前沿：条件性 Rasgrp1 缺陷小鼠外周血 CD4+ T 细胞中 Rasgrp1 的诱导性缺失揭示了 Rasgrp1 在 TCR/CD28 诱导的 Ras-MAPK 信号中的重要作用。
Cutting Edge: Induced Loss of Rasgrp1 in Peripheral CD4+ T Cells of Conditional Rasgrp1-Deficient Mice Reveals an Essential Role for Rasgrp1 in TCR/CD28-Induced Ras-MAPK Signaling.
机构信息
Department of Microbiology and Immunology, University of Michigan Medical School, Ann Arbor, MI.
Department of Anatomy, University of California, San Francisco, San Francisco, CA.
出版信息
J Immunol. 2023 Sep 15;211(6):917-922. doi: 10.4049/jimmunol.2300138.
Ras guanine nucleotide-releasing protein 1 (Rasgrp1) is a Ras guanine nucleotide exchange factor that participates in the activation of the Ras-ERK signaling pathway in developing T cells and is required for efficient thymic T cell positive selection. However, the role of Rasgrp1 in mature peripheral T cells has not been definitively addressed, in part because peripheral T cells from constitutive Rasgrp1-deficient mice show an abnormal activated phenotype. In this study, we generated an inducible Rasgrp1-deficient mouse model to allow acute disruption of Rasgrp1 in peripheral CD4+ T cells in the context of normal T cell development. TCR/CD28-mediated activation of Ras-ERK signaling was blocked in Rasgrp1-deficient peripheral CD4+ T cells. Furthermore, Rasgrp1-deficient CD4+ T cells were unable to synthesize IL-2 and the high-affinity IL-2R and were unable to proliferate in response to TCR/CD28 stimulation. These findings highlight an essential function for Rasgrp1 for TCR/CD28-induced Ras-ERK activation in peripheral CD4+ T cells.
Ras 鸟嘌呤核苷酸释放蛋白 1（Rasgrp1）是一种 Ras 鸟嘌呤核苷酸交换因子，参与发育中的 T 细胞中 Ras-ERK 信号通路的激活，并且是有效胸腺 T 细胞阳性选择所必需的。然而，Rasgrp1 在成熟外周 T 细胞中的作用尚未得到明确解决，部分原因是组成型 Rasgrp1 缺陷型小鼠的外周 T 细胞表现出异常激活表型。在这项研究中，我们生成了一种诱导型 Rasgrp1 缺陷型小鼠模型，以允许在正常 T 细胞发育的情况下急性破坏外周 CD4+T 细胞中的 Rasgrp1。Rasgrp1 缺陷型外周 CD4+T 细胞中 TCR/CD28 介导的 Ras-ERK 信号转导被阻断。此外，Rasgrp1 缺陷型 CD4+T 细胞无法合成 IL-2 和高亲和力的 IL-2R，并且无法对 TCR/CD28 刺激产生增殖反应。这些发现强调了 Rasgrp1 在 TCR/CD28 诱导的外周 CD4+T 细胞中 Ras-ERK 激活中的重要功能。
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