School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
J Immunol. 2013 Aug 15;191(4):1536-46. doi: 10.4049/jimmunol.1203571. Epub 2013 Jul 12.
Although the pathways that permit IL-2 production and the full activation of T cells upon Ag encounter are fairly well defined, the negative regulatory circuits that limit these pathways are poorly understood. In this study, we show that the E3 ubiquitin ligase adaptor Ndfip1 directs one such negative regulatory circuit. T cells lacking Ndfip1 produce IL-2, upregulate IL-2Rα, and proliferate, in the absence of CD28 costimulation. Furthermore, T cells in mice lacking both Ndfip1 and CD28 become activated, produce IL-4, and drive inflammation at barrier surfaces. Ndfip1 constrains T cell activation by limiting the duration of IL-2 mRNA expression after TCR stimulation. Ndfip1 and IL-2 have a similar expression pattern, and, following TCR stimulation, expression of both Ndfip1 and IL-2 requires the activity of NFAT and Erk. Taken together, these data support a negative regulatory circuit in which factors that induce IL-2 expression downstream of TCR engagement also induce the expression of Ndfip1 to limit the extent of IL-2 production and, thus, dampen T cell activation.
虽然允许白细胞介素-2 (IL-2) 产生和 T 细胞在遇到抗原时完全激活的途径已经相当明确，但限制这些途径的负调控回路却知之甚少。在这项研究中，我们表明 E3 泛素连接酶衔接蛋白 Ndfip1 指导着这样一个负调控回路。缺乏 Ndfip1 的 T 细胞在没有 CD28 共刺激的情况下产生 IL-2、上调 IL-2Rα，并增殖。此外，缺乏 Ndfip1 和 CD28 的小鼠中的 T 细胞被激活，产生 IL-4，并在屏障表面引发炎症。Ndfip1 通过限制 TCR 刺激后 IL-2 mRNA 表达的持续时间来限制 T 细胞的激活。Ndfip1 和 IL-2 的表达模式相似，在 TCR 刺激后，Ndfip1 和 IL-2 的表达都需要 NFAT 和 Erk 的活性。综上所述，这些数据支持一个负调控回路，其中诱导 TCR 结合下游 IL-2 表达的因素也诱导 Ndfip1 的表达，以限制 IL-2 产生的程度，从而抑制 T 细胞激活。
