The Inhibitory Potential of Fc Receptor Homolog 4 on Memory B Cells

• Published in: Proceedings of the National Academy of Sciences - PNAS 2003-11, Vol.100 (23), p.13489-13494
• Main Authors: Götz R. A. Ehrhardt, Davis, Randall S., Hsu, Joyce T., Leu, Chuen-Miin, Ehrhardt, Annette, Cooper, Max D.
• Format: Article
• Language: English
• Subjects: Amino Acid Motifs; Animals; Antibodies; B lymphocytes; B-Lymphocytes - immunology; B-Lymphocytes - metabolism; Biological Sciences; Calcium; Calcium - metabolism; Cell Line; Cell lines; Cell Membrane - metabolism; Cells; DNA Mutational Analysis; Fc receptors; Immunologic Memory; Immunology; Mice; Mutagenesis, Site-Directed; Mutation; Peptides; Peptides - chemistry; Phosphatases; Phosphorylation; Plasma cells; Protein Structure, Tertiary; Proteins; Receptors; Receptors, Cell Surface; Receptors, Fc - metabolism; Receptors, Fc - physiology; Recombinant Fusion Proteins - metabolism; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger - metabolism; Signal Transduction; src Homology Domains; Time Factors; Transfection; Tyrosine - chemistry; Tyrosine - metabolism
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.1935944100

Fc receptor homolog 4 (FcRH4) is a B cell-specific member of the recently identified family of FcRHs whose intracellular domain contains three potential immunoreceptor tyrosine-based inhibitory motifs (ITIMs). The signaling potential of this receptor, shown here to be preferentially expressed by memory B cells, was compared with the inhibitory receptor FcγRIIb in B cells expressing either WT FcγRIIb or chimeric proteins in which the intracellular domain of FcRH4 was fused to the transmembrane and extracellular domains of FcγRIIb. Coligation of the FcγRIIb/FcRH4 chimeric protein with the B cell receptor (BCR) led to tyrosine phosphorylation of the two membrane-distal tyrosines and profound inhibition of BCR-mediated calcium mobilization, whole cell tyrosine phosphorylation, and mitogen-activated protein (MAP)-kinase activation. Mutational analysis of the FcRH4 cytoplasmic region indicated that the two membrane-distal ITIMs are essential for this inhibitory potential. Phosphopeptides corresponding to these ITIMs could bind the Src homology 2 (SH2) domain-containing tyrosine phosphatases SHP-1 and SHP-2, which associated with the WT FcRH4 and with mutants having inhibitory capability. These findings indicate the potential for FcRH4 to abort B cell receptor signaling by recruiting SHP-1 and SHP-2 to its two membrane distal ITIMs.