Though binding sites for the complement factor C1q and the canonical fragment crystallizable (Fc) gamma receptors (Fc\(\gamma\)Rs) on immunoglobulin G (IgG) molecules overlap, how C1q decoration of immune complexes (ICs) influences their ability to engage Fc\(\gamma\)Rs remains unknown. In this report, we use recombinant human Fc multimers as stable IC mimics to show that C1q engagement of ICs directly and transiently inhibits their interactions with Fc\(\gamma\)RIII (CD16) on human natural killer (NK) cells. This inhibition occurs by C1q engagement alone as well as in concert with other serum factors. Furthermore, the inhibition of Fc\(\gamma\)RIII engagement mediated by avid binding of C1q to ICs is directly associated with IC size and dependent on the concentrations of both C1q and Fc multimers present. Functionally, C1q-mediated Fc blockade limits the ability of NK cells to induce the upregulation of the cosignaling molecule, 4-1BB (CD137), and to mediate antibody-dependent cell-mediated cytotoxicity (ADCC). Although C1q is traditionally viewed as a soluble effector molecule, we demonstrate that C1q may also take on the role of an “immunologic rheostat,” buffering Fc\(\gamma\)R-mediated activation of immune cells by circulating ICs. These data define a novel role for C1q as a regulator of immune homeostasis and add to our growing understanding that complement factors mediate pleiotropic effects.

尽管补体因子 C1q 和免疫球蛋白 G (IgG) 分子上的典型片段可结晶 (Fc) γ 受体 (Fc \(\gamma\) Rs) 的结合位点重叠，但免疫复合物 (IC) 的 C1q 修饰如何影响它们的能力参与 Fc \(\gamma\) Rs 仍然未知。在本报告中，我们使用重组人 Fc 多聚体作为稳定的 IC 模拟物，以证明 IC 的 C1q 接合直接且短暂地抑制它们与人自然杀伤 (NK) 细胞上的 Fc \(\gamma\) RIII (CD16) 的相互作用。这种抑制作用是由 C1q 单独参与以及与其他血清因子共同作用而发生的。此外，C1q 与 IC 的强烈结合介导的 Fc \(\gamma\) RIII 接合抑制与 IC 大小直接相关，并且取决于存在的 C1q 和 Fc 多聚体的浓度。从功能上来说，C1q 介导的 Fc 阻断限制了 NK 细胞诱导共信号分子 4-1BB (CD137) 上调以及介导抗体依赖性细胞介导的细胞毒性 (ADCC) 的能力。尽管 C1q 传统上被视为可溶性效应分子，但我们证明 C1q 也可能发挥“免疫变阻器”的作用，通过循环 IC 缓冲 Fc \(\gamma\) R 介导的免疫细胞激活。这些数据定义了 C1q 作为免疫稳态调节剂的新作用，并加深了我们对补体因子介导多效性作用的日益了解。