Thymic development beyond beta-selection requires phosphatidylinositol 3-kinase activation by CXCR4.
Thymic development beyond beta-selection requires phosphatidylinositol 3-kinase activation by CXCR4.
复制标题
DOI：
10.1084/jem.20091430
复制
发表时间：
2010-01-18
期刊：
影响因子：
--
通讯作者：
Turner M
中科院分区：
文献类型：
--
作者：
Janas ML;Varano G;Gudmundsson K;Noda M;Nagasawa T;Turner M
T细胞发育需要磷脂酰肌醇3-激酶（PI 3 K）信号传导，其贡献来自IA类p110δ和IB类p110γ催化亚基。然而，这些PI 3 K中的每一种被激活的未成熟T细胞上的受体尚未被鉴定，它们在胸腺中的功能冗余背后的机制也未被鉴定。在这里，我们发现来自preTCR的PI 3 K信号需要p110δ，而不是p110γ。缺乏IB类调节亚基p101的小鼠证明了T细胞发育中对p101的需求，这暗示了β选择中的G蛋白偶联受体信号传导。我们在体外β选择模型中使用小分子拮抗剂发现了CXCR 4作用的证据，并证明了CXCR 4缺陷胚胎在胸腺发育期间对CXCR 4的需求。最后，我们证明了CXCL 12，CXCR 4的配体，允许在没有支持基质细胞的情况下，DN 3胸腺细胞的Notch依赖性分化。这些发现确立了CXCR 4介导的PI 3 K信号传导的作用，其与来自Notch和preTCR的信号一起，有助于超越β选择的持续T细胞发育。
T cell development requires phosphatidylinositol 3-kinase (PI3K) signaling with contributions from both the class IA, p110δ, and class IB, p110γ catalytic subunits. However, the receptors on immature T cells by which each of these PI3Ks are activated have not been identified, nor has the mechanism behind their functional redundancy in the thymus. Here, we show that PI3K signaling from the preTCR requires p110δ, but not p110γ. Mice deficient for the class IB regulatory subunit p101 demonstrated the requirement for p101 in T cell development, implicating G protein–coupled receptor signaling in β-selection. We found evidence of a role for CXCR4 using small molecule antagonists in an in vitro model of β-selection and demonstrated a requirement for CXCR4 during thymic development in CXCR4-deficient embryos. Finally, we demonstrate that CXCL12, the ligand for CXCR4, allows for Notch-dependent differentiation of DN3 thymocytes in the absence of supporting stromal cells. These findings establish a role for CXCR4-mediated PI3K signaling that, together with signals from Notch and the preTCR, contributes to continued T cell development beyond β-selection.
登录
查看更多内容
影响因子：
--
作者：
McKenzie G;Ward G;Stallwood Y;Briend E;Papadia S;Lennard A;Turner M;Champion B;Hardingham GE
通讯作者：
Hardingham GE
影响因子：
30.5
作者：
Molon, B;Gri, G;Viola, A
通讯作者：
Viola, A
DOI：
10.1073/pnas.95.16.9448
发表时间：
1998-08-04
影响因子：
11.1
作者：
Ma, Q;Jones, D;Springer, TA
通讯作者：
Springer, TA
影响因子：
30.5
作者：
Gounari, F;Aifantis, I;von Boehmer, H
通讯作者：
von Boehmer, H
DOI：
10.1073/pnas.0804286105
发表时间：
2008-07-22
影响因子：
11.1
作者：
Contento, Rita Lucia;Molon, Barbara;Viola, Antonella
通讯作者：
Viola, Antonella