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

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Gurusamy,  Malarvizhi
Pharmacology, Max Planck Institute for Heart and Lung Research, Max Planck Society;

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Tischner,  Denise
Pharmacology, Max Planck Institute for Heart and Lung Research, Max Planck Society;

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Shao,  Jingchen
Pharmacology, Max Planck Institute for Heart and Lung Research, Max Planck Society;

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Bonnavion,  Remy
Pharmacology, Max Planck Institute for Heart and Lung Research, Max Planck Society;

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Guenther,  Stefan
Cardiac Development and Remodeling, Max Planck Institute for Heart and Lung Research, Max Planck Society;

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Offermanns,  Stefan
Pharmacology, Max Planck Institute for Heart and Lung Research, Max Planck Society;

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Wettschureck,  Nina
Pharmacology, Max Planck Institute for Heart and Lung Research, Max Planck Society;

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Citation

Gurusamy, M., Tischner, D., Shao, J., Klatt, S., Zukunft, S., Bonnavion, R., et al. (2021). G-protein-coupled receptor P2Y10 facilitates chemokine-induced CD4 T cell migration through autocrine/paracrine mediators. NATURE COMMUNICATIONS, 12(1): 6798. doi:10.1038/s41467-021-26882-9.


Cite as: http://hdl.handle.net/21.11116/0000-0009-9C24-F
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. P2Y10 is a G-protein-coupled receptor that is expressed in CD4 T cells. Here authors show that its ligands, lysophosphatidylserine and ATP, are induced in T cells upon chemokine stimulation and regulate RhoA activation and migration through an autocrine/paracrine loop.