G-protein-coupled receptor P2Y10 facilitates chemokine-induced CD4 T cell migration through autocrine/paracrine mediators.
Adenosine Triphosphate
/ metabolism
Adult
Aged
Animals
Autocrine Communication
/ immunology
CD4-Positive T-Lymphocytes
/ immunology
Case-Control Studies
Cells, Cultured
Chemokines
/ metabolism
Chemotaxis, Leukocyte
/ immunology
Encephalomyelitis, Autoimmune, Experimental
/ blood
Female
Gene Knockdown Techniques
Gene Knockout Techniques
Humans
Lysophospholipids
/ metabolism
Male
Mice
Mice, Transgenic
Middle Aged
Multiple Sclerosis
/ blood
Paracrine Communication
/ immunology
Primary Cell Culture
Receptors, Purinergic P2
/ genetics
Receptors, Purinergic P2Y
/ genetics
rhoA GTP-Binding Protein
/ metabolism
Journal
Nature communications
ISSN: 2041-1723
Titre abrégé: Nat Commun
Pays: England
ID NLM: 101528555
Informations de publication
Date de publication:
23 11 2021
23 11 2021
Historique:
received:
18
12
2020
accepted:
25
10
2021
entrez:
24
11
2021
pubmed:
25
11
2021
medline:
22
12
2021
Statut:
epublish
Résumé
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.
Identifiants
pubmed: 34815397
doi: 10.1038/s41467-021-26882-9
pii: 10.1038/s41467-021-26882-9
pmc: PMC8611058
doi:
Substances chimiques
Chemokines
0
Lysophospholipids
0
P2RY10 protein, human
0
P2ry10 protein, mouse
0
Receptors, Purinergic P2
0
Receptors, Purinergic P2Y
0
lysophosphatidylserine
0
RHOA protein, human
124671-05-2
Adenosine Triphosphate
8L70Q75FXE
RhoA protein, mouse
EC 3.6.5.2
rhoA GTP-Binding Protein
EC 3.6.5.2
Types de publication
Journal Article
Observational Study
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
6798Informations de copyright
© 2021. The Author(s).
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