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Project description: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.
2025-09-03 | GSE236565 | GEO
Project description: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.
2025-09-03 | GSE236564 | GEO
Project description:Nuclear receptor coregulator NRIP1 R448G modulates T cell gut-homing and Teff:Treg balance to control intestinal inflammation.
| PRJNA991565 | ENA
Project description:Nuclear receptor coregulator NRIP1 R448G modulates T cell gut-homing and Teff:Treg balance to control intestinal inflammation [scATAC-Seq]
| PRJNA991570 | ENA
Project description:Nuclear receptor coregulator NRIP1 R448G modulates T cell gut-homing and Teff:Treg balance to control intestinal inflammation [scRNA-seq]
| PRJNA991571 | ENA
Project description:Reestablishing an appropriate balance between T effector cells (Teff) and Tregs is essential for correcting autoimmunity. Multiple sclerosis (MS) is an immune-mediated chronic CNS disease characterized by neuroinflammation, demyelination, and neuronal degeneration, in which the Teff:Treg balance is skewed toward pathogenic Teffs Th1 and Th17 cells. STAT3 is a key regulator of Teff:Treg balance. Using the structure-based design, we have developed a potentially novel small-molecule prodrug LLL12b that specifically inhibits STAT3 and suppresses Th17 differentiation and expansion. Moreover, LLL12b regulates the fate decision between Th17 and Tregs in an inflammatory environment, shifting Th17:Treg balance toward Tregs and favoring the resolution of inflammation. Therapeutic administration of LLL12b after disease onset significantly suppresses disease progression in adoptively transferred, chronic, and relapsing-remitting experimental autoimmune encephalomyelitis. Disease relapses were also significantly suppressed by LLL12b given during the remission phase. Additionally, LLL12b shifts Th17:Treg balance of CD4+ T cells from MS patients toward Tregs and increases Teff sensitivity to Treg-mediated suppression. These data suggest that selective inhibition of STAT3 by the small molecule LLL12b recalibrates the effector and regulatory arms of CD4+ T responses, representing a potentially clinically translatable therapeutic strategy for MS.
| S-EPMC7934926 | biostudies-literature
Project description:PurposeExperimental autoimmune uveitis (EAU) is a representative animal model of human uveitis. In this study, we investigated whether apolipoprotein A1 (APOA1) can alleviate EAU and explored its underlying mechanism.MethodsMice were immunized with interphotoreceptor retinoid-binding protein 1-20 and treated with APOA1 or vehicle. The retinas, draining lymph nodes (DLNs), and spleens were analyzed. Isolated T cells were used for proliferation, differentiation, and function assays in vitro. Selective inhibitors and pathway agonists were used to study signaling pathways. The effect of APOA1 on peripheral blood mononuclear cells (PBMCs) from uveitis patients was also examined.ResultsAdministration of APOA1 ameliorated EAU. APOA1 suppressed pathogenic CD4+ T cell expansion in DLNs and spleen, and decreased the infiltration of effector T (Teff) cells into retina. APOA1 also inhibited T cell proliferation and T helper 1 cell differentiation in vitro and promoted regulatory T (Treg) cell differentiation. APOA1 restricted inflammatory cytokine production from lipopolysaccharide-stimulated PBMCs. Mechanistic studies revealed that the effect of APOA1 was mediated by scavenger receptor class B type I (SR-BI) and downstream signals including phosphatidylinositol 3-kinase/Protein kinase B (PKB, or Akt), p38 mitogen-activated protein kinase, and nuclear factor-κB.ConclusionsAPOA1 ameliorates EAU by regulating the Teff/Treg partially through SR-BI. Our results suggest that APOA1 can be a therapeutic alternative for autoimmune uveitis.
| S-EPMC9339694 | biostudies-literature
Project description:Uveitis, an autoimmune disease, often leads to blindness. CD4+ T cells, including regulatory T cells (Tregs) and effector T cells (Th1 and Th17), play a critical role in its pathogenesis. Caloric restriction (CR) has been shown to alleviate autoimmune diseases. However, careful characterization of the impact of CR on experimental autoimmune uveitis (EAU) is poorly understood. This study used single-cell RNA sequencing to analyze cervical draining lymph nodes in mice under ad libitum (AL) and CR diets, with or without EAU. CR increased Tregs, altered immune cell metabolism, reduced EAU symptoms, and downregulated inflammatory and glycolysis genes. Flow cytometry confirmed CR's inhibitory effect on Th1 and Th17 proliferation and its promotion of Treg proliferation. CR also balanced CD4+ T cells by inhibiting the PI3K/AKT/c-Myc pathway and reducing GM-CSF in Th17 cells. These findings suggest CR as a potential therapeutic strategy for autoimmune diseases.
| S-EPMC11612795 | biostudies-literature
Project description:Immature thymocytes expressing autoreactive T-cell receptors (TCR) can adopt differing cell fates: clonal deletion by apoptosis or deviation into alternative lineages such as FoxP3(+) regulatory T cells (Treg). We revisited the role of the transcription factor Nr4a1 (Nur77), an immediate-early response gene induced by TCR engagement. Nr4a1KO mice show clear quantitative defects in antigen-induced clonal deletion. The impact of the Nr4a1 deletion is not enhanced by deletion of the proapoptotic factor Bim. In addition, Nr4a1 curtails initial differentiation into the Treg lineage in TCR transgenic mice and in nontransgenic mice. Transcriptional profiling of Nr4a1KO thymocytes under selection conditions reveals that Nr4a1 activates the transcription of several targets, consistent with these diverse actions: (i) Nr4a1 partakes in the induction of Bim after TCR triggering; (ii) perhaps paradoxically, Nr4a1 positively controls several transcripts of the Treg signature, in particular Ikzf2 and Tnfrsf9; (iii) consistent with its prosurvival and metabolic role in the liver, Nr4a1 is also required for the induction by TCR of a coordinated set of enzymes of the glycolytic and Krebs cycle pathways, which we propose may antagonize Treg selection as does activation of mTOR/Akt. Thus, Nr4a1 appears to act as a balancing molecule in fate determination at a critical juncture of T-cell differentiation.
| S-EPMC3309794 | biostudies-literature
Project description:Foxp3+ Tregs are key to immune homeostasis, but the contributions of various large, multiprotein complexes that regulate gene expression remain unexplored. We analyzed the role in Tregs of the evolutionarily conserved CoREST complex, consisting of a scaffolding protein, Rcor1 or Rcor2, plus Hdac1 or Hdac2 and Lsd1 enzymes. Rcor1, Rcor2, and Lsd1 were physically associated with Foxp3, and mice with conditional deletion of Rcor1 in Foxp3+ Tregs had decreased proportions of Tregs in peripheral lymphoid tissues and increased Treg expression of IL-2 and IFN-γ compared with what was found in WT cells. Mice with conditional deletion of the gene encoding Rcor1 in their Tregs had reduced suppression of homeostatic proliferation, inability to maintain long-term allograft survival despite costimulation blockade, and enhanced antitumor immunity in syngeneic models. Comparable findings were seen in WT mice treated with CoREST complex bivalent inhibitors, which also altered the phenotype of human Tregs and impaired their suppressive function. Our data point to the potential for therapeutic modulation of Treg functions by pharmacologic targeting of enzymatic components of the CoREST complex and contribute to an understanding of the biochemical and molecular mechanisms by which Foxp3 represses large gene sets and maintains the unique properties of this key immune cell.
| S-EPMC7108912 | biostudies-literature