The Unique Cytoplasmic Domain of Human FcγRIIIA Regulates Receptor-Mediated Function

Li, Xiaoli; Baskin, Julie G.; Mangan, Erin; Su, Kaihong; Gibson, Andrew; Ji, Chuanyi; Edberg, Jeffrey C.; Kimberly, Robert P.

doi:10.4049/jimmunol.1200704

Cited by 21 publications

(17 citation statements)

References 44 publications

(56 reference statements)

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“…( 19 ) Moreover, PI3-K activation has also been reported to play distinct roles in FcγRIIA-mediated degranulation and the production of cytokines. ( 20 ) However, FcγRIIA-dependent passive systemic allergy has generally been thought to be dependent on monocytes/macrophages and neutrophils, but not on mast cells and basophils. ( 21 ) These reports are consistent with the idea that an IgE-FcεRI-mediated mechanism is primarily responsible for basophil activation by CBDCA.…”

Section: Discussionmentioning

confidence: 99%

Carboplatin‐induced severe hypersensitivity reaction: Role of IgE‐dependent basophil activation and FcεRI

et al. 2014

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Basophil activation was observed in patients with a history of carboplatin-induced severe hypersensitivity reaction (HR). However, the precise mechanism by which carboplatin induces basophil activation and the associated surrogate markers remains to be elucidated. To investigate whether IgE-dependent mechanisms, including the overexpression of FcεRI, participate in carboplatin-induced basophil activation, 13 ovarian cancer patients were enrolled: 5 with a history of carboplatin-induced severe hypersensitivity reaction within the past 2 years, and 8 with no such history. The expression levels of FcεRI, IgE, and CD203c on basophils were measured using a flow cytometer. Immunoglobulin E-dependent basophil activation was evaluated by testing for IgE passive sensitization using lactic acid, and by testing for phosphatidylinositol 3-kinase inhibition, using wortmannin. In three patients positive for carboplatin hypersensitivity, pretreatment with wortmannin almost completely inhibited carboplatin-induced basophil activation (P < 0.05). In a healthy control subject, whose own IgE showed no response to carboplatin, acquired reactivity to carboplatin when exposed to plasma from patients positive for carboplatin hypersensitivity. This did not occur when the same experiment was carried out using plasma from the patients negative for carboplatin hypersensitivity. Moreover, pretreatment with omalizumab, a monoclonal anti-IgE antibody, almost completely blocked carboplatin-induced basophil activation in the plasma of patients positive for carboplatin hypersensitivity. On further investigation, the HR-positive group had significantly higher levels of FcεRI compared with the negative group (P < 0.05). In conclusion, an IgE-dependent mechanism incorporating FcεRI overexpression participates in carboplatin-induced severe HR. These results establish the relevance of monitoring the pharmacodynamic changes of basophils to prevent carboplatin-induced severe HR.

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Section: Discussionmentioning

confidence: 99%

Carboplatin‐induced severe hypersensitivity reaction: Role of IgE‐dependent basophil activation and FcεRI

et al. 2014

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“…Moreover, both CD247 and FceR1γ form dimers in the endoplasmic reticulum (ER) that are stabilized by a disulphide bond at the junction between the extracellular and TM domains so that, at the cell surface, CD247 and FceR1γ in complex with their client receptors are dimeric. In general, the receptors known to associate with CD247 and FceR1γ have short intracellular tails and thus are completely dependent on these adaptors to signal, although phosphorylation of a protein kinase C (PKC) motif in the cytoplasmic tail of CD16A can modulate the outcome of receptor ligation (8).…”

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confidence: 99%

Transmembrane features governing Fc receptor CD16A assembly with CD16A signaling adaptor molecules

