UCSF

P2RY8 promotes the confinement and growth regulation of germinal center (GC) B cells and loss of human P2RY8 is associated with B cell lymphomagenesis. Recently the metabolite S-geranylgeranyl-L-glutathione (GGG) was identified as a P2RY8 ligand. However, the mechanisms controlling GGG distribution are little understood. Here we show that gamma-glutamyltransferase-5 (Ggt5) expression in stromal cells is required for GGG catabolism and confinement of P2RY8-expressing cells to GCs. We identify ATP-binding cassette, sub-family C member-1 (Abcc1) as a GGG transporter and show that Abcc1 expression by hematopoietic cells is necessary for P2RY8-mediated GC confinement. Furthermore, we discover that P2RY8 and GGG negatively regulate trafficking of B and T cells to the bone marrow (BM). Importantly, P2RY8 loss-of-function human T cells show increased BM homing. By defining how GGG distribution is determined and identifying sites of P2RY8 activity, this work helps establish how disruptions in P2RY8 function contribute to lymphomagenesis and possibly other disease states.