NFAT5 Regulates T Lymphocyte Homeostasis and CD24-Dependent T Cell Expansion under Pathologic Hypernatremia
NFAT5 Regulates T Lymphocyte Homeostasis and CD24-Dependent T Cell Expansion under Pathologic Hypernatremia
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DOI：
10.4049/jimmunol.1001232
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发表时间：
2010-12-01
影响因子：
4.4
通讯作者：
Lopez-Rodriguez, Cristina
中科院分区：
文献类型：
--
作者：
Berga-Bolanos, Rosa;Drews-Elger, Katherine;Lopez-Rodriguez, Cristina
免疫细胞依靠转录因子 NFAT5 来适应高渗应激。 NFAT5 在体内 T 细胞中的高渗依赖性作用仍不清楚，因为 NFAT5 缺陷的小鼠模型产生了显着不同的 T 细胞表型。在这项研究中，我们分析了 NFAT5 缺失和 T 细胞特异性 NFAT5 敲除小鼠的 T 细胞区室。我们发现 NFAT5 缺失小鼠具有明显的组成性高钠血症，并患有严重的免疫缺陷，伴有 T 细胞淋巴细胞减少、CD8 幼稚/记忆稳态改变以及无法排斥同种异体肿瘤。相比之下，T 细胞特异性 NFAT5 敲除小鼠具有正常的血浆张力，排斥同种异体肿瘤，并且 CD8 细胞仅表现出轻度、低外显率记忆偏差。值得注意的是，当这些小鼠的 T 细胞在高钠培养基中离体培养时，它们表现出 NFAT5 缺失小鼠的特征，具有明显的幼稚/记忆失衡和响应 IL-7 的稳态生存受损，以及其丝裂原诱导的增殖受到严重抑制。通过分析 NFAT5 缺陷细胞中表达可能受到影响的表面受体，我们确定 CD24 是一种新的 NFAT5 靶标，由体外和体内高渗诱导，并且需要在渗透压下维持 T 细胞扩增。 NFAT5 响应高渗状态而与 Cd24 启动子结合，促进染色质局部去抑制并增强 CD24 mRNA 和蛋白质的表达。总而言之，我们的结果表明 NFAT5 缺失小鼠的全身高钠血症是其免疫缺陷的主要原因，并强调了 NFAT5 和 CD24 在体内渗透压下 T 细胞稳态中的作用。免疫学杂志，2010，185：6624-6635。
Immune cells rely on the transcription factor NFAT5 to adapt to hypertonic stress. The hypertonicity-dependent role of NFAT5 in T cells in vivo remains unclear because mouse models of NFAT5 deficiency have produced substantially different T cell phenotypes. In this study, we analyzed the T cell compartment in NFAT5-null and T cell-specific NFAT5 knockout mice. We found that NFAT5-null mice had constitutive, pronounced hypernatremia and suffered a severe immunodeficiency, with T cell lymphopenia, altered CD8 naive/memory homeostasis, and inability to reject allogeneic tumors. By contrast, T cell-specific NFAT5 knockout mice had normal plasma tonicity, rejected allogeneic tumors, and exhibited only a mild, low-penetrance memory bias in CD8 cells. Notably, when T cells from these mice were cultured ex vivo in hypernatremic media, they exhibited features found in NFAT5-null mice, with pronounced naive/memory imbalance and impaired homeostatic survival in response to IL-7, as well as a severe inhibition of their mitogen-induced proliferation. By analyzing surface receptors whose expression might be affected in NFAT5-deficient cells, we identified CD24 as a novel NFAT5 target induced by hypertonicity both in vitro and in vivo, and required to sustain T cell expansion under osmostress. NFAT5 bound to the Cd24 promoter in response to hypertonicity facilitated the local derepression of chromatin and enhanced the expression of CD24 mRNA and protein. Altogether, our results indicate that the systemic hypernatremia of NFAT5-null mice is a major contributor to their immunodeficiency, and highlight the role of NFAT5 and CD24 in the homeostasis of T cells under osmostress in vivo. The Journal of Immunology, 2010, 185: 6624-6635.