Blázquez-Moreno

Park

et al. 2017

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

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Many activating immunoreceptors associate with signaling adaptor molecules like FceR1γ or CD247. FceR1γ and CD247 share high sequence homology and form disulphide-linked homodimers that contain a pair of acidic aspartic acid residues in their transmembrane (TM) domains that mediate assembly, via interaction with an arginine residue at a similar register to these aspartic acids, with the activating immunoreceptors. However, this model cannot hold true for receptors like CD16A, whose TM domains do not contain basic residues. We have carried out an extensive site-directed mutagenesis analysis of the CD16A receptor complex and now report that the association of receptor with the signaling adaptor depends on a network of polar and aromatic residues along the length of the TM domain. Molecular modeling indicates that CD16A TM residues F 202 , D 205, and T 206 form the core of the membrane-embedded trimeric interface by establishing highly favorable contacts to the signaling modules through rearrangement of a hydrogen bond network previously identified in the CD247 TM dimer solution NMR structure. Strikingly, the amino acid D 205 also regulates the turnover and surface expression of CD16A in the absence of FceR1γ or CD247. Modeling studies indicate that similar features underlie the association of other activating immune receptors, including CD64 and FceR1α, with signaling adaptor molecules, and we confirm experimentally that equivalent F, D, and T residues in the TM domain of FceR1α markedly influence the biology of this receptor and its association with FceR1γ. dim natural killer (NK) cells, subsets of monocytes, dendritic cells, and rare T cells. FcγRIIIB (CD16B) is encoded by a distinct gene and is preferentially expressed by neutrophils (1). CD16B is a GPI-anchored glycoprotein whereas CD16A is a type 1 membrane glycoprotein with a single transmembrane (TM) domain and a short cytoplasmic tail whose expression at the cell surface depends on association with the signaling adaptor molecules CD247 (TCRζ) and/or FceR1γ (1-4). First discovered as components of the TCR:CD3 complex and the high affinity receptor for IgE, respectively (5-7), CD247 and FceR1γ are integral membrane proteins that have subsequently been found to be obligate signaling adaptors for many immunoreceptors in different cell types. Both adaptors have very short extracellular domains and cytoplasmic tails that contain immunoreceptor tyrosinebased activating motifs (ITAMs) for signal transduction. Moreover, both CD247 and FceR1γ form dimers in the endoplasmic reticulum (ER) that are stabilized by a disulphide bond at the junction between the extracellular and TM domains so that, at the cell surface, CD247 and FceR1γ in complex with their client receptors are dimeric. In general, the receptors known to associate with CD247 and FceR1γ have short intracellular tails and thus are completely dependent on these adaptors to signal, although phosphorylation of a protein kinase C (PKC) motif in the cytoplasmic tail of CD16A can modulate the outcome of receptor ...

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“…Calcium flux, Syk phosphorylation, cytokine production, and degranulation were shown to be affected by the phosphorylation state of this motif. 49 Moreover, differential outcomes might also be caused by cross-talk with other receptor systems. It has for example been shown that such a cross-talk occurs between murine TLR4 and CD16.…”

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confidence: 99%

FcγRIII (CD16) equips immature 6-sulfo LacNAc–expressing dendritic cells (slanDCs) with a unique capacity to handle IgG-complexed antigens

Döbel

Kunze

Babatz

et al. 2013

Blood

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Key Points• The expression of CD16 by immature slanDCs equips these cells with a unique capacity to handle immune complexes.• CD16 expression on slanDCs is rapidly downregulated during maturation by activation of ADAM10 and ADAM17. We show that CD16 is rapidly shed from the surface of maturing slanDCs, resulting from the combined action of the metalloproteinases ADAM10 and ADAM17. In conclusion, these data provide strong evidence that slanDCs play an important role in IC-driven immune responses. (Blood. 2013;121(18):3609-3618)

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The Unique Cytoplasmic Domain of Human FcγRIIIA Regulates Receptor-Mediated Function

Cited by 21 publications

References 44 publications

Carboplatin‐induced severe hypersensitivity reaction: Role of IgE‐dependent basophil activation and FcεRI

Carboplatin‐induced severe hypersensitivity reaction: Role of IgE‐dependent basophil activation and FcεRI

Transmembrane features governing Fc receptor CD16A assembly with CD16A signaling adaptor molecules

FcγRIII (CD16) equips immature 6-sulfo LacNAc–expressing dendritic cells (slanDCs) with a unique capacity to handle IgG-complexed antigens

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