An essential role for miR-15/16 in Treg suppression and restriction of proliferation

Kristina Johansson; John D Gagnon; Simon K Zhou; Marlys S Fassett; Andrew W Schroeder; Robin Kageyama; Rodriel A Bautista; Hewlett Pham; Prescott G Woodruff; K Mark Ansel

doi:10.1016/j.celrep.2023.113298

An essential role for miR-15/16 in Treg suppression and restriction of proliferation

Cell Rep. 2023 Oct 31;42(10):113298. doi: 10.1016/j.celrep.2023.113298. Epub 2023 Oct 19.

Authors

Affiliations

¹ Department of Microbiology and Immunology, University of California, San Francisco, San Francisco, CA 94143, USA; Sandler Asthma Basic Research Center, University of California, San Francisco, San Francisco, CA 94143, USA; Department of Medicine, Division of Pulmonary and Critical Care Medicine, University of California, San Francisco, San Francisco, CA 94143, USA; Department of Medical Biochemistry and Cell Biology, University of Gothenburg, 40530 Gothenburg, Sweden; Department of Internal Medicine and Clinical Nutrition, University of Gothenburg, 40530 Gothenburg, Sweden.
² Department of Microbiology and Immunology, University of California, San Francisco, San Francisco, CA 94143, USA; Sandler Asthma Basic Research Center, University of California, San Francisco, San Francisco, CA 94143, USA.
³ Department of Microbiology and Immunology, University of California, San Francisco, San Francisco, CA 94143, USA; Department of Dermatology, University of California, San Francisco, San Francisco, CA 94143, USA.
⁴ Department of Medicine, Genomics CoLab, University of California, San Francisco, San Francisco, CA 94143, USA.
⁵ Sandler Asthma Basic Research Center, University of California, San Francisco, San Francisco, CA 94143, USA; Department of Medicine, Division of Pulmonary and Critical Care Medicine, University of California, San Francisco, San Francisco, CA 94143, USA.
⁶ Department of Microbiology and Immunology, University of California, San Francisco, San Francisco, CA 94143, USA; Sandler Asthma Basic Research Center, University of California, San Francisco, San Francisco, CA 94143, USA. Electronic address: mark.ansel@ucsf.edu.

Abstract

The miR-15/16 family targets a large network of genes in T cells to restrict their cell cycle, memory formation, and survival. Upon T cell activation, miR-15/16 are downregulated, allowing rapid expansion of differentiated effector T cells to mediate a sustained response. Here, we used conditional deletion of miR-15/16 in regulatory T cells (Tregs) to identify immune functions of the miR-15/16 family in T cells. miR-15/16 are indispensable to maintain peripheral tolerance by securing efficient suppression by a limited number of Tregs. miR-15/16 deficiency alters expression of critical Treg proteins and results in accumulation of functionally impaired FOXP3^loCD25^loCD127^hi Tregs. Excessive proliferation in the absence of miR-15/16 shifts Treg fate and produces an effector Treg phenotype. These Tregs fail to control immune activation, leading to spontaneous multi-organ inflammation and increased allergic inflammation in a mouse model of asthma. Together, our results demonstrate that miR-15/16 expression in Tregs is essential to maintain immune tolerance.

Keywords: CP: Immunology; T cell; T regulatory cell; TCF1; Treg; allergy; effector Treg; immunosuppression; miR-15; miR-16; miRNA.

Publication types

Research Support, Non-U.S. Gov't
Research Support, N.I.H., Extramural

MeSH terms

Animals
Cell Division
Forkhead Transcription Factors / metabolism
Inflammation / genetics
Inflammation / metabolism
Mice
MicroRNAs* / genetics
MicroRNAs* / metabolism
Phenotype
T-Lymphocytes, Regulatory*

Substances

MicroRNAs
Forkhead Transcription Factors

Abstract

Publication types

MeSH terms

Substances

Grants and funding