title: FCRL3 promotes TLR9-induced B-cell activation and suppresses plasma cell differentiation.
abstract: Fc receptor-like (FCRL) molecules are preferentially expressed by B lymphocytes and possess tyrosine-based immunoregulatory function. Although they generally inhibit B-cell receptor signaling, their influence on other activation pathways remains largely unexplored. In humans, FCRL3 encodes a type I transmembrane protein harboring both cytoplasmic ITAM and ITIM elements that can repress B-cell receptor activation. Despite this inhibitory property, mounting associations for FCRL3 with autoimmune and lympho-proliferative disorders imply a role for it in promoting B-cell pathogenesis. Here, we explore the influence of FCRL3 on B-cell responses to innate TLR9 stimulation. A detailed survey of blood B-cell populations found that FCRL3 expression increased as a function of differentiation and was higher among memory subsets with innate-like features. FCRL3 ligation augmented CpG oligodeoxynucleotide TLR9-mediated B-cell proliferation, activation, and survival, but surprisingly, abrogated plasma cell differentiation and antibody production. Although FCRL3 amplified the NF-κB and mitogen-activated protein kinase signaling cascades, it halted CpG triggered BLIMP1 induction in an ERK-dependent fashion. These findings indicate that FCRL3 differentially modulates innate signaling in B cells and provide new insight into the potential of this disease-associated receptor to counter-regulate adaptive and innate immunity.
authors.affiliation: Division of Hematology/Oncology, University of Alabama at Birmingham, Birmingham, AL, USA; Department of Medicine, University of Alabama at Birmingham, Birmingham, AL, USA.
authors.forename: Fu Jun
authors.initials: FJ
authors.lastname: Li
authors.forename: Daniel M
authors.initials: DM
authors.lastname: Schreeder
authors.forename: Ran
authors.initials: R
authors.lastname: Li
authors.forename: Jiongru
authors.initials: J
authors.lastname: Wu
authors.forename: Randall S
authors.initials: RS
authors.lastname: Davis
mesh_terms: D000917:Antibody Formation / Q000276:immunology; D001402:B-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D002454:Cell Differentiation / Q000276:immunology; D002460:Cell Line; D049109:Cell Proliferation; D006801:Humans; D007156:Immunologic Memory / Q000276:immunology; D008213:Lymphocyte Activation / Q000276:immunology*; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism; D010950:Plasma Cells / Q000378:metabolism*; D000074462:Positive Regulatory Domain I-Binding Factor 1; D011971:Receptors, Immunologic / Q000096:biosynthesis / Q000276:immunology*; D012097:Repressor Proteins / Q000378:metabolism; D015398:Signal Transduction / Q000276:immunology; D051217:Toll-Like Receptor 9 / Q000276:immunology*
chemical_list: C457775:FCRL3 protein, human; D016328:NF-kappa B; D011971:Receptors, Immunologic; D012097:Repressor Proteins; C495371:TLR9 protein, human; D051217:Toll-Like Receptor 9; C087042:PRDM1 protein, human; D000074462:Positive Regulatory Domain I-Binding Factor 1; D020928:Mitogen-Activated Protein Kinases
keywords: B cells; Fc receptor-like; Plasma cell differentiation; TLR