Abcc1 and Ggt5 support lymphocyte guidance through export and catabolism of S-geranylgeranyl-l-glutathione

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Science Immunology  04 Jun 2021:
Vol. 6, Issue 60, eabg1101
DOI: 10.1126/sciimmunol.abg1101

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A bouncer for the bone marrow

P2RY8 is a G protein–coupled receptor (GPCR) that is involved in restraining germinal center (GC) B cell migration and growth. It is unclear how the ligand of P2RY8, S-geranylgeranyl-l-glutathione (GGG), is involved in these processes. Using gain-of-function mouse models and genetically modified human T cells, Gallman et al. showed that expression of gamma-glutamyltransferase-5 (Ggt5) on stromal cells and ATP-binding cassette subfamily C member 1 (Abcc1) on hematopoietic cells was involved in catabolizing and transporting GGG, respectively, and restraining P2RY8+ cells within GCs. GGG and P2RY8 interactions also restrained lymphocyte trafficking to the bone marrow. Thus, GGG and P2RY8 processing and interactions are crucial for the confinement of B cells within GCs and for inhibiting migration of lymphocytes into bone marrow.


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

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