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336.Full.Pdf Murine IgG1 and IgG3 Isotype Switch Variants Promote Phagocytosis of Cryptococcus neoformans through Different Receptors This information is current as of September 28, 2021. Carolyn A. Saylor, Ekaterina Dadachova and Arturo Casadevall J Immunol 2010; 184:336-343; Prepublished online 30 November 2009; doi: 10.4049/jimmunol.0902752 Downloaded from http://www.jimmunol.org/content/184/1/336 References This article cites 43 articles, 21 of which you can access for free at: http://www.jimmunol.org/ http://www.jimmunol.org/content/184/1/336.full#ref-list-1 Why The JI? Submit online. • Rapid Reviews! 30 days* from submission to initial decision • No Triage! Every submission reviewed by practicing scientists by guest on September 28, 2021 • 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 Copyright © 2010 by The American Association of Immunologists, Inc. All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. The Journal of Immunology Murine IgG1 and IgG3 Isotype Switch Variants Promote Phagocytosis of Cryptococcus neoformans through Different Receptors Carolyn A. Saylor,* Ekaterina Dadachova,*,† and Arturo Casadevall*,‡ Almost 3 decades ago, murine IgG3 was proposed to interact with a different receptor than the other IgG subclasses, but the issue remains unresolved. The question of whether a specific receptor exists for IgG3 is critically important for understanding Ab- mediated immunity against Cryptococcus neoformans, where the different isotypes manifest profound differences in protective efficacy. In this study, we revisited this question by analyzing IgG1- and IgG3-mediated phagocytosis with variable region- identical mAbs using mouse macrophages deficient in various receptors and in conditions of FcgR and complement receptor blockage with specific Abs. IgG3 was an efficient opsonin for C. neoformans in FcgR- and CD18-deficient cells and in the presence Downloaded from of blocking Abs to FcgR and complement receptor. Like IgG1, IgG3-mediated phagocytosis was associated with fungal residence in a mature phagosome that was followed by intracellular replication and exocytosis events. We conclude that a specific receptor for IgG3 exists in mice that is structurally different from the known FcgRs. The Journal of Immunology, 2010, 184: 336–343. hagocytosis is a receptor-mediated event in which the although there is a similar system in humans, mouse IgG isotypes specific recognition of microbes by phagocytic cells, such and FcgRs are not synonymous with human ones; although the http://www.jimmunol.org/ P as macrophages or dendritic cells, leads to microbial specificities of human IgG isotypes for the various human FcgRs are internalization and targeting to a phagolysosomal compartment for well characterized (11, 12), the mouse system is different and less degradation and Ag presentation (1–3). During an adaptive well understood. Various studies in mice showed that IgG2a is the immune response, Ab is the primary mediator of this interaction; most promiscuous Ab, interacting with all FcgRs, whereas IgG1 is microbes bound by specific IgG interact with FcgRs on effector more selective and only binds to one activating receptor, FcgRIII cells to promote clearance of infection (4, 5). Characterizing the (13). Although much work has been done to study the interaction of receptor interactions during Ab-mediated phagocytosis is impor- the various Ab isotypes with the different FcgRs, major questions tant for understanding the role of Ab generated during host still remain. In this regard, three of the four mouse IgG subclasses, defense as well as for assessing the mechanism of passive Ab IgG1, IgG2a, and IgG2b, have been well characterized in terms of by guest on September 28, 2021 therapy, by which treatment with immune serum or specific mAbs their affinity and specificity for the different FcgRs (14, 15); how- can ameliorate disease (6–8). ever, the data for IgG3 have been inconsistent, and most current In mice, the activating FcgRs are FcgRI, FcgRIII, and FcgRIV,all reviews conclude that IgG3 interacts only very weakly with known of which share a common g-chain containing an intracellular ITAM FcgRs (13). Understanding the mouse FcgR system is important sequence necessary to mediate activation when Ab is bound (5). because mice continue to be the most commonly used animal system FcgRIIb, the inhibitory receptor, does not pair with the common for immunological studies. g-chain, but rather has an intracellular ITIM sequence and mediates In 1981, Diamond and Yelton (16) proposed that a unique IgG3 inhibitory signaling (9). The balance of positive and negative signals receptor existed, based on the spontaneous J774 cell variant that determines the outcome of the interaction of Ab-bound microbes specifically lost the ability to phagocytose sheep red blood cells with cells, because the threshold to trigger phagocytosis