Activating and inhibitory IgG Fc receptors on human DCs mediate opposing functions
Activating and inhibitory IgG Fc receptors on human DCs mediate opposing functions
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DOI：
10.1172/jci24772
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发表时间：
2005-10-01
影响因子：
15.9
通讯作者：
Young, JW
中科院分区：
文献类型：
--
作者：
Boruchov, AM;Heller, G;Young, JW
人单核细胞衍生的DC（moDC）和循环常规DC共表达IgG Fc γ受体（Fc γ R）II（CD 32）的活化（CD 32a）和抑制（CD 32 b）同种型。这些不同受体之间的平衡建立了DC激活的阈值，并使免疫复合物能够介导对DC成熟和功能的相反作用。IFN-γ最有效地促进未成熟DC上的CD 32a表达，而可溶性抗炎浓度的单体IgG具有相反的作用。CD 32a的连接导致DC成熟，增加对同种异体T细胞的刺激，以及增加炎性细胞因子（IL-12 p70除外）的分泌。CD 32 b的共配限制了通过CD 32a的活化，因此降低了moDC的免疫原性，即使对于强刺激如同种异体抗原也是如此。单独靶向CD 32 b不会使DC成熟或活化，而是维持不成熟状态。DC共表达激活性和抑制性Fc γ R揭示了通过免疫复合物诱导耐受或免疫的稳态检查点。这些发现对于理解免疫复合物疾病的病理生理学和优化治疗性mAb的功效具有重要意义。这些数据还提示了将抗原靶向人DC上的激活性或抑制性Fc γ R以产生抗原特异性免疫或耐受性的新策略。
Human monocyte-derived DCs (moDCs) and circulating conventional DCs coexpress activating (CD32a) and inhibitory (CD32b) isoforms of IgG Fc gamma receptor (Fc gamma R)II (CD32). The balance between these divergent receptors establishes a threshold of DC activation and enables immune complexes to mediate opposing effects on DC maturation and function. IFN-gamma most potently favors CD32a expression on immature DCs, whereas soluble antinflammatory concentrations of monomeric IgG have the opposite effect. Ligation of CD32a leads to DC maturation, increased stimulation of allogeneic T cells, and enhanced secretion of inflammatory cytokines, with the exception of IL-12p70. Coligation of CD32b limits activation through CD32a and hence reduces the immunogenicity of moDCs even for a strong stimulus like alloantigen. Targeting CD32b alone does not mature or activate DCs but rather maintains an immature state. Coexpression of activating and inhibitory Fc gamma Rs by DCs reveals a homeostatic checkpoint for inducing tolerance or immunity by immune complexes. These findings have important implications for understanding the pathophysiology of immune complex diseases and for optimizing the efficacy of therapeutic mAbs. The data also suggest novel strategies for targeting antigens to the activating or inhibitory Fc gamma Rs on human DCs to generate either antigen-specific immunity or tolerance.