The DC-HIL/syndecan-4 pathway inhibits human allogeneic T-cell responses.
The DC-HIL/syndecan-4 pathway inhibits human allogeneic T-cell responses.
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DOI：
10.1002/eji.200838990
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发表时间：
2009-04
影响因子：
5.4
通讯作者：
Ariizumi, Kiyoshi
中科院分区：
文献类型：
--
作者：
Chung, Jin-Sung;Bonkobara, Makoto;Tomihari, Mizuki;Cruz, Ponciano A., Jr.;Ariizumi, Kiyoshi
T细胞活化通过抗原呈递细胞（APC）上的配体与T细胞上的相应受体的结合来调节。在小鼠中，我们发现APC上的DC-HIL与活化的T细胞上的多配体蛋白聚糖-4（SD-4）的结合有效地抑制T细胞活化。在人类中，我们现在表明DC-HIL也通过识别其肝素酶敏感的糖部分与活化T细胞上的SD-4结合。DC-HIL阻断抗CD 3诱导的T细胞应答，减少促炎细胞因子的分泌并阻断进入细胞周期的S期。DC-HIL的结合使SD-4的细胞内酪氨酸和丝氨酸残基磷酸化。抗SD-4 Ab模拟DC-HIL比针对其他抑制性受体（CTLA-4或PD-1）的Ab更有效地减弱抗CD 3应答的能力。在白细胞中，CD 14+单核细胞表达DC-HIL最高，并且这种表达可以被TGF-β显著上调。在APC中，DC-HIL由表皮朗格汉斯细胞（一种未成熟类型的树突状细胞）表达最高。最后，CD 14+单核细胞上DC-HIL的表达水平与同种异体刺激能力呈负相关，因此用TGF-β治疗降低了这种能力，而敲低DC-HIL基因则增强了这种能力。我们的研究结果表明，DC-HIL/SD-4通路可以被操纵来治疗人类T细胞驱动的疾病。
T cell activation is regulated by binding of ligands on antigen presenting cells (APC) to corresponding receptors on T cells. In mice, we discovered that binding of DC-HIL on APC to syndecan-4 (SD-4) on activated T cells potently inhibits T cell activation. In humans, we now show that DC-HIL also binds to SD-4 on activated T cells through recognition of its heparinase-sensitive saccharide moiety. DC-HIL blocks anti-CD3-induced T cell responses, reducing secretion of pro-inflammatory cytokines and blocking entry into the S phase of the cell cycle. Binding of DC-HIL phosphorylates SD-4’s intracellular tyrosine and serine residues. Anti-SD-4 Ab mimics the ability of DC-HIL to attenuate anti-CD3 response more potently than Ab directed against other inhibitory receptors (CTLA-4 or PD-1). Among leukocytes, DC-HIL is expressed highest by CD14+ monocytes and this expression can be upregulated markedly by TGF-β. Among APC, DC-HIL is expressed highest by epidermal Langerhans cells, an immature type of dendritic cells. Finally, the level of DC-HIL expression on CD14+ monocytes correlates inversely with allostimulatory capacity, such that treatment with TGF-β reduced this capacity, whereas knocking-down the DC-HIL gene augmented it. Our findings indicate that the DC-HIL/SD-4 pathway can be manipulated to treat T cell-driven disorders in humans.
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影响因子：
4.4
作者：
Chemnitz, JM;Parry, RV;Riley, JL
通讯作者：
Riley, JL
影响因子：
30.5
作者：
Latchman, Y;Wood, CR;Freeman, GJ
通讯作者：
Freeman, GJ
影响因子：
30.5
作者：
Sabatos, CA;Chakravarti, S;Kuchroo, VK
通讯作者：
Kuchroo, VK
影响因子：
4.8
作者：
Horowitz, A;Simons, M
通讯作者：
Simons, M
DOI：
10.1073/pnas.0708350105
发表时间：
2008-02-19
影响因子：
11.1
作者：
Esquerre, Michael;Tauzin, Baptiste;Valitutti, Salvatore
通讯作者：
Valitutti, Salvatore