Satoguina Judith S, Adjobimey Tomabu, Arndts Kathrin, Hoch Jochen, Oldenburg Johannes, Layland Laura E, Hoerauf Achim
Institute of Medical Microbiology, Immunology and Parasitology, University Clinic Bonn, Bonn, Germany.
Eur J Immunol. 2008 Nov;38(11):3101-13. doi: 10.1002/eji.200838193.
Regulatory T cells exert their function through the modulation of both T and B cell responses. Our previous studies demonstrated that IL-10-producing Treg (Tr1) can induce B cells to secrete IgG4 in a cell-contact-dependent manner. The benefit of such non-inflammatory B-cell responses is apparent in the hyporesponsive state of patients with helminth infections such as Onchocerciasis. Here, we investigated the mechanisms involved to induce IgG4, within B:Tr-cell co-cultures, using IL-10-producing tetanus-toxoid-specific regulatory T cell lines and clones (Tr-TCC) from human PBMC. During the generation process, we found that increasing Foxp3 levels in regulatory T cell lines correlated with their ability to induce IgG4 in B cells. Using Tr-TCC, we found that blocking glucocorticoid-induced tumour necrosis factor receptor-related protein (GITR) molecules selectively prevented IgG4 production as did neutralizing Ab to glucocorticoid-induced tumour necrosis factor receptor-related protein ligand (GITR-L), IL-10 and TGF-beta. Furthermore, the prevention of IgG4 induction by anti-GITR Ab was reversed by excess rIL-10 but not rTGF-beta. In contrast, anti-ICOS and anti-CTLA-4 Abs had no effect. When compared with Tr-TCC, freshly isolated CD4+CD25+ T cells, but not effector T cell populations, induced low levels of IgG4, which were also blocked by anti-GITR and anti-GITR-L Ab. Thus, the mechanism of IgG4 induction by regulatory cells involves GITR-GITR-L interactions, IL-10 and TGF-beta.
调节性T细胞通过调节T细胞和B细胞反应发挥其功能。我们之前的研究表明，产生白细胞介素-10的调节性T细胞（Tr1）能够以细胞接触依赖的方式诱导B细胞分泌IgG4。这种非炎性B细胞反应的益处，在诸如盘尾丝虫病等蠕虫感染患者的低反应状态中很明显。在此，我们使用来自人外周血单个核细胞的产生白细胞介素-10的破伤风类毒素特异性调节性T细胞系和克隆（Tr-TCC），研究了B细胞与Tr细胞共培养体系中诱导IgG4产生的机制。在生成过程中，我们发现调节性T细胞系中叉头框蛋白3（Foxp3）水平的增加与其诱导B细胞产生IgG4的能力相关。使用Tr-TCC，我们发现阻断糖皮质激素诱导的肿瘤坏死因子受体相关蛋白（GITR）分子，以及中和抗糖皮质激素诱导的肿瘤坏死因子受体相关蛋白配体（GITR-L）、白细胞介素-10和转化生长因子-β（TGF-β）的抗体，均能选择性地阻止IgG4的产生。此外，抗GITR抗体对IgG4诱导的抑制作用可被过量的重组白细胞介素-10（rIL-10）逆转，但不能被重组转化生长因子-β（rTGF-β）逆转。相比之下，抗诱导共刺激分子（ICOS）抗体和抗细胞毒性T淋巴细胞相关蛋白4（CTLA-4）抗体则没有作用。与Tr-TCC相比，新鲜分离的CD4⁺CD25⁺ T细胞而非效应T细胞群体，诱导产生的IgG4水平较低，且也被抗GITR和抗GITR-L抗体所阻断。因此，调节性细胞诱导IgG4产生的机制涉及GITR-GITR-L相互作用、白细胞介素-10和转化生长因子-β。
