Unité Mixte de Recherche 8147, Centre National de la Recherche Scientifique, Faculté de Médecine René Descartes, Paris V, Hôpital Necker, 75015 Paris, France.
J Immunol. 2012 Jan 15;188(2):624-31. doi: 10.4049/jimmunol.1102281. Epub 2011 Dec 12.
Invariant NKT (iNKT) cells constitute a versatile T cell subset with important regulatory functions, which are thought to result essentially from their capacity to promptly produce cytokines that influence the Th1/Th2 balance. In this study, we report that these cells can also express Foxp3, an important transcriptional regulator associated with suppressive activity, once they have been exposed to TGF-β. Foxp3 was expressed by iNKT cells from both peripheral and cord blood. CD4(+) iNKT cells acquired Foxp3 expression preferentially, although a lower proportion of their CD4(-) counterpart also became positive. All Foxp3(+) iNKT cells displayed CD25 but not necessarily CTLA4 or GITR, regardless of the upregulation of these markers in the presence of TGF-β. Exposure to TGF-β decreased IL-4 and IFN-γ production while increasing IL-10, independently from Foxp3 expression. IL-17 was not detected. TGF-β induced high levels of Foxp3, but no suppressor activity, which emerged only in the presence of rapamycin. Peripheral and cord blood Foxp3(+) iNKT cells suppressed the proliferation of conventional autologous and heterologous CD4(+) T cells equally, in a cell contact-dependent and Ag-independent manner. Our findings demonstrate that human iNKT cells become suppressive in the presence of TGF-β plus rapamycin, thus adding a new facet to their complex functional properties.
不变自然杀伤 T(iNKT)细胞是具有重要调节功能的多功能 T 细胞亚群，其功能被认为主要来自其迅速产生细胞因子的能力，这些细胞因子影响 Th1/Th2 平衡。在这项研究中，我们报告称，这些细胞在接触 TGF-β后也可以表达 Foxp3，Foxp3 是一种与抑制活性相关的重要转录调节因子。外周血和脐血中的 iNKT 细胞均可表达 Foxp3。CD4+iNKT 细胞优先获得 Foxp3 表达，尽管其 CD4- 对应物的比例较低，但也呈阳性。所有 Foxp3+iNKT 细胞均表达 CD25，但不一定表达 CTLA4 或 GITR，无论 TGF-β 是否上调这些标志物。暴露于 TGF-β 可减少 IL-4 和 IFN-γ 的产生，同时增加 IL-10 的产生，这与 Foxp3 的表达无关。未检测到 IL-17。TGF-β 诱导高水平的 Foxp3，但无抑制活性，只有在存在雷帕霉素的情况下才会出现抑制活性。外周血和脐血 Foxp3+iNKT 细胞以细胞接触依赖和抗原非依赖的方式，同等抑制自身和异体 CD4+T 细胞的增殖。我们的研究结果表明，人 iNKT 细胞在 TGF-β 加雷帕霉素的存在下具有抑制作用，从而为其复杂的功能特性增加了一个新的方面。
