Alloreactive T cells deficient of the short-chain fatty acid receptor GPR(109)A induce less graft-versus-host disease Journal Article


Authors: Docampo, M. D.; da Silva, M. B.; Lazrak, A.; Nichols, K. B.; Lieberman, S. R.; Slingerland, A. E.; Armijo, G. K.; Shono, Y.; Nguyen, C.; Monette, S.; Dwomoh, E.; Lee, N.; Geary, C. D.; Perobelli, S. M.; Smith, M.; Markey, K. A.; Vardhana, S. A.; Kousa, A. I.; Zamir, E.; Greenfield, I.; Sun, J. C.; Cross, J. R.; Peled, J. U.; Jenq, R. R.; Stein-Thoeringer, C. K.; van den Brink, M. R. M.
Article Title: Alloreactive T cells deficient of the short-chain fatty acid receptor GPR(109)A induce less graft-versus-host disease
Abstract: 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. © 2022 American Society of Hematology
Keywords: t lymphocyte; t-lymphocytes; mouse; animal; animals; mice; hematopoietic stem cell transplantation; physiology; graft versus host reaction; graft vs host disease; butyric acid derivative; butyrates; fatty acids, volatile; volatile fatty acid
Journal Title: Blood
Volume: 139
Issue: 15
ISSN: 0006-4971
Publisher: American Society of Hematology  
Date Published: 2022-04-14
Start Page: 2392
End Page: 2405
Language: English
DOI: 10.1182/blood.2021010719
PUBMED: 34653248
PROVIDER: scopus
PMCID: PMC9012131
DOI/URL:
Notes: Article -- Export Date: 2 May 2022 -- Source: Scopus
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