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When T cells with CD4 markers are activated, they give rise to two types of effector cells: helper T cells and regulatory T cells. Meanwhile, T cells with CD8 markers differentiate into effector cytotoxic T cells. The differentiation of CD4 T cells into helper T cell subsets, such as Th1, Th2, and Th17 cells, is dependent on the antigen type, antigen-presenting cell, and regulatory cytokines.
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Related Experiment Video

Updated: Mar 20, 2026

Author Spotlight: Achieving High-Purity In Vitro Differentiation of Th17 Cells Using Cytokine Concentration Modulation
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Enhanced HIF-1α cooperation by a human RORγt mutant potentiates Th17 pathogenicity.

Peixian Dong1, Liang Liu1, John Yu1

  • 1Department of Immunology and Immune Therapeutics, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA; Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.

Cell Reports
|March 18, 2026
PubMed
Summary

A specific mutation in the RORγt protein amplifies T helper 17 cell pathogenicity by cooperating with HIF-1α. This RORγt mutation exacerbates inflammatory diseases like colitis by altering cell metabolism and cytokine production.

Keywords:
CP: immunologyCP: molecular biologyRORγtTh17 cellsinflammatory diseasesmetabolic regulation

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Area of Science:

  • Immunology
  • Molecular Biology
  • Genetics

Background:

  • T helper 17 (Th17) cells are crucial for mucosal immunity and autoimmune diseases.
  • The transcription factor retinoic acid receptor-related orphan receptor gamma t (RORγt) regulates Th17 cell function.
  • Genome-wide association studies suggest RORC gene variants are linked to inflammatory conditions, but their functional impact is unclear.

Purpose of the Study:

  • To investigate the functional consequences of a specific RORγt mutation (N277D) on Th17 cell pathogenicity.
  • To elucidate the molecular mechanisms by which this mutation exacerbates inflammation, particularly in cooperation with hypoxia-inducible factor HIF-1α.

Main Methods:

  • Identification and characterization of a pathogenic RORγt mutation (N277D).
  • Analysis of Th17 cell pathogenicity, cytokine production (IFN-γ), and T cell homeostasis in mouse models.
  • Integrated transcriptomic and metabolomic profiling to identify activated pathways.
  • Investigation of the interaction between mutated RORγt (RORγtN277D) and HIF-1α at the Pdk1 locus.
  • Functional validation by silencing Pdk1.

Main Results:

  • The RORγt N277D mutation amplifies Th17 cell pathogenicity, leading to increased IFN-γ and other Th1-type cytokine production.
  • This mutation exacerbates experimental colitis without affecting T cell development or homeostasis.
  • Transcriptomic and metabolomic data revealed activation of glycolytic and hypoxia-associated pathways.
  • Increased RORγtN277D recruitment by HIF-1α to the Pdk1 locus was observed.
  • Silencing Pdk1 normalized excessive IFN-γ production in RORγtN277D Th17 cells.

Conclusions:

  • A pathogenic RORγt mutation (N277D) cooperates with HIF-1α to enhance Th17 cell pathogenicity.
  • This RORγt-HIF-1α axis coordinates transcriptional and metabolic programs, driving inflammation.
  • The findings provide a framework for understanding the functional impact of autoimmune risk variants in RORC.