Non-Canonical Notch Signaling Drives Activation and Differentiation of Peripheral CD4(+) T Cells.
Non-Canonical Notch Signaling Drives Activation and Differentiation of Peripheral CD4(+) T Cells.
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DOI：
10.3389/fimmu.2014.00054
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发表时间：
2014
影响因子：
7.3
通讯作者：
Osborne BA
中科院分区：
文献类型：
--
作者：
Dongre A;Surampudi L;Lawlor RG;Fauq AH;Miele L;Golde TE;Minter LM;Osborne BA
通过γ-分泌酶切割Notch受体，导致Notch细胞内活性区域的释放，该区域迁移到细胞核并与RBP-Jκ相互作用，导致下游靶基因的激活。这种典型的Notch信号通路已被证明影响T细胞的发育和功能。然而，这一过程背后的机制细节仍然不清楚。除了RBP-Jκ外，Notch的细胞内结构域还与细胞质和细胞核中的其他蛋白相互作用，从而可能产生另一种不依赖RBP-Jκ的Notch通路。然而，这种不依赖RBP-Jκ的“非规范”Notch信号在调节外周T细胞反应中的作用尚不清楚。在本报告中，我们特别证明了Notch1在调节外周CD4+ T细胞远端T细胞受体的信号强度和信号事件中的必要性。通过条件缺失Notch1或RBP-Jκ的小鼠，我们发现Notch1独立于RBP-Jκ调节CD4+ T细胞的激活和增殖。此外，分化到TH1和iTreg谱系虽然依赖于Notch，但与RBP-Jκ无关。我们惊人的观察结果表明，Notch的许多细胞内在功能独立于RBP-Jκ发生。这些过程的非规范调控可能通过NF-κ b发生。这揭示了非规范Notch信号在调节外周T细胞反应中的一个未知的新作用。
Cleavage of the Notch receptor via a γ-secretase, results in the release of the active intra-cellular domain of Notch that migrates to the nucleus and interacts with RBP-Jκ, resulting in the activation of downstream target genes. This canonical Notch signaling pathway has been documented to influence T cell development and function. However, the mechanistic details underlying this process remain obscure. In addition to RBP-Jκ, the intra-cellular domain of Notch also interacts with other proteins in the cytoplasm and nucleus, giving rise to the possibility of an alternate, RBP-Jκ independent Notch pathway. However, the contribution of such RBP-Jκ independent, “non-canonical” Notch signaling in regulating peripheral T cell responses is unknown. In this report, we specifically demonstrate the requirement of Notch1 for regulating signal strength and signaling events distal to the T cell receptor in peripheral CD4+ T cells. By using mice with a conditional deletion in Notch1 or RBP-Jκ, we show that Notch1 regulates activation and proliferation of CD4+ T cells independently of RBP-Jκ. Furthermore, differentiation to TH1 and iTreg lineages although Notch dependent, is RBP-Jκ independent. Our striking observations demonstrate that many of the cell-intrinsic functions of Notch occur independently of RBP-Jκ. Such non-canonical regulation of these processes likely occurs through NF-κ B. This reveals a previously unknown, novel role of non-canonical Notch signaling in regulating peripheral T cell responses.
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DOI：
10.4049/jimmunol.1003658
发表时间：
2011-07-15
期刊：
Journal of immunology (Baltimore, Md. : 1950)
影响因子：
--
作者：
Keerthivasan S;Suleiman R;Lawlor R;Roderick J;Bates T;Minter L;Anguita J;Juncadella I;Nickoloff BJ;Le Poole IC;Miele L;Osborne BA
通讯作者：
Osborne BA
影响因子：
6.4
作者：
Nishioka, Chie;Ikezoe, Takayuki;Yokoyama, Akihito
通讯作者：
Yokoyama, Akihito
影响因子：
6.7
作者：
Auderset F;Schuster S;Coutaz M;Koch U;Desgranges F;Merck E;MacDonald HR;Radtke F;Tacchini-Cottier F
通讯作者：
Tacchini-Cottier F
影响因子：
30.5
作者：
Douglas, NC;Jacobs, H;Hayday, AC
通讯作者：
Hayday, AC
影响因子：
4.4
作者：
Adler, SH;Chiffoleau, E;Pear, WS
通讯作者：
Pear, WS