RGS1 Modulates Autophagic and Metabolic Programs and Is a Critical Mediator of Human Treg 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, as their enrichment in the tumor microenvironment contributes to immunosuppression. Conversely, dysregulation in the Treg compartment can disrupt self-tolerance, leading to autoimmunity. Herein, we describe a novel regulator of Tregs, the GTPase activator, Regulator of G Protein 1 (RGS1), 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. To investigate the function of RGS1 in human Tregs, we knocked down RGS1 via siRNA (siRGS1) and used a non-targeting scrambled control siRNA (siNT) for comparison We then performed RNAseq on ex vivo expanded Tregs with siRGS1 and siNT knockdowns on 5 human Treg donors Comparative gene expression profiling analysis of RNAseq data from siRGS1 and siNT human Tregs