Retinoic acid signaling acts as a rheostat to balance Treg function

Govindarajan Thangavelu, Gabriela Andrejeva, Sara Bolivar-Wagers, Sujeong Jin, Michael C. Zaiken, Michael Loschi, Ethan G. Aguilar, Scott N. Furlan, Chrysothemis C. Brown, Yu Chi Lee, Cameron Mc Donald Hyman, Colby J. Feser, Angela Panoskaltsis-Mortari, Keli L. Hippen, Kelli P. MacDonald, William J. Murphy, Ivan Maillard, Geoffrey R. Hill, David H. Munn, Robert ZeiserLeslie S. Kean, Jeffrey C. Rathmell, Hongbo Chi, Randolph J. Noelle, Bruce R. Blazar

Research output: Contribution to journalArticlepeer-review

Abstract

Regulatory T cells (Tregs) promote immune homeostasis by maintaining self-tolerance and regulating inflammatory responses. Under certain inflammatory conditions, Tregs can lose their lineage stability and function. Previous studies have reported that ex vivo exposure to retinoic acid (RA) enhances Treg function and stability. However, it is unknown how RA receptor signaling in Tregs influences these processes in vivo. Herein, we employed mouse models in which RA signaling is silenced by the expression of the dominant negative receptor (DN) RARα in all T cells. Despite the fact that DNRARα conventional T cells are hypofunctional, Tregs had increased CD25 expression, STAT5 pathway activation, mTORC1 signaling and supersuppressor function. Furthermore, DNRARα Tregs had increased inhibitory molecule expression, amino acid transporter expression, and metabolic fitness and decreased antiapoptotic proteins. Supersuppressor function was observed when wild-type mice were treated with a pharmacologic pan-RAR antagonist. Unexpectedly, Treg-specific expression of DNRARα resulted in distinct phenotypes, such that a single allele of DNRARα in Tregs heightened their suppressive function, and biallelic expression led to loss of suppression and autoimmunity. The loss of Treg function was not cell intrinsic, as Tregs that developed in a noninflammatory milieu in chimeric mice reconstituted with DNRARα and wild-type bone marrow maintained the enhanced suppressive capacity. Fate mapping suggested that maintaining Treg stability in an inflammatory milieu requires RA signaling. Our findings indicate that RA signaling acts as a rheostat to balance Treg function in inflammatory and noninflammatory conditions in a dose-dependent manner.

Original languageEnglish (US)
JournalCellular and Molecular Immunology
DOIs
StateAccepted/In press - 2022

Keywords

  • Autoimmunity
  • Metabolism
  • mTORC1
  • Retinoic acid
  • STAT5
  • Tregulatory cells

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology
  • Infectious Diseases

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