Non-Canonical Notch Signaling Drives Activation and Differentiation of Peripheral CD4(+) T Cells.
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ABSTRACT: Cleavage of the Notch receptor via a ?-secretase, results in the release of the active intra-cellular domain of Notch that migrates to the nucleus and interacts with RBP-J?, 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-J?, 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-J? independent Notch pathway. However, the contribution of such RBP-J? 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-J?, we show that Notch1 regulates activation and proliferation of CD4(+) T cells independently of RBP-J?. Furthermore, differentiation to TH1 and iTreg lineages although Notch dependent, is RBP-J? independent. Our striking observations demonstrate that many of the cell-intrinsic functions of Notch occur independently of RBP-J?. Such non-canonical regulation of these processes likely occurs through NF-? B. This reveals a previously unknown, novel role of non-canonical Notch signaling in regulating peripheral T cell responses.
SUBMITTER: Dongre A
PROVIDER: S-EPMC3921607 | biostudies-literature | 2014
REPOSITORIES: biostudies-literature
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