de Haij Simone, Woltman Andrea M, Trouw Leendert A, Bakker Astrid C, Kamerling Sylvia W, van der Kooij Sandra W, Chen Lieping, Kroczek Richard A, Daha Mohamed R, van Kooten Cees
Department of Nephrology, Leiden University Medical Center, The Netherlands.
Kidney Int. 2005 Nov;68(5):2091-102. doi: 10.1111/j.1523-1755.2005.00665.x.
Renal tubular epithelial cells (TECs) play an active role in renal inflammation. Previous studies have demonstrated the capacity of TECs to modulate T-cell responses both positively and negatively. Recently, new costimulatory molecules [inducible T cell costimulator-L (ICOS-L) and B7-H1] have been described, which appear to be involved in peripheral T-cell activation.
We characterized expression and regulation of costimulatory molecules on primary human TECs and the TEC line human kidney-2 (HK-2) with reverse transcription-polymerase chain reaction (RT-PCR) and flow cytometry. Immunohistochemistry was performed on human kidney biopsies. The capacity of TECs to modulate T-cell activation was studied in TEC/T-cell cultures.
We demonstrate that TECs express ICOS-L and B7-H1 in vitro and in vivo. Stimulation with interferon-gamma (IFN-gamma) resulted in increased expression of B7-H1, whereas ICOS-L expression was marginally increased upon stimulation with CD40L, with no effect of interleukin (IL-1), IL-17, or tumor necrosis factor-alpha (TNF-alpha). Furthermore, we show that TECs are able to costimulate T cells that have received signal-1 using alphaCD3 antibodies, inducing strong IL-10 production, which was partially mediated by ICOS-L. In contrast, B7-H1 appeared to be involved in inhibition of proliferation and cytokine synthesis. In addition, TECs were able to alter the cytokine profile of fully activated T cells, which were incubated with alphaCD3 and alphaCD28 antibodies, resulting in low IFN-gamma and high IL-10 production. This activity appeared to be independent of ICOS-L and B7-H1.
Interaction of tubular epithelial cells and kidney infiltrating T cells via ICOS-L and B7-H1 may change the balance of positive and negative signals to the T cells, leading to IL-10 production and limitation of local immune responses.
肾小管上皮细胞(TECs)在肾脏炎症中发挥积极作用。既往研究已证实TECs具有正向和负向调节T细胞反应的能力。最近,新的共刺激分子[诱导性T细胞共刺激分子-L(ICOS-L)和B7-H1]已被描述,它们似乎参与外周T细胞的激活。
我们采用逆转录-聚合酶链反应(RT-PCR)和流式细胞术对原代人TECs和TEC系人肾-2(HK-2)细胞上共刺激分子的表达及调节进行了表征。对人肾活检组织进行免疫组织化学检测。在TEC/T细胞培养物中研究了TECs调节T细胞激活的能力。
我们证明TECs在体外和体内均表达ICOS-L和B7-H1。用γ干扰素(IFN-γ)刺激导致B7-H1表达增加,而用CD40L刺激时ICOS-L表达略有增加,白细胞介素(IL-1)、IL-17或肿瘤坏死因子-α(TNF-α)刺激则无影响。此外,我们表明TECs能够使用αCD3抗体共刺激已接受信号1的T细胞,诱导强烈的IL-10产生,这部分由ICOS-L介导。相比之下,B7-H1似乎参与抑制增殖和细胞因子合成。此外,TECs能够改变与αCD3和αCD28抗体孵育的完全活化T细胞的细胞因子谱,导致低水平的IFN-γ和高水平的IL-10产生。这种活性似乎独立于ICOS-L和B7-H1。
肾小管上皮细胞与肾内浸润T细胞通过ICOS-L和B7-H1相互作用可能改变T细胞正负信号的平衡,导致IL-10产生并限制局部免疫反应。