Binding of DC-HIL to Dermatophytic Fungi Induces Tyrosine Phosphorylation and Potentiates Antigen Presenting Cell Function
Binding of DC-HIL to Dermatophytic Fungi Induces Tyrosine Phosphorylation and Potentiates Antigen Presenting Cell Function
复制标题
DOI：
10.4049/jimmunol.0901319
复制
发表时间：
2009-10-15
影响因子：
4.4
通讯作者：
Ariizumi, Kiyoshi
中科院分区：
文献类型：
--
作者：
Chung, Jin-Sung;Yudate, Tatsuo;Ariizumi, Kiyoshi
APC表达识别微生物的受体，并通过与免疫细胞上的相应配体结合来调节免疫应答。在发现了通过APC上的DC-HIL与活化的T细胞上的多配体蛋白聚糖-4的肝素/硫酸乙酰肝素样糖的连接触发的新的抑制途径之后，我们假设DC-HIL可以以类似的方式识别微生物病原体。我们发现可溶性重组DC-HIL结合皮肤真菌红色毛癣菌和奥杜氏小孢子菌，但不是几种细菌，也不是白色念珠菌。加入肝素可完全抑制皮肤癣菌结合。由于DC-HIL含有ITAM样细胞内序列，我们质疑其与皮肤真菌的结合是否能诱导树突状细胞（DC）中的酪氨酸磷酸化。用T.红色（但不是白色念珠菌假菌丝）诱导DC-HIL的磷酸化，但不是当ITAM样序列的酪氨酸残基突变为苯丙氨酸。为了研究这种信号在DC上的功能意义，我们将DC-HIL与mAb（替代配体）交联，其不仅诱导酪氨酸磷酸化，而且通过基因阵列分析上调了662个基因中的23个基因的表达，包括profilin-1、富含豆蔻酰化丙氨酸的蛋白激酶C底物样-1、C/EBP、LOX-1、IL-1 β和TNF-α的基因。这种交联还上调了活化标志物CD 80/CD 86的表达，并提高了DC活化同基因T细胞的APC能力。我们的研究结果支持了DC-HIL的双重作用：在激活的T细胞上连接多配体蛋白聚糖-4后抑制获得性免疫，以及诱导针对皮肤真菌的先天免疫。免疫学杂志，2009，183：5190-5198.
APCs express receptors recognizing microbes and regulating immune responses by binding to corresponding ligands on immune cells. Having discovered a novel inhibitory pathway triggered by ligation of DC-HIL on APC to a heparin/heparan sulfate-like saccharide of syndecan-4 on activated T cells, we posited DC-HIL can recognize microbial pathogens in a similar manner. We showed soluble recombinant DC-HIL to bind the dermatophytes Trichophyton rubrum and Microsporum audouinii, but not several bacteria nor Candida albicans. Dermatophyte binding was inhibited completely by the addition of heparin. Because DC-HIL contains an ITAM-like intracellular sequence, we questioned whether its binding to dermatophytes can induce tyrosine phosphorylation in dendritic cells (DC). Culturing DC with T. rubrum (but not with C albicans pseudohyphae) induced phosphorylation of DC-HIL, but not when the tyrosine residue of the ITAM-like sequence was mutated to phenylalanine. To examine the functional significance of such signaling on DC, we cross-linked DC-HIL with mAb (surrogate ligand), which not only induced tyrosine phosphorylation but also up-regulated expression of 23 genes among 662 genes analyzed by gene-array, including genes for profilin-1, myristoylated alanine rich protein kinase C substrate like-1, C/EBP, LOX-1, IL-1 beta, and TNF-alpha. This cross-linking also up-regulated expression of the activation markers CD80/CD86 and heightened APC capacity of DC to activate syngeneic T cells. Our findings support a dual role for DC-HIL: inhibition of adaptive immunity following ligation of syndecan-4 on activated T cells and induction of innate immunity against dermatophytic fungi. The Journal of Immunology, 2009, 183: 5190-5198.