FcRL4 acts as an adaptive to innate molecular switch dampening BCR signaling and enhancing TLR signaling

• Published in: Blood Vol. 118; no. 24; pp. 6332 - 6341
• Main Authors: Sohn, Hae Won, Krueger, Peter D., Davis, Randall S., Pierce, Susan K.
• Format: Journal Article
• Language: English
• Published: Washington, DC Elsevier Inc 08.12.2011; Americain Society of Hematology; American Society of Hematology
• Subjects: B-Lymphocytes - cytology; B-Lymphocytes - immunology; B-Lymphocytes - metabolism; Biological and medical sciences; Cell Line; Down-Regulation; Hematologic and hematopoietic diseases; Humans; Immunobiology; Immunological Synapses - metabolism; Intracellular Signaling Peptides and Proteins - metabolism; Isoenzymes - metabolism; Lymphocyte Activation; Medical sciences; Mutant Proteins - chemistry; Mutant Proteins - metabolism; Phospholipase C gamma - metabolism; Phosphorylation; Protein Processing, Post-Translational; Protein Transport; Protein Tyrosine Phosphatase, Non-Receptor Type 11 - metabolism; Protein Tyrosine Phosphatase, Non-Receptor Type 6 - metabolism; Protein-Tyrosine Kinases - metabolism; Proto-Oncogene Proteins c-bcr - metabolism; Proto-Oncogene Proteins c-vav - metabolism; Receptors, Fc - chemistry; Receptors, Fc - genetics; Receptors, Fc - metabolism; Recombinant Fusion Proteins - chemistry; Recombinant Fusion Proteins - metabolism; Signal Transduction; Syk Kinase; Toll-Like Receptor 9 - antagonists & inhibitors; Toll-Like Receptor 9 - metabolism; Up-Regulation; Signal transduction; Toll like receptor; Hematology; C-Onc gene
• ISSN: 0006-4971; 1528-0020
• DOI: 10.1182/blood-2011-05-353102

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.