title: The G protein-coupled receptor P2RY8 and follicular dendritic cells promote germinal center confinement of B cells, whereas S1PR3 can contribute to their dissemination.
abstract: The orphan Gα13-coupled receptor P2RY8 is mutated in human germinal center (GC)-derived lymphomas and was recently found to promote B cell association with GCs in a mouse model. Here we establish that P2RY8 promotes clustering of activated B cells within follicles in a follicular dendritic cell (FDC)-dependent manner. Although mice lack a P2RY8 orthologue, we show that mouse GC B cell clustering is also dependent on FDCs acting to support the function of a Gα13-coupled receptor. Mutations in GNA13 and its downstream effector ARHGEF1 are associated with the development of disseminated GC-derived lymphomas. We find that egress of Gna13 mutant GC B cells from lymph nodes in the mouse depends on sphingosine-1-phosphate receptor-3. These findings provide evidence that FDCs promote GC confinement of both human and mouse GC B cells via Gα13-dependent pathways, and they show that dissemination of Gα13-deficient GC B cells additionally requires an egress-promoting receptor.
authors.affiliation: Department of Microbiology and Immunology, University of California, San Francisco, San Francisco, CA 94143 Department of Medicine, University of California, San Francisco, San Francisco, CA 94143 Howard Hughes Medical Institute, University of California, San Francisco, San Francisco, CA 94143.
authors.forename: Jagan R
authors.initials: JR
authors.lastname: Muppidi
authors.affiliation: Department of Microbiology and Immunology, University of California, San Francisco, San Francisco, CA 94143 Howard Hughes Medical Institute, University of California, San Francisco, San Francisco, CA 94143.
authors.forename: Erick
authors.initials: E
authors.lastname: Lu
authors.affiliation: Department of Microbiology and Immunology, University of California, San Francisco, San Francisco, CA 94143 Howard Hughes Medical Institute, University of California, San Francisco, San Francisco, CA 94143 Jason.Cyster@ucsf.edu.
authors.forename: Jason G
authors.initials: JG
authors.lastname: Cyster
mesh_terms: D000818:Animals; D001402:B-Lymphocytes / Q000378:metabolism*; D020566:Dendritic Cells, Follicular / Q000378:metabolism*; D044365:GTP-Binding Protein alpha Subunits, G12-G13 / Q000378:metabolism; D018858:Germinal Center / Q000378:metabolism*; D006801:Humans; D008198:Lymph Nodes / Q000378:metabolism; D008810:Mice, Inbred C57BL; D049349:Receptors, Lysosphingolipid / Q000378:metabolism*; D058470:Receptors, Purinergic P2Y / Q000378:metabolism*
chemical_list: C578279:P2RY8 protein, human; D049349:Receptors, Lysosphingolipid; D058470:Receptors, Purinergic P2Y; D044365:GTP-Binding Protein alpha Subunits, G12-G13