Cutting Edge: Regulator of G Protein Signaling-1 Selectively Regulates Gut T Cell Trafficking and Colitic Potential

Abstract

The Regulator of G Protein Signaling 1 [RGS1] gene is associated with celiac disease, multiple sclerosis (MS) and Type I diabetes (T1D), which are all T cell-mediated pathologies. And yet there is no reported analysis of RGS1 biology in human T cells. This study shows that RGS1 expression is substantially higher in T cells from human gut versus peripheral blood, and that this can be exaggerated in intestinal inflammation. Elevated RGS1 levels profoundly reduce T cell migration to lymphoid-homing chemokines, whereas RGS-1 depletion selectively enhances such chemotaxis in gut T cells, and impairs their colitogenic potential. These findings provide a revised framework in which to view the linkage of RGS1 to inflammatory disease.

Regulator of G-protein Signaling (RGS)1 and RGS10 Proteins as Potential Drug Targets for Neuroinflammatory and Neurodegenerative Diseases

“…CCL19 is mediated by chemokine (C-C motif) receptor 7 (CCR7), and CXCL12 is mediated by chemokine (C-X-C motif) receptor 4 (CXCR4) (31) which both promote T cell egress from tissues to lymph nodes. The high level of RGS1 in human T cells in the gut especially in inflammatory bowel disease (IBD) suggests that RGS1 may contribute to the colitogenic potential of T cells via limiting gut T cell response to chemokines (31).…”

“…RGS1 overexpression inhibits T cell migration in response to chemokines that control lymphoid homing, while depletion of RGS1 selectively enhances such chemotaxis. These chemokines include chemokine (C-C motif) ligand 19 (CCL19) and CXCL12 in gut T cells (31). CCL19 is mediated by chemokine (C-C motif) receptor 7 (CCR7), and CXCL12 is mediated by chemokine (C-X-C motif) receptor 4 (CXCR4) (31) which both promote T cell egress from tissues to lymph nodes.…”

Human Tissue-Resident Memory T Cells Are Defined by Core Transcriptional and Functional Signatures in Lymphoid and Mucosal Sites

“…This core signature included upregulation of the adhesion markers ITGAE (CD103) and ITGA1 (CD49a), the chemokine-receptors CXCR6 and CX3CR1, and molecules with known inhibitory functions in T cells including PDCD1 (PD-1) , the dualspecificity phosphatase DUSP6 that turns off MAP Kinase signaling (Bertin et al, 2015), and IL10 (IL-10). Downregulated genes within the core signature included S1PR1 and its associated transcription factor KLF2, which together control T cell homing and tissue retention (Skon et al, 2013), the related Kruppel-like transcription factor KLF3, the lymph node homing receptor SELL (CD62L), as well as RAP1GAP1 and RGS1, G protein signaling genes that modulate T cell trafficking (Gibbons et al, 2011).…”

Gene Expression Profiling of Bronchoalveolar Lavage Cells Preceding a Clinical Diagnosis of Chronic Lung Allograft Dysfunction

“…Similarly, KLRB1 was upregulated in incipient CLAD samples, which is primarily thought to mediate NK cell function [32]. We also find increased expression of transcripts encoding key regulators of cytotoxic cells including regulator of G Protein Signaling-1 (RGS1), eomesodermin (EOMES), B-cell CLL/lymphoma 11B (zinc finger protein), synuclein, alpha (SNCA), and T cell receptor beta constant 1 (TRBC1), all of which are involved in different aspects of differentiation and proliferation/clonal expansion of effector memory cells [33][34][35][36][37]. Finally, both CD8 + T cells and NK cells have conserved pathways that mediate target allograft cell injury via perforin, granzymes and granulysin, each of which is differentially over-expressed in incipient CLAD cases [38].…”