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Retinoic acid signaling acts as a rheostat to balance Treg function

Cellular & Molecular Immunology volume 19, pages 820–833 (2022)Cite this article

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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.

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Acknowledgements

We thank Brent Koehn and Nicole Chapman for critical reading of the manuscript, Jamie Panthera for excellent animal husbandry, and Ron Mc Elmurry, Christopher Less, Juan E. Abrahante Lloréns, and the UMN genomics center for technical assistance. This work was supported by grants from the National Institutes of Health, National Institute of Allergy and Infectious Diseases P01 AI056299, R37 AI034495 (BRB), and R01 AI091627 (IM) and the National Heart, Lung, and Blood Institute R01 HL56067 (BRB). This work was supported in part using the resources of the Center for Innovative Technology at Vanderbilt University. GT was supported by a Canadian Institutes of Health Research (CIHR) fellowship. Figures were created with Biorender.com.

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Authors and Affiliations

  1. Department of Pediatrics, Center for Immunology, University of Minnesota, Minneapolis, MN, USA

    Govindarajan Thangavelu, Sara Bolivar-Wagers, Sujeong Jin, Michael C. Zaiken, Michael Loschi, Ethan G. Aguilar, Cameron McDonald Hyman, Colby J. Feser, Angela Panoskaltsis-Mortari, Keli L. Hippen & Bruce R. Blazar

  2. Center for Immunobiology, Vanderbilt University Medical Center, Nashville, TN, USA

    Gabriela Andrejeva & Jeffrey C. Rathmell

  3. Department of Pediatrics, University of Washington, Seattle, WA, USA

    Scott N. Furlan

  4. Fred Hutchinson Cancer Research Center, Seattle, WA, USA

    Scott N. Furlan & Geoffrey R. Hill

  5. Howard Hughes Medical Institute, Immunology Program, and Ludwig Center, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY, USA

    Chrysothemis C. Brown

  6. Department of Microbiology and Immunology, Geisel School of Medicine at Dartmouth, Norris Cotton Cancer Center, Lebanon, USA

    Yu-Chi Lee & Randolph J. Noelle

  7. Department of Immunology, Queensland Institute of Medical Research (QIMR) Berghofer Medical Research Institute and School of Medicine, University of Queensland, Brisbane, QLD, Australia

    Kelli P. MacDonald

  8. Department of Dermatology, School of Medicine, University of California, Davis, Sacramento, CA, USA

    William J. Murphy

  9. Division of Hematology/Oncology, Department of Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA

    Ivan Maillard

  10. Georgia Cancer Center, Augusta University, Augusta, GA, USA

    David H. Munn

  11. Department of Haematology, Oncology and Stem Cell Transplantation, Faculty of Medicine, Freiburg University Medical Centre, Freiburg, Germany

    Robert Zeiser

  12. Boston Children’s Hospital and the Dana-Farber Cancer Institute, Boston, MA, USA

    Leslie S. Kean

  13. Department of Immunology, St. Jude Children’s Research Hospital, Memphis, TN, USA

    Hongbo Chi

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  1. Govindarajan Thangavelu
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Contributions

GT designed and performed research, provided, and analyzed the data, and wrote the paper. GA, SBW, SJ, MCZ, ML, EA, CCB, YL, CMH, CJF performed and helped in the experiments, analyzed the data, and edited the manuscript.  SNF peformed RNA seq and integrated ChIP-Seq/RNA-Seq data analysis. APM performed histopathological analysis. KLH, KPM, WJM, IM, GRH, DHM, RZ, LSK, JCR, HS, RJN provided advice and edited the paper. BB supervised research and edited the paper. All authors contributed to the article and approved the submitted version.

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Correspondence to Govindarajan Thangavelu.

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Competing interests

BB receives remuneration as an advisor to Kamon Pharmaceuticals, Five Prime Therapeutics, Regeneron Pharmaceuticals, Magenta Therapeutics, and BlueRock Therapeuetics; research support from Fate Therapeutics, RXi Pharmaceuticals, Alpine Immune Sciences, Abbvie, the Leukemia and Lymphoma Society, the Children’s Cancer Research Fund, and the KidsFirst Fund and is a cofounder of Tmunity. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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Thangavelu, G., Andrejeva, G., Bolivar-Wagers, S. et al. Retinoic acid signaling acts as a rheostat to balance Treg function. Cell Mol Immunol 19, 820–833 (2022). https://doi.org/10.1038/s41423-022-00869-y

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