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Front Immunol. 2014 Feb 12;5:54. doi: 10.3389/fimmu.2014.00054. eCollection 2014.

Non-Canonical Notch Signaling Drives Activation and Differentiation of Peripheral CD4(+) T Cells.

Author information

1
Program in Molecular and Cellular Biology, University of Massachusetts Amherst , Amherst, MA , USA ; Department of Veterinary and Animal Sciences, University of Massachusetts Amherst , Amherst, MA , USA.
2
Department of Veterinary and Animal Sciences, University of Massachusetts Amherst , Amherst, MA , USA.
3
PAR, Chemical Synthesis Core Facility, Mayo Clinic Florida , Jacksonville, FL , USA.
4
Cancer Institute, University of Mississippi Medical Center , Jackson, MS , USA.
5
Department of Neuroscience, Center for Translational Research in Neurodegenerative Disease, McKnight Brain Institute, University of Florida , Gainesville, FL , USA.

Abstract

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.

KEYWORDS:

CD4+ T cell; Notch1; activation; differentiation; non-canonical

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