Molecular mechanisms of Foxp3-mediated gene regulation and their contribution to T cell and thymic epithelial cell function

Hench, Virginia Kathleen

Molecular mechanisms of Foxp3-mediated gene regulation and their contribution to T cell and thymic epithelial cell function Public Deposited

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March 21, 2019

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Hench, Virginia Kathleen
- Affiliation: School of Medicine, Department of Microbiology and Immunology

Abstract

Severe autoinflammatory disease is associated with mutations in the Foxp3 gene in mice and humans. Foxp3 is required for the development, function, and maintenance of natural regulatory T cells, a subset of thymic-derived CD4pos T cells that suppress T cell activation and inflammatory processes. Also, Foxp3 expression and function has been reported in thymic epithelial cells (TECs), suggesting a T cell extrinsic function for Foxp31. TECs contribute to tolerance and immunity by supporting T cell development. In chapter two, I will discuss the interaction between FOXP3 and Siva, a previously unknown binding partner of FOXP3. Siva is a pro-apoptotic molecule that is expressed across a range of tissues, including CD4posFOXP3pos T cells. FOXP3 interacts with Siva-1 and Siva-2 isoforms in 293T cells. The FOXP3-binding domain maps to Siva's C-terminus. A central region of FOXP3 is involved in binding to Siva. Siva repressed IL-2 gene expression in Jurkat T cells. Further, I investigated whether Siva and FOXP3 functionally interact to repress IL-2 gene expression. The presence of Siva negatively affects the repressive effect of FOXP3 on IL-2 gene expression. Lastly, we showed that FOXP3 enhances Jurkat T cell apoptosis in unstimulated cells, but protects from apoptosis in response to stimulation with PMA and Ionomycin. In summary, the data support the hypothesis that both FOXP3 and Siva are negative regulators of T cell activation. In chapter three, I will present data pertaining to Foxp3 regulation of Her2/neu in TECs and the effect of Her2/neu signaling on thymopoiesis. Previously, it was reported that Her2/neu is upregulated in TECs from scurfy mice, a Foxp3-deficient strain1. We showed that Foxp3 expression was negatively correlated with Her2/neu expression across mouse TEC lines. Further, a Her2/neu-specific monoclonal antibody, Herceptin, partially rescued defective thymopoiesis in scurfy mice1. To investigate the effect of Her2/neu signaling on thymopoiesis, we treated fetal thymic organ cultures (FTOC) with a dual inhibitor of Her2/neu and EGFR, GW572016 (GW57). GW57 moderately enhanced thymopoiesis in FTOCs, suggesting that GW57 could have therapeutic potential for immunodeficient patients such as HIV-1 infected individuals and those who are recovering from intensive cytotoxic cancer treatments.

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