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Monocyte-Derived Macrophages I Differential Effect of Cytokine Treatment on Fc α Receptor I- and Fcγ Receptor I-Mediated Tumor Cytotoxicity by Monocyte-Derived Macrophages This information is current as of September 27, 2021. Tibor Keler, Paul K. Wallace, Laura A. Vitale, Christina Russoniello, Karuna Sundarapandiyan, Robert F. Graziano and Yashwant M. Deo J Immunol 2000; 164:5746-5752; ; doi: 10.4049/jimmunol.164.11.5746 Downloaded from http://www.jimmunol.org/content/164/11/5746 References This article cites 34 articles, 21 of which you can access for free at: http://www.jimmunol.org/ http://www.jimmunol.org/content/164/11/5746.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 27, 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 © 2000 by The American Association of Immunologists All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. Differential Effect of Cytokine Treatment on Fc␣ Receptor I- and Fc␥ Receptor I-Mediated Tumor Cytotoxicity by Monocyte-Derived Macrophages Tibor Keler,1* Paul K. Wallace,† Laura A. Vitale,* Christina Russoniello,* Karuna Sundarapandiyan,* Robert F. Graziano,* and Yashwant M. Deo* Macrophages represent an important effector cell for Ab-mediated tumor therapy. Previous studies have documented that cyto- kines can influence Fc receptor (FcR) expression and function. In this study we examined the tumoricidal activities of the type I receptors for IgG (Fc␥RI) and the IgA FcR (Fc␣RI) on monocyte-derived macrophages (MDM) cultured in the presence of IFN-␥, M-CSF, or GM-CSF. Bispecific Abs were used to target a Her2/neu breast carcinoma cell line, SKBR-3, to Fc␣RI or Fc␥RI on MDM. Although Fc␣RI and Fc␥RI share a common signaling pathway contingent on association with the ␥-chain (FcR␥ subunit), Downloaded from a marked difference in their efficiency in mediating tumoricidal functions was seen in response to specific cytokines. M-CSF- and GM-CSF-treated MDM mediated efficient phagocytosis of SKBR-3 cells by Fc␣RI and Fc␥RI; however, IFN-␥-treated MDM phagocytosed tumor cells only with the Fc␥RI-directed bispecific Abs. Similarly, IFN-␥-cultured MDM lysed tumor cells more efficiently via Fc␥RI then by Fc␣RI as measured in Ab-dependent cellular cytotoxicity assays. Conversely, GM-CSF-treated MDM mediated more efficient lysis of tumor cells via Fc␣RI than Fc␥RI, while M-CSF-cultured MDM were relatively less efficient in http://www.jimmunol.org/ mediating Ab-dependent cellular cytotoxicity through either receptor. With the exception of IFN-␥-mediated enhancement of Fc␥RI expression and Fc␥RI ␥-chain complexes, the regulation of Fc␥RI- or Fc␣RI-mediated activity occurred without significant change in either receptor expression or total complexes with ␥ subunit. These data suggest that the efficiency of Ab-mediated tumor therapy, which depends on FcR effector cell functions, may be modified by the use of specific cytokines. The Journal of Immunology, 2000, 164: 5746–5752. acrophages are a critical part of the immune system, ulations (monocytes, macrophages, and PMN) has not been clearly participating in both natural and specific immunity. delineated. M Macrophages can function as effector cells to elimi- Fc␥RI (CD64) binds monomeric human IgG1 and IgG3 with by guest on September 27, 2021 nate pathogens and as accessory cells that recruit and activate other high affinity (3, 4), and Fc␥RIIIA (CD16) has intermediate affinity immune cells. Furthermore, macrophages have been implicated to for monomeric IgG. Fc␥RIIA (CD32) efficiently binds to IgG im- be critical in mediating Ab-dependent tumor regression in some mune complexes and IgG-opsonized particles, but not to mono- animal models (1, 2). Many of these effector and accessory func- meric IgG (3). On macrophages, a single class of IgA Fc receptor, tions are mediated through Fc receptors (FcR) (2) that bind Ag- Fc␣RI (CD89), has been characterized and binds both Ag-com- complexed Igs. Human macrophages constitutively express the Fc plexed and monomeric IgA1 and IgA2 (5, 11). This suggests that ␣ receptor for IgA (Fc RI), and the high and low affinity Fc recep- in vivo Fc␣RI may be saturated with monomeric IgA in the same tors specific for IgG (Fc␥RI, Fc␥RIIA, and Fc␥RIIIA). These FcR manner as Fc␥RI and Fc␥RIIIA are significantly occupied mediate effector functions that are well documented, including Ab- with IgG. dependent cellular cytotoxicity (ADCC)2 and phagocytosis (3–7). mAb have been developed that bind to Fc␥RI (mAb 32.2 and In contrast, polymorphonuclear cells (PMN), an other myeloid 22) and Fc␣RI (mAb A77) at sites distinct from their ligand bind- effector cell with phagocytic and cytolytic capacity, constitutively express Fc␣RI, but not Fc␥RI. However, Fc␥RI expression can be ing domains (11–13). ADCC mediated by bispecific Abs (BsAb) induced in vitro with IFN-␥ treatment or in vivo with either G-CSF prepared using these anti-FcR Abs is not blocked by human IgG or or IFN-␥ (8–10). The relative importance of these two FcR types IgA (6, 7, 14–16). In addition to triggering effector functions under in promoting cytotoxic effector functions of various myeloid pop- physiologically relevant conditions, BsAb made from these mAbs bind exclusively to the targeted FcR and provide a suitable method to study the capacity of individual FcR in a variety of functional assays. Both Fc␥RI and Fc␣RI have been shown to be functionally *Medarex, Inc., Annandale, NJ 08801; and †Department of Microbiology, Dartmouth ␥ Medical School, Lebanon, NH 03756 associated with the subunit, which mediates signaling events following receptor clustering (17, 18). Although these receptors Received for publication May 19, 1999. Accepted for publication March 16, 2000. share a common signaling component (the ␥ subunit), their ex- The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance pression on the surface of effector cells is differentially regulated. with 18 U.S.C. Section 1734 solely to indicate this fact. Fc␣RI expression on monocytes can be enhanced by TNF-␣ (19, 1 Address correspondence and reprint requests to Dr. Tibor Keler, Medarex, Inc., 20), IL-1␤, GM-CSF, and bacterial LPS (20), whereas TGF-␤1 has 1545 Route 22 East, Annadale, NJ 08801. E-mail address: [email protected] been shown to decrease Fc␣RI expression (21). Monocyte Fc␥RI 2 Abbreviations used in this paper: ADCC, Ab-dependent cellular cytotoxicity; ␥ MDM, monocyte-derived macrophages; BsAb, bispecific Ab; PMN, polymorphonu- expression is up-regulated with IFN- and IL-10, and can be clear leukocytes. down-regulated with IL-4 (8, 9, 22, 23). Copyright © 2000 by The American Association of Immunologists 0022-1767/00/$02.00 The Journal of Immunology 5747 Previous studies have demonstrated that treatment of monocyte- Dickinson, Mountain View, CA) and examined with a Bio-Rad MRC1024 derived macrophages (MDM) with M-CSF or IFN-␥ differentially laser scanning confocal microscope (Hercules, CA). Cells were scanned for regulates FcR-mediated phagocytosis and lysis of tumor cells (22, fluorescence using the 488-nm line from a 15-mW KR/AR laser and two photodetectors (522/32 nm dichroic for FITC fluorescence and 585 nm 24, 25). These data showed that that M-CSF-cultured MDM were longpass for PKH-26 fluorescence). A ϫ63 Plan-Apo 1.4 NA objective proficient in mediating phagocytosis of tumor cells via Fc␥RII and (Carl Zeiss, Thornwood, NY) was used in conjunction with an iris setting Fc␥RIII, whereas cells incubated with IFN-␥ were ineffective at of 2.5, which allowed for detection of optical sections of the fluorescence mediating phagocytosis of tumor cells via these two low affinity image that were ϳ1.5 ␮m thick. A minimum of 100 cells/sample were examined for quantitative evaluation of phagocytosis. IgG receptors. The reverse has been demonstrated with regard to ADCC. MDM propagated in IFN-␥ appear to be more efficient at Tumor cell survival assay mediating Fc␥RII- and Fc␥RIII-dependent tumor cell lysis than ␥ To determine the tumor cell survival following phagocytosis, samples were untreated or M-CSF-cultured MDM (22, 24). However, the Fc RI- obtained from the trypsin-harvested cells and plated in 96-well tissue cul- mediated effector functions of MDM (ADCC and phagocytosis) ture plates. Live tumor cells were allowed to adhere overnight in RPMI can be enhanced with IFN-␥ (15, 26). containing 10% FBS. The medium was removed from each well, and the The cytotoxic capacity of the macrophage Fc␣RI has not been cells were fixed with 0.25% glutaraldehyde. Plates were blocked with 5% BSA solution, then reacted with mAb 251.03, which binds HER2/neu at a fully explored. Recently, we and Valerius et al. reported that different site than 520C9 mAb. The 251.03 mAb was detected with goat Fc␣RI on monocytes, PMN, and macrophages is a potent trigger anti-murine IgG Fc-specific alkaline phosphatase probe (The Jackson Lab- molecule for ADCC and phagocytosis of tumor cells (6, 7). Be- oratory, Bar Harbor, ME). The plates were developed using p-nitrophenyl cause of the role of IgA and Fc␣RI in mucosal immunity, the phosphate and read at a wavelength of 405–650 nm.
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