Inside-Out Regulation of FcαRI (CD89) Depends on PP2A

Bakema, Jantine E.; Bakker, Annie; Haij, Simone de; Honing, Henk; Bracke, Madelon; Koenderman, Leo; Vidarsson, Gestur; Winkel, Jan G. J. van de; Leusen, Jeanette H.W.

doi:10.4049/jimmunol.181.6.4080

Cited by 28 publications

(38 citation statements)

References 48 publications

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“…17 Unlike Fc␣RI, however, serine phosphorylation of the cytosolic tail of Fc␥RI ␣-chain is unlikely to play a role during inside-out regulation, because a truncated receptor lacking all serines was found to respond to cytokine stimulation (data not shown). Strikingly, PI-3K inhibition did not affect cytokine-enhanced IC binding to Fc␥R,I suggesting distinct mechanisms underlying Fc␥RI regulation compared with Fc␣RI.…”

Section: Discussionmentioning

confidence: 96%

“…It has been shown that Fc␣RI inside-out regulation in Ba/F3 cells is dependent on PI-3K and protein phosphatase 2 (PP2a). 17,18 We investigated whether similar signaling pathways underlie Fc␥RI inside-out regulation. In our model, both a PI3-Kinase inhibitor (LY294002) 32 and a MEK1/2 inhibitor (U0126) 33 did not affect IL-3-enhanced binding to mIgG2a-IC ( Figure 4A).…”

Section: Cytokine Stimulation Enhances Fc␥ri Binding To Opsonized Tummentioning

confidence: 99%

“…[13][14][15][16] It remains unclear how Fc␥RI contributes to immune complex clearance in the presence of high IgG levels. For Fc␣RI 17,18 and Fc␥RIIa 19,20 it has been shown that cytokine stimulation can increase ligand binding of these receptors. This appears analogous to inside-out regulation described for integrins.…”

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confidence: 99%

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Cytokine-induced immune complex binding to the high-affinity IgG receptor, FcγRI, in the presence of monomeric IgG

Poel

Karssemeijer

Boross

et al. 2010

Blood

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IntroductionFc receptors are receptors for immunoglobulins that play a central role in immunity. On human leukocytes, a myriad of Fc␥ receptors are expressed; among these receptors, Fc␥RI is the only known high-affinity receptor for immunoglobulin G (IgG). 1 Fc␥RI is constitutively expressed on monocytes, macrophages, and myeloid dendritic cells. Interferon␥ (IFN␥) can enhance surface expression of Fc␥RI on these cells, and Fc␥RI expression can be induced on granulocytes by IFN␥ or granulocyte colony-stimulating factor (G-CSF) stimulation. In contrast, cytokines such as interleukin-4 (IL-4), IL-10, and transforming growth factor-␤ (TGF-␤) downregulate activating Fc receptors, including Fc␥RI, and enhance expression of the inhibitory receptor Fc␥RIIb. 2,3 In vitro, IFN␥ treatment leads to increased Fc␥ receptor-induced cytokine production. 4 In vivo, the role of Fc␥RI in immunity remains unclear, as due to its high affinity Fc␥RI is believed to be saturated with monomeric IgG. This has led to the concept that prebound monomeric IgG prevents participation of Fc␥RI in clearing immune complexes by extravasated effector cells. 5 Nevertheless, several in vivo studies documented a role for Fc␥RI, varying from a contribution during inflammation and autoimmune reactions, 6-8 or, during monoclonal antibody (mAb)-based immunotherapy in melanoma and B-cell lymphoma models, 9,10 to a malaria model in which transgenic expression of human Fc␥RI was central for effective mAb treatment. 11 Furthermore, Fc␥RI can induce potent proinflammatory signaling compared with Fc␥RIIa, 12 and can efficiently mediate both major histocompatibility complex class II (MHC-II) antigen presentation and cross-presentation. [13][14][15][16] It remains unclear how Fc␥RI contributes to immune complex clearance in the presence of high IgG levels. For Fc␣RI 17,18 and Fc␥RIIa 19,20 it has been shown that cytokine stimulation can increase ligand binding of these receptors. This appears analogous to inside-out regulation described for integrins. Many integrins are expressed in a low-affinity binding state, which can be transformed to a high-affinity form upon cellular activation. 21 We hypothesized that inside-out regulation could contribute to immune complex binding to Fc␥R occupied by IgG. Indeed, several studies support intracellular proteins interacting with Fc␥RI and possibly affecting ligand binding. 22,23 In this study, we investigated the effect of cytokine stimulation on Fc␥RI ligand binding. Stimulation of Fc␥RI-expressing Ba/F3 cells and primary monocytes resulted in increased binding of immune complexes, whereas binding of monomeric IgG was only moderately enhanced. Upon cellular activation, Fc␥RI could readily bind immune complexes despite pre-engaged monomeric IgG. Taken together, these data might explain how Fc␥RI supports leukocyte interaction with immune complexes. Methods Antibodies and reagentsAnti-Fc␥RI-A647 was from BioLegend (clone 10.1). Unlabeled 10.1 mAb and mouse IgG1/IgG2a isotype were from eBioscience and BD Pharmingen, respect...

