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Human Fc Receptor−Like 5 Binds Intact Igg Via Mechanisms Distinct from Those of Fc Receptors

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Human Fc Receptor−Like 5 Binds Intact Igg Via Mechanisms Distinct from Those of Fc Receptors Human Fc Receptor−Like 5 Binds Intact IgG via Mechanisms Distinct from Those of Fc Receptors This information is current as Andrea Franco, Bazarragchaa Damdinsuren, Tomoko Ise, of September 24, 2021. Jessica Dement-Brown, Huifang Li, Satoshi Nagata and Mate Tolnay J Immunol 2013; 190:5739-5746; Prepublished online 24 April 2013; doi: 10.4049/jimmunol.1202860 Downloaded from http://www.jimmunol.org/content/190/11/5739 Supplementary http://www.jimmunol.org/content/suppl/2013/04/24/jimmunol.120286 Material 0.DC1 http://www.jimmunol.org/ References This article cites 45 articles, 24 of which you can access for free at: http://www.jimmunol.org/content/190/11/5739.full#ref-list-1 Why The JI? Submit online. • Rapid Reviews! 30 days* from submission to initial decision by guest on September 24, 2021 • No Triage! Every submission reviewed by practicing scientists • Fast Publication! 4 weeks from acceptance to publication *average Subscription Information about subscribing to The Journal of Immunology is online at: http://jimmunol.org/subscription Permissions Submit copyright permission requests at: http://www.aai.org/About/Publications/JI/copyright.html Email Alerts Receive free email-alerts when new articles cite this article. Sign up at: http://jimmunol.org/alerts The Journal of Immunology is published twice each month by The American Association of Immunologists, Inc., 1451 Rockville Pike, Suite 650, Rockville, MD 20852 All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. The Journal of Immunology Human Fc Receptor–Like 5 Binds Intact IgG via Mechanisms Distinct from Those of Fc Receptors Andrea Franco,* Bazarragchaa Damdinsuren,* Tomoko Ise,† Jessica Dement-Brown,* Huifang Li,* Satoshi Nagata,† and Mate Tolnay* Fc receptor–like (FCRL) 5 regulates B cell Ag receptor signaling and has been reported to bind aggregated IgG. Using surface plasmon resonance, we analyzed the interaction of native IgG samples with FCRL5, revealing a complex binding mechanism, where isotype is just one factor. FCRL5 bound IgG1 and IgG4 with ∼1 mM KD, whereas the interaction with IgG3 was a magnitude weaker. However, IgG2 samples displayed a wide range of affinities, indicating that additional factors affect binding. We used a panel of 19 anti-FCRL5 mAbs with defined reactivity to identify domains involved in ligand binding. Six mAbs blocked IgG binding, indicating critical roles of FCRL5 domains 1 and 3, as well as epitopes at the domain 1/2 and domain 2/3 boundaries. We found that only glycosylated IgG containing both Fab arms and the Fc region bound with high affinity. Furthermore, the presence Downloaded from of sialic acid in the IgG carbohydrate altered FCRL5 binding. The interaction of IgG and FCRL5 consisted of two kinetic components, suggesting a complex binding mechanism. We established that the IgG-Fc and IgG-F(ab9)2 fragments bind FCRL5 independently but with low affinity, revealing the mechanism behind the two-step binding of whole IgG. This complex binding mechanism is distinct from that of Fc receptors, which bind through the Fc. We propose that FCRL5 is a new type of receptor that recognizes intact IgG, possibly enabling B cells to sense Ig quality. Recognition of undamaged IgG molecules by FCRL5 could allow B cells to engage recently produced Abs. The Journal of Immunology, 2013, 190: 5739–5746. http://www.jimmunol.org/ he family of Fc receptor–like (FCRL) proteins was dis- diseases, including cancer and autoimmune conditions (13, 14). We covered in part by searching for Fc receptor homologs (1– and others reported FCRL5 to be overexpressed on malignant B cells T 3). Human FCRL1–6 (CD307a–f) are membrane proteins of hairy cell leukemia, chronic lymphocytic leukemia, mantle cell preferentially expressed on B cells (4), whereas FCRLA and FCRLB lymphoma, and multiple myeloma patients (11, 14–16). Addition- reside in the cytoplasm. FCRL1–6 possess cytoplasmic tails with ally, serum levels of soluble FCRL5 are elevated in patients with inhibitory ITIM and/or activating ITAM phosphorylation signaling several types of B cell tumors (16). A recent study demonstrated the motifs. The signaling potential of FCRL1–5 was established in usefulness of FCLR5 as a combination biomarker to predict non- by guest on September 24, 2021 model systems using either stimulation with Abs or chimeric FCRL response to anti-CD20 therapy in rheumatoid arthritis (17). FCRL5 cytoplasmic tails fused to FcgRIIB extracellular domains. FCRL1 is a novel target in the treatment of multiple myeloma (18). was found to promote B cell activation, whereas FCRL2–5 were Despite substantial progress suggesting physiological roles for each shown to inhibit B cell Ag receptor signaling (5–9). In par- FCRL proteins in B cell biology, the identification of FCRL ligands ticular, chimeric FCRL5 recruited SHP1 to two ITIM motifs upon has been lagging. During