Alloreactive T cells deficient of the short-chain fatty acid receptor GPR109A induce less graft-versus-host disease.
Journal
Blood
ISSN: 1528-0020
Titre abrégé: Blood
Pays: United States
ID NLM: 7603509
Informations de publication
Date de publication:
14 04 2022
14 04 2022
Historique:
received:
08
01
2021
accepted:
31
08
2021
pubmed:
16
10
2021
medline:
19
4
2022
entrez:
15
10
2021
Statut:
ppublish
Résumé
The intestinal microbiota is essential for the fermentation of dietary fiber into short-chain fatty acids (SCFA) such as butyrate, acetate, and propionate. SCFAs can bind to the G-protein-coupled receptors GPR43 and GPR109A (HCAR2), with varying affinities to promote cellular effects in metabolism or changes in immune function. We explored the role of GPR109A as the main receptor for butyrate in mouse models of allogeneic hematopoietic cell transplantation (allo-HCT) and graft-versus-host disease (GVHD). Deletion of GPR109A in allo-HCT recipients did not affect GVHD, but transplantation of T cells from GPR109A knockout (KO) (Gpr109a-/-) mice into allo-HCT recipient mice significantly reduced GVHD morbidity and mortality compared with recipients of wild-type (WT) T cells. Recipients of Gpr109a-/- T cells exhibited less GVHD-associated target organ pathology and decreased proliferation and homing of alloreactive T cells to target tissues. Although Gpr109a-/- T cells did not exhibit immune deficits at a steady state, following allo-activation, Gpr109a-/- T cells underwent increased apoptosis and were impaired mitochondrial oxidative phosphorylation, which was reversible through antioxidant treatment with N-acetylcysteine (NAC). In conclusion, we found that GPR109A expression by allo-activated T cells is essential for metabolic homeostasis and expansion, which are necessary features to induce GVHD after allo-HCT.
Identifiants
pubmed: 34653248
pii: S0006-4971(21)01749-3
doi: 10.1182/blood.2021010719
pmc: PMC9012131
doi:
Substances chimiques
Butyrates
0
Fatty Acids, Volatile
0
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Langues
eng
Sous-ensembles de citation
IM
Pagination
2392-2405Subventions
Organisme : NCI NIH HHS
ID : P30 CA016672
Pays : United States
Organisme : NCI NIH HHS
ID : P01 CA023766
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA228308
Pays : United States
Organisme : NHLBI NIH HHS
ID : R01 HL147584
Pays : United States
Organisme : NHLBI NIH HHS
ID : R01 HL124112
Pays : United States
Organisme : NCI NIH HHS
ID : P30 CA008748
Pays : United States
Organisme : NHLBI NIH HHS
ID : K08 HL143189
Pays : United States
Organisme : NHLBI NIH HHS
ID : R01 HL123340
Pays : United States
Commentaires et corrections
Type : CommentIn
Informations de copyright
© 2022 by The American Society of Hematology.
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