C1q limits dendritic cell differentiation and activation by engaging LAIR-1
C1q limits dendritic cell differentiation and activation by engaging LAIR-1
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DOI：
10.1073/pnas.1212753109
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发表时间：
2012-11-13
影响因子：
11.1
通讯作者：
Diamond, Betty
中科院分区：
文献类型：
--
作者：
Son, Myoungsun;Santiago-Schwarz, Frances;Diamond, Betty
补体的第一组分C1 q和造血细胞上表达的抑制性受体白细胞相关Ig样受体1（LAIR-1; CD 305）均与单核细胞衍生的树突状细胞（DC）分化的停滞和浆细胞样DC中Toll样受体活性的抑制相关。这两种分子的缺陷与系统性红斑狼疮的易感性和进展有关。单核细胞和树突状细胞上C1 q的抑制性信号传导伴侣仍不确定。由于C1 q含有胶原样基序，LAIR-1是一种通用的胶原受体，我们假设C1 q是LAIR-1的功能性配体。无细胞系统和细胞膜上的结合分析表明，C1 q及其胶原尾部与LAIR-1和LAIR-2（CD 306）（LAIR-1的可溶性抑制剂）相关。C1 q和它的胶原蛋白尾都触发单核细胞中LAIR-1免疫受体酪氨酸抑制基序（ITIM）的磷酸化。功能分析表明，C1 q介导的单核细胞-DC分化的抑制和C1 q介导的浆细胞样DC产生IFN-α的抑制都被LAIR-2逆转。此外，C1 q介导的DC分化抑制被LAIR-1 siRNA逆转。因此，C1 q是LAIR-1限制免疫细胞分化和活化的功能性配体。C1 q与LAIR-1和LAIR-2相互作用的发现为防止耐受性丧失的分子机制提供了急需的见解，特别是在系统性红斑狼疮中。
C1q, the first component of complement, and leukocyte-associated Ig-like receptor 1 (LAIR-1; CD305), an inhibitory receptor expressed on hematopoietic cells, have both been associated with arrest of monocyte-derived dendritic cell (DC) differentiation and inhibition of Toll-like receptor activity in plasmacytoid DCs. Defects in both molecules have been implicated in susceptibility to, and progression of, systemic lupus erythematosus. Inhibitory signaling partners for C1q on monocytes and DCs remain undefined. Because C1q contains collagen-like motifs and LAIR-1 is a universal collagen receptor, we hypothesized that C1q is a functional ligand for LAIR-1. Binding analyses in cell-free systems and on the cell membrane demonstrate that C1q and its collagen tail associate with LAIR-1 and LAIR-2 (CD306), a soluble inhibitor of LAIR-1. Both C1q and its collagen tail trigger phosphorylation of LAIR-1 immunoreceptor tyrosine-based inhibitory motifs (ITIMs) in monocytes. Functional analyses show that C1q-mediated inhibition of monocyte-DC differentiation and C1q-mediated inhibition of IFN-alpha production by plasmacytoid DCs were both reversed by LAIR-2. Moreover, C1q-mediated inhibition of DC differentiation was reversed by LAIR-1 siRNA. Thus, C1q is a functional ligand for LAIR-1 restricting immune cell differentiation and activation. The discovery of C1q interactions with LAIR-1 and LAIR-2 lends much needed insight into molecular mechanisms operating to prevent the loss of tolerance, particularly in systemic lupus erythematosus.