Lebbink Robert Jan, Raynal Nicolas, de Ruiter Talitha, Bihan Dominique G, Farndale Richard W, Meyaard Linde
Department of Immunology, University Medical Center Utrecht, Utrecht, The Netherlands.
Matrix Biol. 2009 May;28(4):202-10. doi: 10.1016/j.matbio.2009.03.005. Epub 2009 Apr 2.
Immune responses are tightly controlled by the opposing actions of activating and inhibitory immune receptors. Previously we identified collagens as ligands for the inhibitory leukocyte-associated Ig-like receptor-1 (LAIR-1), revealing a novel mechanism of peripheral immune regulation by inhibitory immune receptors binding to extracellular matrix collagens. This interaction can be blocked by LAIR-2, a secreted member of the LAIR-1 family. LAIR-1 specifically interacts with synthetic trimeric peptides containing 10 repeats of glycine-proline-hydroxyproline (GPO) residues which can directly inhibit immune cell activation in vitro. Here we studied the interaction of human LAIR-1 and LAIR-2 with collagen in more detail by using novel overlapping synthetic trimeric peptides (Toolkits) encompassing the entire triple-helical domain of human collagens II and III. LAIR-1 and LAIR-2 bind several of these collagen-like peptides, with LAIR-2 being able to bind more than LAIR-1. LAIR binding to trimeric collagen peptides was influenced by GPO content of the peptide, although additional non-GPO triplets contributed to the interaction. Furthermore, we identified several trimeric peptides that were potent LAIR-1 ligands and could efficiently induce inhibition of T cell activation and FceRI-induced degranulation of RBL-2H3 cells through binding to LAIR-1. A detailed understanding of the LAIR recognition motifs within collagen may lead to the development of potent reagents that can be used in in vitro, ex vivo, and in vivo functional studies to dissect the biology and function of the collagen/LAIR-1 interaction.
免疫反应受到激活和抑制性免疫受体相反作用的严格控制。此前我们鉴定出胶原蛋白是抑制性白细胞相关免疫球蛋白样受体-1（LAIR-1）的配体，揭示了抑制性免疫受体与细胞外基质胶原蛋白结合对外周免疫调节的新机制。这种相互作用可被LAIR-1家族的分泌成员LAIR-2阻断。LAIR-1与含有10个甘氨酸-脯氨酸-羟脯氨酸（GPO）残基重复序列的合成三聚体肽特异性相互作用，该肽在体外可直接抑制免疫细胞激活。在此，我们通过使用包含人胶原蛋白II和III整个三螺旋结构域的新型重叠合成三聚体肽（工具包），更详细地研究了人LAIR-1和LAIR-2与胶原蛋白的相互作用。LAIR-1和LAIR-2与其中几种胶原样肽结合，LAIR-2比LAIR-1能结合更多肽。LAIR与三聚体胶原肽的结合受肽的GPO含量影响，尽管其他非GPO三联体也参与了相互作用。此外，我们鉴定出几种三聚体肽是有效的LAIR-1配体，通过与LAIR-1结合可有效诱导T细胞激活抑制以及RBL-2H3细胞的FceRI诱导的脱颗粒。对胶原蛋白内LAIR识别基序的详细了解可能会促成开发有效的试剂，可用于体外、离体和体内功能研究，以剖析胶原蛋白/LAIR-1相互作用的生物学和功能。
