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

Malarvizhi Gurusamy,Stefan Günther,Stefan Offermanns,Jingchen Shao,Remy Bonnavion,Stephan Klatt,Roxane-Isabelle Kestner,Ingrid Fleming,Nina Wettschureck,Kai Siebenbrodt,Tanja Kuhlmann,Denise Tischner,Sven Zukunft

doi:10.1038/s41467-021-26882-9

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.

Highlights

G-protein-coupled receptors (GPCRs), especially chemokine receptors, play a central role in the regulation of T cell migration
To identify GPCRs involved in T cell regulation during neuroinflammation, we determined GPCR expression in naïve and spinal cord-infiltrating CD4 T cells during experimental autoimmune encephalomyelitis (EAE), a mouse model of Multiple sclerosis (MS)
Female mice with the genotype CD4Crepos; P2ry10flox/flox and male mice with the genotype CD4Crepos; P2ry10flox/y showed a strong reduction of P2Y10 expression in CD4 T cells in immunoblotting (Fig. 1c) and RNA sequencing (Fig. 1d), whereas expression of the related GPCRs P2ry10b or Gpr[174], which are located in close proximity to P2ry[10] on the X chromosome, were not affected (Fig. 1d)

Summary

Introduction

G-protein-coupled receptors (GPCRs), especially chemokine receptors, play a central role in the regulation of T cell migration. G-protein-coupled receptors (GPCRs) are well known regulators of leukocyte migration, they allow cells to respond to a wide range of chemoattractants such as chemokines[1], lysophospholipids[2,3], or prostanoids[4,5] These three groups of receptors represent only a small fraction of known GPCRs, and a systematic analysis of GPCR expression in murine lymphoid organs revealed that approximately 173 GPCRs are expressed in spleen, thymus, and bone marrow[6], among them many orphan GPCRs, i.e., GPCRs for which neither ligand nor function is known[7,8,9]. We show that P2Y10 facilitates chemokineinduced migration of CD4 T cells through an auto-/paracrine feedback loop involving adenine nucleotides and LysoPS, and that mice with CD4 T cell-specific P2Y10 deficiency show reduced infiltration of CD4 T cells into the spinal cord and reduced disease severity in neuroinflammation

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Results

Conclusion