Formation of IL-7Rαhigh and IL-7Rαlow CD8 T cells during infection is regulated by the opposing functions of GABPα and Gfi-1
Formation of IL-7Rαhigh and IL-7Rαlow CD8 T cells during infection is regulated by the opposing functions of GABPα and Gfi-1
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DOI：
10.4049/jimmunol.180.8.5309
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发表时间：
2008-04-15
影响因子：
4.4
通讯作者：
Kaech, Susan M.
中科院分区：
文献类型：
--
作者：
Chandele, Anmol;Joshi, Nikhil S.;Kaech, Susan M.
IL-7对幼稚T细胞和记忆T细胞的存活至关重要，在急性病毒和细菌感染期间，IL-7受体a链（IL-7R α）的表达在活化的CD8 T细胞中受到动态调节。大多数病毒特异性CD8 T细胞变成IL-7R α（低），寿命相对较短，但一些逃避IL-7R α抑制（称为IL-711 α（高）记忆前体效应细胞）并优先进入记忆CD8 T细胞池。抗病毒效应CD8 T细胞如何以“开和关”的方式调节IL-7Ra的表达仍有待研究。在淋巴细胞性脉络丛脑膜炎病毒感染期间，我们发现转录因子GABP α （GA结合蛋白α）和Gfi-1（生长因子独立1）的相反作用控制效应CD8 T细胞中IL-7R α的表达。具体来说，记忆前体效应细胞中IL-7R α的表达需要GABPa，这与Il7ra启动子的超乙酰化有关。相比之下，Gfi-1在效应CD8 T细胞中稳定抑制IL-7R α是必需的，它通过拮抗GABP α结合和募集组蛋白去乙酰化酶1起作用，使Il7ra启动子去乙酰化。因此，Il7ra启动子乙酰化和活性依赖于GABP α和Gfi-1的相互结合，这些数据为在病毒特异性效应CD8 T细胞中产生稳定的IL-7R α（高）和IL-7R α（低）状态提供了生化机制。
IL-7 is essential for the survival of naive and memory T cells, and IL-7 receptor a-chain (IL-7R alpha) expression is dynamically regulated in activated CD8 T cells during acute viral and bacterial infections. Most virus-specific CD8 T cells become IL-7R alpha(low) and are relatively short-lived, but some escape IL-7R alpha repression (referred to as IL-711 alpha(high) memory precursor effector cells) and preferentially enter the memory CD8 T cell pool. How antiviral effector CD8 T cells regulate IL-7Ra expression in an "on and off" fashion remains to be characterized. During lymphocytic choriomeningitis virus infection, we found that opposing actions of the transcription factors GABP alpha (GA binding protein alpha) and Gfi-1 (growth factor independence 1) control IL-7R alpha expression in effector CD8 T cells. Specifically, GABPa was required for IL-7R alpha expression in memory precursor effector cells, and this correlated with hyperacetylation of the Il7ra promoter. In contrast, Gfi-1 was required for stable IL-7R alpha repression in effector CD8 T cells and acted by antagonizing GABP alpha binding and recruiting histone deacetylase 1, which deacetylated the Il7ra promoter. Thus, Il7ra promoter acetylation and activity was dependent on the reciprocal binding of GABP alpha and Gfi-1, and these data provide a biochemical mechanism for the generation of stable IL-7R alpha(high) and IL-7R alpha(low) states in virus-specific effector CD8 T cells.