or other coated in IgG3 but retained the ability to phagocytose via the other events is based on the ratio of activating/inhibitory receptor Ab isotypes. A subsequent study by Gavin et al. (17) showed that engagement (10). Because Ab isotypes have different affinities for the known receptor FcgRI, which has high affinity for IgG2a, the various FcgRs, they can trigger different effector functions could also interact with IgG3. However, this study demonstrated based on their receptor binding specificity. It is critical to note that only low-affinity binding of IgG3 to FcgRI-transfected cells. Additionally, in bone marrow-derived macrophages from FcgRI- *Department of Microbiology and Immunology, †Department of Nuclear Medicine, deficient mice, phagocytosis of IgG3-coated particles failed and ‡Medicine (Infectious Diseases), Albert Einstein College of Medicine, Bronx, compared with macrophages derived from wild-type mice in NY 10461 which they visualized internalization via IgG3. However, this Received for publication September 18, 2009. Accepted for publication October 27, study was not consistent with the original observation by Diamond 2009. and Yelton (16), in which phagocytosis by the variant cell line via This work was supported by National Institutes of Health Grants AI33774, AI33142, other Ab isotypes, such as IgG2a, was unchanged, which would AI51519, and HL59842-01 (to A.C.), T32 AI07506 (to C.A.S), and AI60507 (to E.D.). E.D. is the Sylvia and Robert S. Olnick Faculty Scholar in Cancer Research. not be true if FcgRI was the receptor lost by the J774 variant. Address correspondence and reprint requests to Dr. Arturo Casadevall, Forchheimer Moreover, the study by Gavin et al. (17) did not examine the role 411, 1300 Morris Park Avenue, Bronx, NY 10461. E-mail address: arturo.casadevall@ of IgG3 phagocytosis in terms of a microbe-specific Ab in- einstein.yu.edu teraction with host cells during infection. The role of IgG3 in Abbreviations used in this paper: CR, complement receptor; Lamp1, lysosomal- phagocytosis is not clear. In addition to these studies, there is other associated membrane protein 1. evidence strongly supporting the notion that IgG3 Abs engage Copyright Ó 2009 by The American Association of Immunologists, Inc. 0022-1767/10/$16.00 a different receptor than other IgG subclasses: 1) IgG1 and IgG3 www.jimmunol.org/cgi/doi/10.4049/jimmunol.0902752 The Journal of Immunology 337 have very different protective efficacy in mice (18); 2) IgG1 is cultures grown in Sabouraud media (Difco, Sparks, MD) at 30˚C. Yeast cells toxic, whereas IgG3 is nontoxic in mice with chronic cryptococcal were washed three times with sterile PBS then counted on a hemocytometer infection and high serum Ag levels (19, 20); and 3) IgG3, but not and suspended at the appropriate cell density in RPMI 1640 media. the other IgG subclasses, mediates Ag–Ab complex enhancement MAbs of the Ab response in Fcg-deficient mice (21). The 3E5 IgG1, IgG2a, and IgG3 mAbs were described previously (23). In this study, we revisitedthe topic of IgG3-mediated phagocytosis Briefly, mAb 3E5 was originally isolated as an IgG3 mAb following bycomparingtheopsonicefficacyofIgG1andIgG3forCryptococcus immunization of mice with capsular polysaccharide glucuronoxylomannan neoformans. Many mAbs specific for C. neoformans have been conjugated to tetanus toxoid, and the other isotypes were later generated via generated and used to study the effects of passive mAb treatment on in vitro isotype switching. Ascites was generated by injecting hybridoma cells into the peritoneal cavity of pristine-primed BALB/c mice (National cryptococcal infection (22–24). The in vitro system of C. neofor- Cancer Institute, Frederick, MD) and harvesting the fluid. Abs were purified mans and macrophage interactions is ideal to study receptor-medi- from ascites using a protein G column following the manufacturer’s in- ated phagocytosis because in the absence of opsonin, phagocytosis of structions (Pierce, Rockford, IL) and then dialyzed in PBS and quantified by C. neoformans by macrophages is essentially zero, and yeast cells are ELISA with an isotype-matched standard to determine concentration. Abs 2 easily identified and counted by microscopy (25–27). However, this were aliquoted, stored in PBS at 20˚C, and thawed once before use. system has some unique features that need to be taken into account, Phagocytosis assays including the phenomenon of Ab-mediated phagocytosis proceeding Phagocytosis assays were performed in 96-well plates containing primary through FcgRs and complement receptors (CRs) in the absence of peritoneal cells isolated 1 d prior to the experiment. In the case of CR- or complement. In this system, IgG can function as directly opsonizing FcgR-blocking experiments, Abs to CR3 and CR4 (CD18, CD11b, and Ab, where the Fc portions of Ab bound to the capsule of C.
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