CD4⁺ T cells in the intestine. The present review discusses the role of RORγt in cellular and molecular differentiation of Th17 and Treg, and examines how targeting RORγt in inflammatory bowel disease therapy could influence the development of these two diverse subsets of immune cells with opposing functions.