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

Malarvizhi Gurusamy, Denise Tischner, Jingchen Shao, Stephan Klatt, Sven Zukunft, Remy Bonnavion, Stefan Günther, Kai Siebenbrodt, Roxane-Isabelle Kestner, Tanja Kuhlmann, Ingrid Fleming, Stefan Offermanns and Nina Wettschureck ()
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Malarvizhi Gurusamy: Max Planck Institute for Heart and Lung Research
Denise Tischner: Max Planck Institute for Heart and Lung Research
Jingchen Shao: Max Planck Institute for Heart and Lung Research
Stephan Klatt: Goethe University
Sven Zukunft: Goethe University
Remy Bonnavion: Max Planck Institute for Heart and Lung Research
Stefan Günther: Max Planck Institute for Heart and Lung Research
Kai Siebenbrodt: University of Frankfurt
Roxane-Isabelle Kestner: University of Frankfurt
Tanja Kuhlmann: University of Münster
Ingrid Fleming: Goethe University
Stefan Offermanns: Max Planck Institute for Heart and Lung Research
Nina Wettschureck: Max Planck Institute for Heart and Lung Research

Nature Communications, 2021, vol. 12, issue 1, 1-16

Abstract: 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.

Date: 2021
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DOI: 10.1038/s41467-021-26882-9

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