RGS1 Modulates Autophagic and Metabolic Programs and Is a Critical Mediator of Human Regulatory T Cell Function

Regulatory T cells (Tregs) are critical mediators of immune tolerance and play a diametric role in cancer and autoimmunity. Tumor-infiltrating Tregs are often associated with poor prognosis in solid tumors because their enrichment in the tumor microenvironment contributes to immunosuppression. Conve...

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Bibliographic Details
Published in:The Journal of immunology (1950) 2023-12, Vol.211 (11), p.1656-1668
Main Authors: Flynn, Alyssa L, Gans, Joseph, Escobedo, Javier, Zhu, Cheng, Florescu, Ana-Maria, Shankara, Srinivas, Madden, Stephen L, Kim, Peter S, Pao, Lily I
Format: Article
Language:English
Subjects:
Autoimmune Diseases - pathology
Autoimmunity
Autophagy - genetics
Forkhead Transcription Factors - metabolism
Humans
Neoplasms - pathology
RGS Proteins - genetics
RGS Proteins - metabolism
T-Lymphocytes, Regulatory
Tumor Microenvironment
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Summary:Regulatory T cells (Tregs) are critical mediators of immune tolerance and play a diametric role in cancer and autoimmunity. Tumor-infiltrating Tregs are often associated with poor prognosis in solid tumors because their enrichment in the tumor microenvironment contributes to immunosuppression. Conversely, dysregulation in the Treg compartment can disrupt self-tolerance, leading to autoimmunity. In the present study, we describe what is, to our knowledge, a novel regulator of Tregs, the GTPase activator regulator of G protein 1 (RGS1), demonstrating that RGS1-deficient human Tregs show downregulation of Treg-associated genes and are less immunosuppressive. These RGS1-deficient Tregs exhibit perturbations to the FOXP3-c-MYC transcriptional axis and downstream metabolic and autophagy programs by shifting their energy demands toward glycolysis and rendering them less autophagic. Taken together, RGS1 may serve as an apical node of Treg function by regulating the FOXP3-c-MYC transcriptional axis, thereby providing a therapeutic rationale for targeting RGS1 for treatment of cancer and autoimmune diseases.
ISSN:0022-1767
1550-6606
DOI:10.4049/jimmunol.2200402