Nuclear receptor coregulator NRIP1 R448G modulates T cell gut-homing and Teff:Treg balance to control intestinal inflammation [scRNA-seq]

Nuclear receptors (NRs) are crucial to integrate metabolite sensing and immune responses in the gut. Nuclear receptor-interacting protein 1 (NRIP1) is an important coregulator of various NRs that has been implicated in inflammatory bowel disease risk, but mechanistic details of how NRIP1 controls NR activities mediating immune homeostasis and inflammation remain elusive. We unveil pleiotropic functions of NRIP1 in distinct CD4+ T cell subsets during intestinal inflammation. We demonstrate that a coding risk variant, NRIP1 R448G, promotes activated CD4+ T cell gut homing and inflammatory cytokine production but impairs regulatory T cell stability, ultimately leading to exacerbated intestinal inflammation. Mechanistically, NRIP1 acts as a corepressor in retinoic acid signaling by modulating VDR (vitamin D receptor) expression and BATF (Basic leucine zipper transcription factor, ATF-like) activity. Our study reveals the impacts of NRIP1 on CD4+ T cells in immune regulation during intestinal inflammation, providing insights into mechanisms by which an NR coregulator controls immune homeostasis and tissue inflammation. Overall design: Mouse splenic naïve CD4+ T cells were purified using EasySep™ Mouse Naïve CD4+ T Cell Isolation Kit (STEMCELL). Cells were then stimulated by plates coated with 2µg/ml anti-mouse CD3e and 2µg/ml anti-mouse CD28 antibodies, with or without 100nM atRA supplement in full RPMI 1640 medium. Cells were harvested on day 3 and submitted for 10x genomics single-cell multiome sequencing.