Schmidt Silvia K, Müller Anika, Heseler Kathrin, Woite Claudia, Spekker Katrin, MacKenzie Colin R, Däubener Walter
Institute of Medical Microbiology and Hospital Hygiene, Heinrich-Heine-University, Düsseldorf 40225, Germany.
Eur J Immunol. 2009 Oct;39(10):2755-64. doi: 10.1002/eji.200939535.
In mammals, the regulation of local tryptophan concentrations by the IFN-gamma-i inducible enzyme IDO is a prominent antimicrobial and immunoregulatory effector mechanism. Here, we show for the first time that another tryptophan-degrading enzyme, the liver-specific tryptophan 2,3-dioxygenase (TDO), is also capable of mediating antimicrobial and immunoregulatory effects. Using a tetracycline inducible eukaryotic system, we were able to express recombinant TDO protein, which exhibits functional properties of native TDO. We found that HeLa cells expressing recombinant TDO were capable of inhibiting the growth of bacteria (Staphylococcus aureus), parasites (Toxoplasma gondii) and viruses (herpes simplex virus). These TDO-mediated antimicrobial effects could be blocked by the addition of tryptophan. In addition, we observed that, similar to IDO-positive cells, TDO-positive cells were capable of inhibiting anti CD3-driven T-cell proliferation and IFN-gamma production. Furthermore, TDO-positive cells also restricted alloantigen-induced T-cell activation. Here, we describe for the first time that TDO mediates antimicrobial and immunoregulatory effects and suggest that TDO-dependent inhibition of T-cell growth might be involved in the immunotolerance observed in vivo during allogeneic liver transplantation.
在哺乳动物中，由干扰素γ诱导的酶吲哚胺2,3-双加氧酶（IDO）对局部色氨酸浓度的调节是一种重要的抗菌和免疫调节效应机制。在此，我们首次表明另一种色氨酸降解酶，肝脏特异性色氨酸2,3-双加氧酶（TDO），也能够介导抗菌和免疫调节作用。利用四环素诱导的真核系统，我们能够表达重组TDO蛋白，其具有天然TDO的功能特性。我们发现表达重组TDO的HeLa细胞能够抑制细菌（金黄色葡萄球菌）、寄生虫（弓形虫）和病毒（单纯疱疹病毒）的生长。这些TDO介导的抗菌作用可通过添加色氨酸来阻断。此外，我们观察到，与IDO阳性细胞类似，TDO阳性细胞能够抑制抗CD3驱动的T细胞增殖和干扰素γ的产生。此外，TDO阳性细胞还限制了同种异体抗原诱导的T细胞活化。在此，我们首次描述了TDO介导抗菌和免疫调节作用，并表明TDO依赖性抑制T细胞生长可能参与了同种异体肝移植过程中体内观察到的免疫耐受。
