N-ras couples antigen receptor signaling to Eomesodermin and to functional CD8+ T cell memory but not to effector differentiation.
N-ras couples antigen receptor signaling to Eomesodermin and to functional CD8+ T cell memory but not to effector differentiation.
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DOI：
10.1084/jem.20112495
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发表时间：
2013-07-01
期刊：
影响因子：
--
通讯作者：
Del Val M
中科院分区：
文献类型：
--
作者：
Iborra S;Ramos M;Arana DM;Lázaro S;Aguilar F;Santos E;López D;Fernández-Malavé E;Del Val M
N-ras−/− CD 8 + T细胞在Eomes表达中存在内在缺陷，导致保护性记忆细胞的产生受损，这些细胞可以通过强制Eomes表达来拯救。来自TCR的信号特异性地促进效应与记忆CD 8 + T细胞分化的理解很少。使用小鼠和过继转移的T淋巴细胞缺乏小GT3 N-ras，我们发现，N-ras缺陷的CD 8 + T细胞有效地分化成抗病毒的主要效应，但有一个严重的缺陷，在产生保护性记忆细胞。这种缺陷被挽救，虽然只有部分，雷帕霉素介导的抑制哺乳动物靶雷帕霉素（mTOR）在体内。记忆缺陷与体外和体内抗原介导的T-box转录因子Eomesodermin（Eomes）的早期诱导的显著损害相关，而T-bet不受影响。除N-ras外，体外早期Eomes诱导需要磷酸肌醇3-激酶（PI 3 K）-AKT而不是细胞外信号调节激酶（ERK）激活，并且对雷帕霉素基本不敏感。与N-ras偶联Eomes与T细胞记忆一致，逆转录病毒增强N-ras缺陷型CD 8 + T细胞中Eomes的表达有效地挽救了它们的记忆分化。因此，我们的研究确定了N-ras作为Eomes的TCR近端调节因子在早期确定CD 8 + T细胞记忆命运中的关键作用。
N-ras−/− CD8+ T cells have an intrinsic defect in Eomes expression resulting in impaired generation of protective memory cells that can be rescued by enforced Eomes expression. Signals from the TCR that specifically contribute to effector versus memory CD8+ T cell differentiation are poorly understood. Using mice and adoptively transferred T lymphocytes lacking the small GTPase N-ras, we found that N-ras–deficient CD8+ T cells differentiate efficiently into antiviral primary effectors but have a severe defect in generating protective memory cells. This defect was rescued, although only partly, by rapamycin-mediated inhibition of mammalian target of rapamycin (mTOR) in vivo. The memory defect correlated with a marked impairment in vitro and in vivo of the antigen-mediated early induction of T-box transcription factor Eomesodermin (Eomes), whereas T-bet was unaffected. Besides N-ras, early Eomes induction in vitro required phosphoinositide 3-kinase (PI3K)–AKT but not extracellular signal-regulated kinase (ERK) activation, and it was largely insensitive to rapamycin. Consistent with N-ras coupling Eomes to T cell memory, retrovirally enforced expression of Eomes in N-ras–deficient CD8+ T cells effectively rescued their memory differentiation. Thus, our study identifies a critical role for N-ras as a TCR-proximal regulator of Eomes for early determination of the CD8+ T cell memory fate.
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影响因子：
64.8
作者：
Daniels, Mark A.;Teixeiro, Emma;Palmer, Ed
通讯作者：
Palmer, Ed
影响因子：
3.8
作者：
Johnstone, C;de León, P;Del Val, M
通讯作者：
Del Val, M
影响因子：
82.9
作者：
Badovinac, VP;Messingham, KAN;Harty, JT
通讯作者：
Harty, JT
影响因子：
30.5
作者：
Cannarile, Michael A.;Lind, Nicholas A.;Goldrath, Ananda W.
通讯作者：
Goldrath, Ananda W.
DOI：
10.4049/jimmunol.0802598
发表时间：
2009-03-15
期刊：
Journal of immunology (Baltimore, Md. : 1950)
影响因子：
--
作者：
Cho OH;Shin HM;Miele L;Golde TE;Fauq A;Minter LM;Osborne BA
通讯作者：
Osborne BA