FOXO3 Regulates the CD8 T Cell Response to a Chronic Viral Infection

StephenW

http://jvi.asm.org/content/86/17/9025.abstract?etoc
FOXO3 Regulates the CD8 T Cell Response to a Chronic Viral Infection

    Jeremy A. Sullivan,
    Eui Ho Kim,
    Erin H. Plisch and
    M. Suresh

- Author Affiliations

    Department of Pathobiological Sciences, University of Wisconsin—Madison, Madison, Wisconsin, USA

ABSTRACT

Chronic infections with viruses such as hepatitis B virus, hepatitis C virus, and HIV constitute a major global public health problem. Studies of chronic viral infections in humans and mice show that persistent antigenic stimulation induces dysregulation of T cell responses; virus-specific T cells either undergo clonal deletion or lose their ability to display the full spectrum of effector functions, a condition termed functional exhaustion. The ability to generate and retain sufficient numbers of functionally competent T cells, therefore, becomes vitally important in controlling chronic viral infections. Our understanding of the mechanisms governing T cell homeostasis during chronic viral infections, however, is poor. The phosphatidylinositol 3-kinase (PI3K)/Akt signaling pathway controls cell fate decisions in many cell types by modulating the activity of downstream effectors, including the FOXO family of transcription factors. We have observed dynamic, in vivo alterations in the phosphorylation levels of three key proteins (Akt, FOXO1/FOXO3 [FOXO1/3], and mammalian target of rapamycin [mTOR]) involved in this signaling cascade and have identified the transcription factor FOXO3 as a negative regulator of the magnitude and effector function of CD8 T cells during chronic lymphocytic choriomeningitis virus (LCMV) infection in mice. We report that ablation of FOXO3 in T cells reduced apoptosis, increased the abundance of polyfunctional virus-specific CD8 T cells, and improved viral control. Thus, FOXO3 is a promising candidate target for immunotherapies of chronic viral infection.
FOOTNOTES

        Received 17 April 2012.
        Accepted 30 May 2012.
    Address correspondence to M. Suresh, [email protected].

StephenW

FOXO3调节到慢性病毒感染的CD8 + T细胞反应

    杰里米答：沙利文，
    李义何金，
    艾琳H.的Plisch和
    研究苏雷什

- 作者背景

    病理生物学科学系，麦迪逊，威斯康星 - 麦迪逊大学，美国威斯康星州

摘要

与慢性乙型肝炎病毒，丙型肝炎病毒和艾滋病毒等病毒感染，构成了重大的全球性公共卫生问题。在人类和小鼠的慢性病毒感染的研究表明，持续性抗原刺激诱导T细胞的反应失调;病毒特异性T细胞进行克隆缺失或失去他们的能力，显示全谱效应的功能，这种情况被称为功能衰竭。功能主管T细胞的生成和保留足够数量的能力，因此，控制慢性病毒感染变得非常重要。然而，我们在慢性病毒感染T细胞的动态平衡机制的理解是穷人。磷酸肌醇3激酶（PI3K）/ Akt的信号转导通路控制，通过调节下游效应的活动，包括转录因子FOXO家族在多种细胞类型的细胞命运的决定。我们观察到体内三个关键蛋白质的磷酸化水平的改变，动态（Akt的，FOXO1/FOXO3 [的FOXO1 / 3]，哺乳动物雷帕霉素靶mTOR的[]）这个信号级联参与，并已确定的转录因子FOXO3一个负调控的规模和效应功能的CD8 T细胞在慢性淋巴细胞性脉络丛脑膜炎病毒（LCMV）感染小鼠。我们报告，FOXO3消融在T细胞凋亡减少，增加了丰富的官能病毒特异性CD8 T细胞，改善病毒控制。因此，FOXO3是一种慢性病毒感染的免疫疗法有希望的候选目标。
脚注

        2012年4月收到17。
        2012年5月30日。
    解决通信研究苏雷什，[email protected]。

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