Pankratz Susann, Bittner Stefan, Herrmann Alexander M, Schuhmann Michael K, Ruck Tobias, Meuth Sven G, Wiendl Heinz
Department of Neurology and.
Department of Neurology, University of Würzburg, Würzburg, Germany.
FASEB J. 2014 Aug;28(8):3435-45. doi: 10.1096/fj.14-251074. Epub 2014 Apr 17.
CD4(+) T cells expressing the immunotolerizing molecule HLA-G have been described as a unique human thymus-derived regulatory T (tTreg) cell subset involved in immunoregulation and parenchymal homeostasis during infectious and autoimmune inflammation. We compared properties and molecular characteristics of human CD4(+)HLA-G(+) with those of CD4(+)CD25(+)FoxP3-expressing tTreg cells using in vitro studies of T-cell receptor (TCR) signaling, single-cell electrophysiology, and functional in vivo studies. Both tTreg populations are characterized by alterations in proximal-signaling pathways on TCR stimulation and a hyperpolarization of the plasma membrane when compared to conventional CD4(+) T cells. However, both clearly differ in phenotype and pattern of secreted cytokines, which results in distinct mechanisms of suppression: While CD4(+)HLA-G(+) cells secrete high levels of inhibitory molecules (IL-10, soluble HLA-G, IL-35), CD4(+)CD25(+)FoxP3(+) cells express these molecules at significantly lower levels and seem to exert their function mainly in a contact-dependent manner via cyclic adenosine-monophosphate. Finally we demonstrate that human CD4(+)HLA-G(+) tTreg cells significantly ameliorated graft-versus-host disease in a humanized mouse model as a first proof of their in vivo relevance. Our data further characterize and establish CD4(+)HLA-G(+) cells as a potent human tTreg population that can modulate polyclonal adaptive immune responses in vivo and thus being a promising candidate for potential clinical applications in the future.
表达免疫耐受分子HLA - G的CD4(+) T细胞已被描述为一种独特的人类胸腺来源的调节性T（tTreg）细胞亚群，在感染性和自身免疫性炎症期间参与免疫调节和实质内稳态。我们使用T细胞受体（TCR）信号传导的体外研究、单细胞电生理学和体内功能研究，比较了人类CD4(+)HLA - G(+)细胞与表达CD4(+)CD25(+)FoxP3的tTreg细胞的特性和分子特征。与传统的CD4(+) T细胞相比，这两种tTreg细胞群体的特征均为TCR刺激时近端信号通路的改变以及质膜的超极化。然而，两者在表型和分泌细胞因子的模式上明显不同，这导致了不同的抑制机制：虽然CD4(+)HLA - G(+)细胞分泌高水平的抑制性分子（IL - 10、可溶性HLA - G、IL - 35），但CD4(+)CD25(+)FoxP3(+)细胞表达这些分子的水平明显较低，并且似乎主要通过环磷酸腺苷以接触依赖的方式发挥其功能。最后，我们证明人类CD4(+)HLA - G(+) tTreg细胞在人源化小鼠模型中显著改善了移植物抗宿主病，这是它们体内相关性的首个证据。我们的数据进一步表征并确立CD4(+)HLA - G(+)细胞为一种有效的人类tTreg细胞群体，其可在体内调节多克隆适应性免疫反应，因此是未来潜在临床应用的有希望的候选者。