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Section: Discussionmentioning

confidence: 96%

Section: Cytokine Stimulation Enhances Fc␥ri Binding To Opsonized Tummentioning

confidence: 99%

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Cytokine-induced immune complex binding to the high-affinity IgG receptor, FcγRI, in the presence of monomeric IgG

Poel

Karssemeijer

Boross

et al. 2010

Blood

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“…This observation might be related to Fc␣RI splice variants differently expressed by human leukocytes (36,37) and upon cellular activation (38). Furthermore, the functionality of Fc␣RI is dependent on the interaction with the FcR␥ chain and sensitive to inside-out signaling (39,40). Thus, the (1) antibodies as well as 225-IgG1 induced similar specific lysis in macrophage-mediated ADCC assays of A431 tumor cells.…”

Section: Advantages and Disadvantages Of Iga Iso-and Allotypementioning

confidence: 94%

Characterization of a Mutated IgA2 Antibody of the m(1) Allotype against the Epidermal Growth Factor Receptor for the Recruitment of Monocytes and Macrophages

Lohse

Brunke

Derer

et al. 2012

Journal of Biological Chemistry

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Background: IgA constitutes a promising antibody isotype, which requires optimization before immunotherapeutic application. Results: P221R-mutated and wild type IgA2m(1) antibodies were similarly effective in killing tumor cells and in recruiting myeloid effector cells. Conclusion: Improved IgA antibodies constitute promising next generation antibodies for tumor therapy. Significance: These studies support the clinical development of therapeutic IgA antibodies.

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“…Our previous finding that the C2 domains play little or no role in the kinetics of IgY binding to receptor (6), unlike the homologous C⑀2 domains in IgE (30) (29). Dephosphorylation of Fc␣RI by protein phosphatase 2A has now been identified as the activation switch for IgA bound to its receptor on neutrophils (31). A mutant IgG, binding only one molecule of FcRn, the fetal and IgG homeostasis receptor (32), has been used to show that 1:1 receptor:antibody stoichiometry does decrease the efficiency of transcytosis and recycling and also does increase the proportion of antibody targeted for degradation (33).…”

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A Monomeric Chicken IgY Receptor Binds IgY with 2:1 Stoichiometry

Taylor

Beavil

Sutton

et al. 2009

Journal of Biological Chemistry

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Fc receptors link the specificity of the adaptive immune system with the effector mechanisms of innate immune cells. In birds and reptiles, IgY is the principal serum antibody, and both mammalian IgG and IgE have evolved from an IgY-like ancestor, so studies of IgY offer insights into their origins (1). The historical contribution of chicken immunology to a wider understanding of the subject has been considerable (2), and recently several chicken IgY-Fc receptors have been identified. In this paper, the chicken antibody, IgY, is shown to bind to a chicken leukocyte receptor, CHIR-AB1, 4 in a different manner from that of its mammalian orthologues, IgG and IgE, to their respective Fc receptors. Phagocytosis, mediated in mammals by IgG, and passive cutaneous anaphylaxis, mediated by both IgG and IgE in mammals, have been observed in chickens (3, 4), presumably both effected by IgY. In vitro, IgY binds to monocyte cell lines (5, 6), and an IgY receptor (CHIR-AB1) has been identified that is able to mediate the influx of calcium into cells (5).The genes for the mammalian high affinity IgE receptor, and several IgG receptors, are located in the classical Fc receptor cluster, whereas in chickens, this cluster is represented by a single gene, the product of which has been expressed and found not to bind IgY (7). Intriguingly, the first IgY leukocyte receptor, CHIR-AB1, was found to be a member of the chicken leukocyte receptor cluster (LRC) (5), adjacent to over 100 genes with high intersequence homology (8). This finding, together with phylogenetic analysis of the orthologous Fc receptor gene clusters (7, 9), implies that during the evolution of the IgY-like ancestor of both IgG and IgE, antibody-Fc binding function migrated from proteins expressed in the LRC to those in the classical Fc receptor cluster. The human LRC is the site of Fc␣RI, the leukocyte receptor for IgA (an antibody involved in mucosal immunity), the fetal IgG receptor (FcRn, involved in adult IgG homeostasis), and also a number of natural killer cell receptors including the HLA-G ligand, KIR2DL4 (10). A further leukocyte receptor for chicken IgY, also related to LRC receptors, was identified recently, on chromosome 20 (11), and remains to be characterized.Typically, the stoichiometry of the receptor-antibody complex differs for receptors located in the classical Fc receptor cluster and the LRC. Crystal structures of IgG complexes with Fc␥RIII and of IgE with Fc⑀RI show 1:1 receptor:antibody stoichiometry, with the receptor binding across both heavy chains in the lower hinge (12). In contrast, the crystal structure of Fc␣RI complexed with IgA shows 2:1 stoichiometry (13)

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Inside-Out Regulation of FcαRI (CD89) Depends on PP2A

Cited by 28 publications

References 48 publications

Cytokine-induced immune complex binding to the high-affinity IgG receptor, FcγRI, in the presence of monomeric IgG

Cytokine-induced immune complex binding to the high-affinity IgG receptor, FcγRI, in the presence of monomeric IgG

Characterization of a Mutated IgA2 Antibody of the m(1) Allotype against the Epidermal Growth Factor Receptor for the Recruitment of Monocytes and Macrophages

A Monomeric Chicken IgY Receptor Binds IgY with 2:1 Stoichiometry

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