CD8⁺无反应性T细胞中相互作用的NFAT1和NFAT2核定位受次优钙信号调节。

Reciprocal NFAT1 and NFAT2 nuclear localization in CD8+ anergic T cells is regulated by suboptimal calcium signaling.

作者信息

Srinivasan Mathangi, Frauwirth Kenneth A

机构信息

Department of Cell Biology and Molecular Genetics, University of Maryland, College Park, MD 20742, USA.

出版信息

J Immunol. 2007 Sep 15;179(6):3734-41. doi: 10.4049/jimmunol.179.6.3734.

DOI:10.4049/jimmunol.179.6.3734

PMID:17785810

Abstract

Anergy is an important mechanism of maintaining peripheral immune tolerance. T cells rendered anergic are refractory to further stimulation and are characterized by defective proliferation and IL-2 production. We used a model of in vivo anergy induction in murine CD8+ T cells to analyze the initial signaling events in anergic T cells. Tolerant T cells displayed reduced phospholipase Cgamma activation and calcium mobilization, indicating a defect in calcium signaling. This correlated with a block in nuclear localization of NFAT1 in anergic cells. However, we found that stimulation of anergic, but not naive T cells induced nuclear translocation of NFAT2. This suggested that NFAT2 is activated preferentially by reduced calcium signaling, and we confirmed this hypothesis by stimulating naive T cells under conditions of calcium limitation or partial calcineurin inhibition. Thus, our work provides new insight into how T cell stimulation conditions might dictate specific NFAT isoform activation and implicates NFAT2 involvement in the expression of anergy-related genes.

摘要

无反应性是维持外周免疫耐受的重要机制。处于无反应状态的T细胞对进一步刺激具有抗性，其特征为增殖缺陷和白细胞介素-2生成缺陷。我们利用小鼠CD8+ T细胞体内无反应性诱导模型来分析无反应性T细胞中的初始信号事件。耐受T细胞表现出磷脂酶Cγ激活和钙动员减少，表明钙信号存在缺陷。这与无反应性细胞中NFAT1的核定位受阻相关。然而，我们发现刺激无反应性T细胞而非初始T细胞可诱导NFAT2的核转位。这表明NFAT2优先通过降低的钙信号被激活，并且我们通过在钙限制或部分钙调神经磷酸酶抑制条件下刺激初始T细胞证实了这一假设。因此，我们的工作为T细胞刺激条件如何决定特定NFAT异构体激活提供了新的见解，并表明NFAT2参与无反应性相关基因的表达。