Signaling pathway cross-talk upstream of regulatory T cell differentiation

2008 2008

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Abstract (summary)

Notch and its ligands have been implicated in the regulation and differentiation of various CD4+ T-helper cells. By directly inducing the expression of the master gene regulators T-bet and GATA-3, Notch signaling has been shown to function upstream of the differentiation pathways of TH1 and TH2 cells, respectively. Regulatory T cells (Treg), which express the transcription factor Foxp3, suppress aberrant immune responses that are typically associated with autoimmunity or excessive inflammation. Previous studies have shown that the anti-inflammatory cytokine transforming growth factor beta (TGFβ1) induces Foxp3 expression and a regulatory phenotype in peripheral CD4+ T cells. In various cell types and biochemical assays, Notch has been shown to interact directly with Smad proteins, the intracellular mediators of TGFβ signaling.

Based on these observations, we hypothesized that synergy between Notch and TGFβ signaling is required for Foxp3 induction in peripheral T cells. Here, we show that pharmacologic inhibition of Notch signaling using γ-secretase inhibitor (GSI) treatment blocks (i) TGFβ1-induced Foxp3 expression, (ii) the upregulation of Foxp3-target genes, and (iii) the ability to suppress naïve T cell proliferation. Additionally, the binding of Notch1, CSL, and Smad to conserved binding sites in the foxp3 promoter can be inhibited by treatment with GSI. Finally, in vivo administration of GSI results in reduced Foxp3 expression and the development of symptoms of autoimmune hepatitis, a disease previously found to result from dysregulation of TGFβ signaling and regulatory T cells. Data from Notch1 anti-sense mice, which express reduced levels of Notch1, recapitulates in vitro GSI data, and these mice also have impaired regulatory T cell maintenance, similar to TGFβ-deficient mice. Furthermore, preliminary data indicate that Runx transcription factors may also play a role in the induction of Foxp3 in the periphery. Together, these results indicate that an intricate degree of signaling pathway cross-talk is required to maintain the regulatory T cell pool in the periphery.

Indexing (details)

0982: Immunology
Identifier / keyword
Health and environmental sciences; Cell differentiation; Cross talk; Regulatory T cells
Signaling pathway cross-talk upstream of regulatory T cell differentiation
Samon, Jeremy B.
Number of pages
Publication year
Degree date
School code
DAI-B 69/12, Dissertation Abstracts International
Place of publication
Ann Arbor
Country of publication
United States
Osborne, Barbara A.
Committee member
Garman, Scott C; Minter, Lisa M; Telfer, Janice C
University of Massachusetts Amherst
Animal Science
University location
United States -- Massachusetts
Source type
Dissertations & Theses
Document type
Dissertation/thesis number
ProQuest document ID
Database copyright ProQuest LLC; ProQuest does not claim copyright in the individual underlying works.
Document URL
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