Cutting Edge: Human FcRL4 and FcRL5 Are Receptors for IgA and IgG

Wilson, T.; Fuchs, Anja; Colonna, Marco

doi:10.4049/jimmunol.1102651

Cited by 116 publications

(110 citation statements)

References 31 publications

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“…To further investigate the roles of these src-kinase family members in FCRL4-mediated immune regulation, we took advantage of the recently reported IgA-binding activity of FCRL4 (30). We confirmed binding of heat-aggregated human IgA to the Burkitt's lymphoma BJAB cell line expressing FCRL4 (Fig.…”

Section: Binding Of Aggregated Iga To Cells Expressing Fcrl4mentioning

confidence: 56%

Involvement of the HCK and FGR src-Family Kinases in FCRL4-Mediated Immune Regulation

Liu

Bezverbnaya

Zhao

et al. 2015

The Journal of Immunology

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FCRL4 is an immunoregulatory receptor expressed by a subpopulation of memory B cells. These tissue-based cells express increased levels of the src-family kinases HCK and FGR. In this study, we investigate the roles of these src-family kinases in FCRL4-mediated immunoregulation of B cells in the context of previously unrecognized palmitoylation of the receptor. We observed enhanced phosphorylation of FCRL4 on tyrosine residues in the presence of the HCK p59 or FGR. This phosphorylation was markedly reduced in assays using a palmitoylation-defective mutant of FCRL4. In reporter gene studies, we observe that FCRL4 expression enhances CpG-mediated activation of NF-κB signaling. Surprisingly, using a reporter gene linked to activation of the MAPK substrate Elk-1 in response to Ag receptor ligation, we find that FCRL4 has inhibitory activity in cells coexpressing FGR but an activating function in cells coexpressing HCK p59. We provide evidence that in primary memory B cells, expression of FCRL4 leads to increased expression of IL-10 in the presence of FGR or HCK p59 in response to CpG, but increased levels of IFN-γ only in the context of coexpression of FGR. Our study supports the specific requirement of HCK p59 and FGR src-family kinases for FCRL4-mediated immunomodulatory activity and indicates that palmitoylation serves as an additional level of regulatory control of FCRL4.

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Section: Binding Of Aggregated Iga To Cells Expressing Fcrl4mentioning

confidence: 56%

Involvement of the HCK and FGR src-Family Kinases in FCRL4-Mediated Immune Regulation

Liu

Bezverbnaya

Zhao

et al. 2015

The Journal of Immunology

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“…Using a chimeric receptor containing the cytoplasmic tail of FCRL5, crosslinking FCRL5 and the BCR was shown to recruit SHP-1 to the two ITIM motifs of FCRL5, resulting in reduced BCR-induced calcium mobilization and protein tyrosine phos-phorylation (20). We and others reported that FCRL5 binds intact IgG via a complex mechanism (21,22), and therefore immune complexes may link FCRL5 to the BCR, potentially blocking B cell activation similarly to the inhibitory FcgRIIB. Potential activating functions were also proposed for FCRL5 (23), similarly to FCRL3 (24) and FCRL4 (25), suggesting dual regulatory capacities.…”

Section: T He Generation Of B Cell Memory Is An Important Component Omentioning

confidence: 94%

Fc Receptor–like 5 Expression Distinguishes Two Distinct Subsets of Human Circulating Tissue–like Memory B Cells

Borrego

Nagata

et al. 2016

The Journal of Immunology

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Fc receptor–like (FCRL) 5 is a novel IgG binding protein expressed on B cells, with the capacity to regulate Ag receptor signaling. We assessed FCRL5 expression on circulating B cells from healthy donors and found that FCRL5+ cells are most enriched among atypical CD21−/lo/CD27− tissue-like memory (TLM) B cells, which are abnormally expanded in several autoimmune and infectious diseases. Using multicolor flow cytometry, FCRL5+ TLM cells were found to express more CD11c and several inhibitory receptors than did the FCRL5− TLM subset. The homing receptor profiles of the two TLM subsets shared features consistent with migration away from lymphoid tissues, but they also displayed distinct differences. Analysis of IgH V regions in single cells indicated that although both subsets are diverse, the FCRL5+ subset accumulated significantly more somatic mutations. Furthermore, the FCRL5+ subset had more switched isotype expression and more extensive proliferative history. Microarray analysis and quantitative RT-PCR demonstrated that the two TLM subsets possess distinct gene expression profiles, characterized by markedly different CD11c, SOX5, T-bet, and RTN4R expression, as well as differences in expression of inhibitory receptors. Functional analysis revealed that the FCRL5+ TLM subset responds poorly to multiple stimuli compared with the FCRL5− subset, as reflected by reduced calcium mobilization and blunted cell proliferation. We propose that the FCRL5+ TLM subset, but not the FCRL5− TLM subset, underwent Ag-driven development and is severely dysfunctional. The present study elucidates the heterogeneity of TLM B cells and provides the basis to dissect their roles in the pathogenesis of inflammatory and infectious diseases.

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“…Very recent studies by the Colonna group identified that human FCRL4 and FCRL5 bind heat-aggregated IgA and IgG (19), but the endogenous ligands for other B-cell-expressed FCRLs, including mouse FCRL5, have yet to be elucidated. Notably, two additional members interact with MHC-like proteins.…”

Section: Discussionmentioning

confidence: 99%

“…Although Ig binding has been detected recently for two human members (19), antibodies do not appear to associate with other FCRL proteins. Intriguingly, two other representatives have been found to interact with MHC-like molecules (20,21).…”

mentioning

confidence: 99%

FCRL5 exerts binary and compartment-specific influence on innate-like B-cell receptor signaling

Zhu¹,

Li²,

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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Innate-like splenic marginal zone (MZ) and peritoneal cavity B1 B lymphocytes share critical responsibilities in humoral responses but have divergent B-cell receptor (BCR) signaling features. A discrete marker of these subsets with tyrosine-based dual regulatory potential termed "Fc receptor-like 5" (FCRL5) was investigated to explore this discrepancy. Although FCRL5 repressed the robust BCR activity that is characteristic of MZ B cells, it had no influence on antigen receptor stimulation that is blunted in peritoneal cavityderived B1 B cells. The molecular basis for the receptor's inhibitory function derived from recruitment of the Src homology-2 domaincontaining tyrosine phosphatase 1 (SHP-1) to a cytoplasmic immunoreceptor tyrosine-based inhibitory motif. Surprisingly, mutagenesis of this docking site unearthed coactivation properties for FCRL5 that were orchestrated by independent association of the Lyn Src-family kinase with an intracellular immunoreceptor tyrosine-based activation motif-like sequence. FCRL5's unique binary regulation directly correlated with SHP-1 and Lyn activity, which, like BCR function, differed between MZ and B1 B cells. These findings collectively imply a specialized counterregulatory role for FCRL molecules at the intersection of innate and adaptive immunity.

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Cutting Edge: Human FcRL4 and FcRL5 Are Receptors for IgA and IgG

Cited by 116 publications

References 31 publications

Involvement of the HCK and FGR src-Family Kinases in FCRL4-Mediated Immune Regulation

Involvement of the HCK and FGR src-Family Kinases in FCRL4-Mediated Immune Regulation

Fc Receptor–like 5 Expression Distinguishes Two Distinct Subsets of Human Circulating Tissue–like Memory B Cells

FCRL5 exerts binary and compartment-specific influence on innate-like B-cell receptor signaling

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