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

Abstract

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.

Germinal center versus extrafollicular responses in systemic autoimmunity: Who turns the blade on self?

“…Although there is no physical barrier surrounding GC, B cells are equipped with G protein-coupled receptors (GPCRs), such as P2RY8 ( Gallman et al, 2021 ; Lu et al, 2019 ; Muppidi, Lu and Cyster, 2015 ) and S1PR2 ( Green and Cyster, 2012 ), which confine the B cells to the GC region, thus allowing them to undergo cyclic rounds of SHM and selection. P2RY8 has been shown to be important to confine B cells to GCs ( Muppidi, Lu and Cyster, 2015 ; Muppidi et al, 2014 ).…”

T cell activation niches—Optimizing T cell effector function in inflamed and infected tissues*

“…While the ligand for P2PY8 (S‐geranylgeranyl‐L‐glutathione, Ggg) is expressed broadly across the LN, it can be metabolized to an inactive form by glutamyltransferase enzymes. In a fascinating addition to the GC retention story, FDC were shown to express one of these enzymes (Ggt5), actively playing a role in creating a gradient of P2PY8‐ligand from the GC (low expression) to the outer follicle (high expression) to constrain GB B cells to the GC 57,58 . Additional positional control for GC B cells comes with movement from the light zone to the dark zone.…”

“…In a fascinating addition to the GC retention story, FDC were shown to express one of these enzymes (Ggt5), actively playing a role in creating a gradient of P2PY8-ligand from the GC (low expression) to the outer follicle (high expression) to constrain GB B cells to the GC. 57,58 Additional positional control for GC B cells comes with movement from the light zone to the dark zone. This repositioning within the GC is once again regulated by expression of a chemokine receptor, CXCR4, by the B cells that is responsive to CXCL12 enriched in the dark zone and made by a specific subset of stromal cells, termed CXCL12-expressing reticular cells (CRCs).…”