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Identification of natural RORγ ligands that regulate the development of lymphoid cells

Fabio R Santori1, Pengxiang Huang2, Serge A van de Pavert3

  • 1The Kimmel Center for Biology and Medicine of the Skirball Institute, New York University School of Medicine, New York, NY 10016, USA.

Cell Metabolism
|February 5, 2015
PubMed

Insights

Cholesterol biosynthetic intermediates (CBIs) are essential for RORγt-driven gene transcription and lymphocyte development. These findings reveal a novel role for sterol lipids in regulating immune cell maturation.

Area of Science:

  • Immunology
  • Molecular Biology
  • Metabolic Biochemistry

Background:

  • The nuclear hormone receptor RORγt is crucial for the development of thymocytes, lymphoid organs, Th17 cells, and type 3 innate lymphoid cells.
  • While RORγt binds oxysterols, its natural ligands remain unidentified, hindering understanding of its regulatory mechanisms.

Purpose of the Study:

  • To investigate whether sterol lipids, specifically cholesterol biosynthetic intermediates (CBIs), function as natural ligands for RORγt.
  • To elucidate the role of CBIs in RORγt-dependent transcription and lymphocyte development.

Main Methods:

  • Utilized a combination of overexpression, RNA interference (RNAi), and genetic deletion of metabolic enzymes to study RORγt-dependent transcription.
  • Analyzed lipids bound to RORγt and assessed the impact of metabolic enzyme manipulation on lymphocyte development.

Main Results:

  • Sterol lipids were found to be necessary and sufficient for driving RORγt-dependent transcription.
  • Cholesterol biosynthetic intermediates (CBIs) were identified as potential RORγt ligands, stabilizing the receptor and promoting coactivator recruitment.
  • Genetic disruption of CBI synthesis impaired lymph node and Th17 cell development.

Conclusions:

  • Cholesterol biosynthetic intermediates (CBIs) are likely natural ligands for RORγt, playing a critical role in its transcriptional activity.
  • CBIs are implicated in regulating lymphocyte development, potentially by modulating RORγt function.
  • This study uncovers a novel link between cholesterol metabolism and immune cell differentiation.

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