Phosphatidylserine phospholipase A1 enables GPR34-dependent immune cell accumulation in the peritoneal cavity.

in The Journal of experimental medicine by Hanson Tam, Ying Xu, Jinping An, Torsten Schöneberg, Angela Schulz, Jagan R Muppidi, Jason G Cyster

TLDR

  • The study found that a specific type of receptor called GPR34 helps immune cells accumulate in a part of the body called the peritoneal cavity. The study found that a mutation in this receptor called GPR34 KI promotes the accumulation of certain types of immune cells called plasma cells and memory B cells. The study also found that a protein called PLA1A helps produce a chemical called lysoPS that helps GPR34 do its job. The study suggests that PLA1A could be a target for new treatments to help immune cells accumulate in the peritoneal cavity.

Abstract

The peritoneal cavity (PerC) is an important site for immune responses to infection and cancer metastasis. Yet few ligand-receptor axes are known to preferentially govern immune cell accumulation in this compartment. GPR34 is a lysophosphatidylserine (lysoPS)-responsive receptor that frequently harbors gain-of-function mutations in mucosa-associated B cell lymphoma. Here, we set out to test the impact of a GPR34 knock-in (KI) allele in the B-lineage. We report that GPR34 KI promotes the PerC accumulation of plasma cells (PC) and memory B cells (MemB). These KI cells migrate robustly to lysoPS ex vivo, and the KI allele synergizes with a Bcl2 transgene to promote MemB but not PC accumulation. Gene expression and labeling studies reveal that GPR34 KI enhances PerC MemB proliferation. Both KI PC and MemB are specifically enriched at the omentum, a visceral adipose tissue containing fibroblasts that express the lysoPS-generating PLA1A enzyme. Adoptive transfer and chimera experiments revealed that KI PC and MemB maintenance in the PerC is dependent on stromal PLA1A. These findings provide in vivo evidence that PLA1A produces lysoPS that can regulate GPR34-mediated immune cell accumulation at the omentum.

Overview

  • The study investigates the impact of a GPR34 knock-in (KI) allele on the peritoneal cavity (PerC) immune cell accumulation in the B-lineage. The study reports that GPR34 KI promotes the PerC accumulation of plasma cells (PC) and memory B cells (MemB).
  • The methodology used for the experiment includes the use of a B-lineage knock-in (KI) allele of GPR34, ex vivo migration assays, gene expression and labeling studies, adoptive transfer and chimera experiments, and the use of the PLA1A enzyme to generate lysoPS.

Comparative Analysis & Findings

  • The study found that GPR34 KI promotes the PerC accumulation of PC and MemB. The KI cells migrated robustly to lysoPS ex vivo, and the KI allele synergized with a Bcl2 transgene to promote MemB but not PC accumulation. Gene expression and labeling studies revealed that GPR34 KI enhances PerC MemB proliferation. Both KI PC and MemB were specifically enriched at the omentum, a visceral adipose tissue containing fibroblasts that express the PLA1A enzyme. Adoptive transfer and chimera experiments revealed that KI PC and MemB maintenance in the PerC is dependent on stromal PLA1A.

Implications and Future Directions

  • The study's findings provide in vivo evidence that PLA1A produces lysoPS that can regulate GPR34-mediated immune cell accumulation at the omentum. The study identifies PLA1A as a potential therapeutic target for modulating immune cell accumulation in the PerC. Future research could explore the role of PLA1A in other immune cell types and the potential of PLA1A inhibitors as immunotherapeutics.
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