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

  • Sci Immunol. 2021 Jun 4;6(60):eabg1101. doi: 10.1126/sciimmunol.abg1101.
Antonia E Gallman  1  2  3 ,  Finn D Wolfreys  4  2 ,  David N Nguyen  5  6 ,  Moriah Sandy  1  2 ,  Ying Xu  1  2 ,  Jinping An  1  2 ,  Zhongmei Li  5  6 ,  Alexander Marson  5  6 ,  Erick Lu  1  2 ,  Jason G Cyster  4  2
Affiliations
  • 1. Howard Hughes Medical Institute, University of California, San Francisco, San Francisco, CA 94143, USA.
  • 2. Department of Microbiology and Immunology, University of California, San Francisco, San Francisco, CA 94143, USA.
  • 3. Medical Scientist Training Program, University of California, San Francisco, San Francisco, CA 94143, USA.
  • 4. Howard Hughes Medical Institute, University of California, San Francisco, San Francisco, CA 94143, USA. [email protected] [email protected].
  • 5. J. David Gladstone Institutes, San Francisco, CA 94158, USA.
  • 6. Department of Medicine, University of California, San Francisco, San Francisco, CA 94143, USA.
PMID: 34088745 DOI: 10.1126/sciimmunol.abg1101
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.

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