title: Non-Canonical Notch Signaling Drives Activation and Differentiation of Peripheral CD4(+) T Cells.
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.
authors.affiliation: 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.
authors.forename: Anushka
authors.initials: A
authors.lastname: Dongre
authors.affiliation: Department of Veterinary and Animal Sciences, University of Massachusetts Amherst , Amherst, MA , USA.
authors.forename: Lalitha
authors.initials: L
authors.lastname: Surampudi
authors.affiliation: Department of Veterinary and Animal Sciences, University of Massachusetts Amherst , Amherst, MA , USA.
authors.forename: Rebecca G
authors.initials: RG
authors.lastname: Lawlor
authors.affiliation: PAR, Chemical Synthesis Core Facility, Mayo Clinic Florida , Jacksonville, FL , USA.
authors.forename: Abdul H
authors.initials: AH
authors.lastname: Fauq
authors.affiliation: Cancer Institute, University of Mississippi Medical Center , Jackson, MS , USA.
authors.forename: Lucio
authors.initials: L
authors.lastname: Miele
authors.affiliation: Department of Neuroscience, Center for Translational Research in Neurodegenerative Disease, McKnight Brain Institute, University of Florida , Gainesville, FL , USA.
authors.forename: Todd E
authors.initials: TE
authors.lastname: Golde
authors.affiliation: 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.
authors.forename: Lisa M
authors.initials: LM
authors.lastname: Minter
authors.affiliation: 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.
authors.forename: Barbara A
authors.initials: BA
authors.lastname: Osborne
keywords: CD4+ T cell; Notch1; activation; differentiation; non-canonical