the last 2 y, the first ligand candidates B cell Ag receptor costimulation, resulting in diminished calcium emerged. FCRL6, expressed on cytotoxic T cells and NK cells, binds influx and protein tyrosine phosphorylation (7). We showed that HLA-DR, a MHC class II molecule related to Igs (19). FCRLA in the costimulation of FCRL5 and the B cell Ag receptor promotes endoplasmic reticulum binds IgG, IgM and IgA (20, 21). FCRL5 has proliferation and differentiation of naive B cells (10). FCRL5 is recently been shown to bind aggregated IgG, while FCRL4 binds expressed on both mature B cells and plasma cells and is induced IgA (22). Specifically, FCRL5 expressed on HEK293T cells bound by EBV proteins (11, 12). FCRL proteins are implicated in human heat-aggregated IgG1 and IgG2, and it bound IgG3 and IgG4 less efficiently. An FCRL5 fragment containing three N-terminal domains *Division of Monoclonal Antibodies, Center for Drug Evaluation and Research, Food was shown capable of binding IgG1 and an Ab reactive to domain and Drug Administration, Silver Spring, MD 20993; and †Cancer Biology Research (D)1–3-inhibited IgG binding. The discovery that FCRL5 is a spe- Center, Sanford Research/USD, Sioux Falls, SD 57105 cific IgG receptor suggests a role for secreted IgG regulating B cells Received for publication October 12, 2012. Accepted for publication March 15, through FCRL5, analogous to FcgRIIB (23). 2013. We sought to further define the IgG ligands of FCRL5 by This work was supported by the Intramural Research Program of the Center for Drug Evaluation and Research/Food and Drug Administration. A.F. and H.L. were supported scrutinizing the interactions of a large panel of native as well as through the Research Fellowship Program for the Center for Drug Evaluation and Re- various fragmented and modified IgG samples using surface plas- search administered by the Oak Ridge Associated Universities. B.D. was supported by mon resonance, which provides the detailed kinetics of the inter- the Food and Drug Administration Commissioner’s Fellowship Program. S.N. and T.I. were supported by the Leukemia Research Foundation, the Chronic Lymphocytic Leu- actions. Our studies revealed a complex interaction that requires kemia Global Research Foundation, and National Institutes of Health Centers of Bio- intact IgG molecules. This novel concept will help in understanding medical Research Excellence Grant 1P20RR024219-01A2. the physiological roles of FCRL5 and related proteins. Address correspondence and reprint requests to Dr. Mate Tolnay, Division of Mono- clonal Antibodies, Center for Drug Evaluation and Research, Food and Drug Admin- istration, HFD-123, 10903 New Hampshire Avenue, Silver Spring, MD 20993. E-mail address: [email protected] Materials and Methods Native and modified IgG samples The online version of this article contains supplemental material. Abbreviations used in this article: D, domain; FCRL, Fc receptor–like; Rmaximum response, Intact IgG samples are listed in Table I. Ig samples were obtained from Rmax; RU, relative unit. Athens Research (Athens, GA), Bethyl Laboratories (Montgomery, TX), www.jimmunol.org/cgi/doi/10.4049/jimmunol.1202860 5740 FCRL5 BINDS INTACT IgG Sigma-Aldrich (St. Louis, MO), Calbiochem-EMD Millipore (Darmstadt, ∼14 mM (2.1 mg/ml) in HBS-P containing 1 mg/ml nonspecific binding Germany), and SouthernBiotech (Birmingham, AL). Therapeutic mAbs reducer (GE Healthcare), were injected over FCRL5 for 8 min at 20 ml/min were obtained from the National Institutes of Health pharmacy (Bethesda, and 25˚C, and then dissociation was monitored for 10 min. Bound Ig and MD) or were a gift. Polyclonal IgG-Fab and polyclonal IgG-Fc were ob- FCRL5-His were removed with a 1 min injection of 10 mM glycine-HCl tained from Athens Research. Polyclonal IgG-F(ab9)2 was from Jackson (pH 1.5). Data were analyzed using the Biacore T200 evaluation software ImmunoResearch (West Grove, PA). Sample purities were assessed by (GE Healthcare), subtracting the reference surface (immobilized anti-His SDS-PAGE analysis, followed by protein staining. To produce the Fab-Fc mouse IgG1 mAb but no captured FCRL5-His) and buffer control signals fragment, we used the strategy developed by Hambly et al. (24) taking from each curve. Data were globally fitted by simultaneous numerical in- advantage of partial resistance of IgG1 to LysC cleavage upon extended tegration to the association and dissociation parts of the interaction, using the incubation of IgG1 at pH 5.2, owing to isomerization of Asp222. Briefly, 1:1 and two-state kinetic analysis models. Steady-state equilibrium was not mIgG1 (no. 1) in 10 mg/ml in 150 mM NaCl, 10 mM Na acetate (pH 5.2) reached during the association phase with the majority of full IgG samples was incubated for 3 mo at 37˚C. Then, limited proteolysis was performed (except with sample nos. 13 and 16); nevertheless, global fitting produced in 0.1 M Tris-HCl (pH 7.5) using 0.1 mg LysC (Pierce/Fisher Scientific, reproducible kinetic parameters. Experimental Rmaximum response (Rmax) Pittsburgh, PA) per milligram IgG1 for 15 min at 37˚C.
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