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G-protein-coupled receptor P2Y10 facilitates chemokine-induced CD4 T cell migration through autocrine/paracrine mediators.

ABSTRACT: G-protein-coupled receptors (GPCRs), especially chemokine receptors, play a central role in the regulation of T cell migration. Various GPCRs are upregulated in activated CD4 T cells, including P2Y10, a putative lysophospholipid receptor that is officially still considered an orphan GPCR, i.e., a receptor with unknown endogenous ligand. Here we show that in mice lacking P2Y10 in the CD4 T cell compartment, the severity of experimental autoimmune encephalomyelitis and cutaneous contact hypersensitivity is reduced. P2Y10-deficient CD4 T cells show normal activation, proliferation and differentiation, but reduced chemokine-induced migration, polarization, and RhoA activation upon in vitro stimulation. Mechanistically, CD4 T cells release the putative P2Y10 ligands lysophosphatidylserine and ATP upon chemokine exposure, and these mediators induce P2Y10-dependent RhoA activation in an autocrine/paracrine fashion. ATP degradation impairs RhoA activation and migration in control CD4 T cells, but not in P2Y10-deficient CD4 T cells. Importantly, the P2Y10 pathway appears to be conserved in human T cells. Taken together, P2Y10 mediates RhoA activation in CD4 T cells in response to auto-/paracrine-acting mediators such as LysoPS and ATP, thereby facilitating chemokine-induced migration and, consecutively, T cell-mediated diseases.

SUBMITTER: Gurusamy M

PROVIDER: S-EPMC8611058 | biostudies-literature |

REPOSITORIES: biostudies-literature

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G-protein-coupled receptor P2Y10 facilitates chemokine-induced CD4 T cell migration through an autocrine feedback loop involving ATP and lysophosphatidylserine

Project description:G-Protein-coupled receptors (GPCRs), especially chemokine receptors, play a central role in the regulation of T cell migration. Various GPCRs are upregulated in activated CD4 T cells, among them P2Y10, a putative lysophospholipid receptor that is officially still considered an orphan GPCR. P2Y10-deficient CD4 T cells showed normal activation, differentiation, and proliferation, but reduced chemokine-induced migration and polarization. Chemokine-induced activation of RhoA, a central regulator of polarization and migration, was reduced in the absence of P2Y10, and this was due to loss of an autocrine feedback loop involving chemokine-triggered release of lysophosphatidylserine and adenosine triphosphate and consecutive P2Y10-dependent RhoA activation. In line with impaired chemokine-induced T cell migration, we found that mice with CD4 T cell-specific P2Y10 deficiency showed reduced T cell infiltration into the spinal cord in experimental autoimmune encephalomyelitis, a mouse model of multiple sclerosis

2021-09-21 | GSE162246 | GEO

G-protein-coupled receptor P2Y10 facilitates chemokine-induced CD4 T cell migration through an autocrine feedback loop involving ATP and lysophosphatidylserine

Project description:G-protein-coupled receptor P2Y10 facilitates chemokine-induced CD4 T cell migration through an autocrine feedback loop involving ATP and lysophosphatidylserine

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