TY - JOUR
T1 - Alloreactive T cells deficient of the short-chain fatty acid receptor GPR109A induce less graft-versus-host disease
AU - Docampo, Melissa D.
AU - da Silva, Marina B.
AU - Lazrak, Amina
AU - Nichols, Katherine B.
AU - Lieberman, Sophia R.
AU - Slingerland, Ann E.
AU - Armijo, Gabriel K.
AU - Shono, Yusuke
AU - Nguyen, Chi
AU - Monette, Sebastien
AU - Dwomoh, Emmanuel
AU - Lee, Nicole
AU - Geary, Clair D.
AU - Perobelli, Suelen M.
AU - Smith, Melody
AU - Markey, Kate A.
AU - Vardhana, Santosha A.
AU - Kousa, Anastasia I.
AU - Zamir, Eli
AU - Greenfield, Itamar
AU - Sun, Joseph C.
AU - Cross, Justin R.
AU - Peled, Jonathan U.
AU - Jenq, Robert R.
AU - Stein-Thoeringer, Christoph K.
AU - van den Brink, Marcel R.M.
N1 - Publisher Copyright:
© 2022 American Society of Hematology
PY - 2022/4/14
Y1 - 2022/4/14
N2 - 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.
AB - 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.
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U2 - 10.1182/blood.2021010719
DO - 10.1182/blood.2021010719
M3 - Article
C2 - 34653248
AN - SCOPUS:85127090021
SN - 0006-4971
VL - 139
SP - 2392
EP - 2405
JO - Blood
JF - Blood
IS - 15
ER -