Distinct effector functions mediated by Fc regions of bovine IgG subclasses and their interaction with Fc gamma receptors.
Distinct effector functions mediated by Fc regions of bovine IgG subclasses and their interaction with Fc gamma receptors.
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DOI：
10.3389/fimmu.2023.1286903
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发表时间：
2023
影响因子：
7.3
通讯作者：
中科院分区：
文献类型：
--
作者：
牛具有三个IgG亚类。然而，牛IgG 1、2和3的关键免疫功能（包括补体和NK细胞活化以及吞噬作用增强）尚未得到充分描述。我们生产了嵌合单克隆抗体（mAb），其由与牛IgG 1、2和3恒定区连接的定义可变区组成，并表达His标记的可溶性重组牛Fc γ受体（Fcγ R）IA（CD 64）、IIA（CD 32A）、III（CD 16）和Fcγ 2 R。开发了使用牛源化mAb的功能测定。IgG 1和IgG 3，而不是IgG 2，激活补体依赖性细胞毒性。只有IgG 1可以激活牛NK细胞动员抗原交联后的CD 107 a，抗体依赖性细胞毒性的替代试验。IgG 1和IgG 2均能触发单核细胞源性巨噬细胞吞噬荧光标记的抗原表达靶细胞。IgG 3仅诱导弱的抗体依赖性细胞吞噬作用（ADCP）。相比之下，单核细胞仅在IgG 2触发时表现出强ADCP。IgG 1与重组FcγRs IA、IIA和III的结合最强，IgG 3的结合较弱，IgG 2无结合，IgG 2仅与Fcγ 2 R结合。含有IgG 1、2和3的免疫复合物与白细胞亚群的结合有差异，IgG 2与中性粒细胞和单核细胞的结合强烈，而所有亚类与血小板的结合强烈。通过分选细胞的表面染色和/或RT-qPCR证明Fcγ R在白细胞亚群上的差异表达，例如，Fcγ 2 R mRNA在单核细胞/巨噬细胞、中性粒细胞和血小板中表达，可能解释了其与IgG 2的强相互作用，FcγRIII在NK细胞上表达，推测介导IgG 1依赖性NK细胞活化。这些数据揭示了牛IgG亚类功能性的差异，其与人、小鼠或猪中描述的功能性不一致，这与疫苗和治疗性抗体开发中这些IgG亚类的研究相关。
Cattle possess three IgG subclasses. However, the key immune functions, including complement and NK cell activation, and enhancement of phagocytosis, are not fully described for bovine IgG1, 2 and 3. We produced chimeric monoclonal antibodies (mAbs) consisting of a defined variable region linked to the constant regions of bovine IgG1, 2 and 3, and expressed His-tagged soluble recombinant bovine Fc gamma receptors (FcγRs) IA (CD64), IIA (CD32A), III (CD16) and Fcγ2R. Functional assays using bovinized mAbs were developed. IgG1 and IgG3, but not IgG2, activated complement-dependent cytotoxicity. Only IgG1 could activate cattle NK cells to mobilize CD107a after antigen crosslinking, a surrogate assay for antibody-dependent cell cytotoxicity. Both IgG1 and IgG2 could trigger monocyte-derived macrophages to phagocytose fluorescently labelled antigen-expressing target cells. IgG3 induced only weak antibody-dependent cellular phagocytosis (ADCP). By contrast, monocytes only exhibited strong ADCP when triggered by IgG2. IgG1 bound most strongly to recombinant FcγRs IA, IIA and III, with weaker binding by IgG3 and none by IgG2, which bound exclusively to Fcγ2R. Immune complexes containing IgG1, 2 and 3 bound differentially to leukocyte subsets, with IgG2 binding strongly to neutrophils and monocytes and all subclasses binding platelets. Differential expression of the FcγRs on leukocyte subsets was demonstrated by surface staining and/or RT-qPCR of sorted cells, e.g., Fcγ2R mRNA was expressed in monocytes/macrophages, neutrophils, and platelets, potentially explaining their strong interactions with IgG2, and FcγRIII was expressed on NK cells, presumably mediating IgG1-dependent NK cell activation. These data reveal differences in bovine IgG subclass functionality, which do not correspond to those described in humans, mice or pigs, which is relevant to the study of these IgG subclasses in vaccine and therapeutic antibody development.
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