title: FcRL4 acts as an adaptive to innate molecular switch dampening BCR signaling and enhancing TLR signaling.
abstract: Fc receptor-like 4 (FcRL4) is expressed on the surface of a subset of memory B cells (MBCs) located at sites of invading pathogens in mucosal lymphoid tissues in healthy individuals. Recently, FcRL4(+) MBCs were shown to be greatly increased in number in the peripheral blood of HIV-infected viremic individuals, in whom they are associated with B-cell exhaustion, and in individuals chronically reinfected with malaria. In the present study, we provide evidence that the expression of FcRL4 in human B-cell lines disrupts immune synapse formation and blocks antigen-induced BCR signaling at the point of Syk phosphorylation, blocking downstream activation of PLC-γ2 and Vav and the induction of calcium responses and CD69 expression. FcRL4 functions by ligation-independent mechanisms that require the 3 tyrosine residues in its cytoplasmic domain and involves its phosphorylation and association with the tyrosine phosphatases SHP-1 and SHP-2. Remarkably, FcRL4 is concentrated in endosomes after treatment with the TLR9 agonist CpG and enhances signaling through TLR9, as measured by increased expression of CD23. These findings suggest that FcRL4 may act as a molecular switch in B cells to dampen adaptive immune signaling and enhance innate signaling in response to chronic antigenic stimulation.
authors: Laboratory of Immunogenetics, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Rockville, MD 20852, USA.
authors: Hae Won
authors: HW
authors: Sohn
authors: Peter D
authors: PD
authors: Krueger
authors: Randall S
authors: RS
authors: Davis
authors: Susan K
authors: SK
authors: Pierce
mesh_terms: D001402:B-Lymphocytes / Q000166:cytology / Q000276:immunology / Q000378:metabolism*; D002460:Cell Line; D015536:Down-Regulation; D006801:Humans; D054992:Immunological Synapses / Q000378:metabolism; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism; D007527:Isoenzymes / Q000378:metabolism; D008213:Lymphocyte Activation; D050505:Mutant Proteins / Q000737:chemistry / Q000378:metabolism; D051966:Phospholipase C gamma / Q000378:metabolism; D010766:Phosphorylation; D011499:Protein Processing, Post-Translational; D021381:Protein Transport; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11 / Q000378:metabolism; D053824:Protein Tyrosine Phosphatase, Non-Receptor Type 6 / Q000378:metabolism; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D051562:Proto-Oncogene Proteins c-bcr / Q000378:metabolism*; D051567:Proto-Oncogene Proteins c-vav / Q000378:metabolism; D011961:Receptors, Fc / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D011993:Recombinant Fusion Proteins / Q000737:chemistry / Q000378:metabolism; D015398:Signal Transduction; D000072377:Syk Kinase; D051217:Toll-Like Receptor 9 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D015854:Up-Regulation
chemical_list: C423544:FCRL4 protein, human; D047908:Intracellular Signaling Peptides and Proteins; D007527:Isoenzymes; D050505:Mutant Proteins; D051567:Proto-Oncogene Proteins c-vav; D011961:Receptors, Fc; D011993:Recombinant Fusion Proteins; C495371:TLR9 protein, human; D051217:Toll-Like Receptor 9; D011505:Protein-Tyrosine Kinases; C000606896:SYK protein, human; D000072377:Syk Kinase; C496613:BCR protein, human; D051562:Proto-Oncogene Proteins c-bcr; C516724:PTPN11 protein, human; C509249:PTPN6 protein, human; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11; D053824:Protein Tyrosine Phosphatase, Non-Receptor Type 6; D051966:Phospholipase C gamma