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Author ORCID Identifier

N/A

AccessType

Open Access Dissertation

Document Type

dissertation

Degree Name

Doctor of Philosophy (PhD)

Degree Program

Molecular and Cellular Biology

Year Degree Awarded

2014

Month Degree Awarded

February

First Advisor

Barbara A. Osborne

Subject Categories

Immunity

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. 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 towards TH1 and iTreg lineages is also Notch dependent but RBP-JΚ independent. Our data provide evidence that non-canonical regulation of these processes likely occurs through NF-ΚB. Additionally, we also provide evidence suggestive of cross-talk between Notch and the mTOR pathway. Notch1, but not RBP-JΚ, is required for phosphorylation of several substrates directly downstream of mTORC2. Collectively, these striking observations demonstrate that many of the cell intrinsic functions of Notch occur independently of RBP-JΚ. This reveals a previously unknown, novel role of non-canonical Notch signaling in regulating peripheral T-cell responses.

DOI

https://doi.org/10.7275/x5s9-7275

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