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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

2017

Month Degree Awarded

May

First Advisor

Lisa M. Minter

Subject Categories

Immunity | Immunology and Infectious Disease

Abstract

Notch signaling modulates the developmental program of multiple cell types. The cleaved intracellular region of the receptor possess the functional domain which influences T cell activation, proliferation and differentiation. However, in naïve CD4 T cells the mechanistic details underlying cleavage of Notch1 is not clearly understood. Notch functions by acting as a signaling hub and interacting with its canonical (CSL) and non-canonical (NFkB, mTOR, Akt) binding partners to cross-talk with other signaling pathways. Notch signaling drives the differentiation program of multiple T helper cell subsets (Th1, Th2, Th17, Th9, iTreg and TFH). Recent discoveries also demonstrated a role for microRNAs in T helper cell differentiation, particularly in Th1 cells. The miR-29 family of microRNAs limit Th1 differentiation by directly targeting the signature molecules of Th1 cells, ifng and tbx21. The post translational modifications of Notch1 during activation and differentiation of CD4 T cells are described here. We specifically demonstrate that Notch1 is constitutively cleaved in naïve cells and it is hyper-phosphorylated. Phosphorylation status of Notch1 changes upon TCR mediated activation, probably through dephosphorylation, resulting in different forms of phosphorylated Notch1. In Chapter 3, we study Notch1-mediated regulation of miR-29. We show that Notch1 suppresses miR-29 through CSL-dependent, canonical Notch signaling. Thus, our data indicate a novel mechanism for regulating miR-29 transcription in addition to STAT1 and NFkB. We demonstrated that Notch1 and IFNg act in an opposing manner to regulate the expression of miR-29, therefore modulating Th1 response.

DOI

https://doi.org/10.7275/10014137.0

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