Student Theses and Dissertations

Date of Award

2004

Document Type

Thesis

RU Laboratory

Deans Office

Keywords

regulatory T-cell function, CD8, itch mice, E3 ligase itch

Abstract

Cloning of the inversion breakpoints in the agouti mutant strain a has implicated the E3 ligase Itch in the spontaneous inflammation that occurs in these mice. 1 RH Anaylsis of a mice suggests that the inflammatory disease is due to a dysregulated T helper type-2 immune response. In order to verify the importance of Itch inactivation in the spontaneous inflammation of a mice and to determine which cell type is responsible for the pathology, the Itch gene has been targeted for conditional deletion in mice using the Cre-loxP system. The results presented in this thesis provide the first direct evidence that Itch deficient CD4+ T cells are sufficient to cause spontaneous inflammation. The function of CD4+CD25+ regulatory T cells was found to be intact in vitro. Instead, sensitivity to the immunomodulatory cytokine TGF-(3 was reduced in Itch deficient CD4+ T cells. Inadequacies in peripheral tolerance mechanisms were observed based on oral tolerance studies. Itch deficiency was found to directly contribute to the CD4+ bias towards T helper type-2 (Th2) differentiation observed in a mice. Itch modulation of Th2 differentiation occurs in a Stat6 dependent pathway. Itch fl/fl CD4 Cre Stat 6 -/- CD4+ T cells were found to be incapable of differentiating into Th2 cells in vitro. Itch fl/fl CD4 Cre Stat 6 -/- did not develop spontaneous inflammation disease, underscoring the 1 ST-T importance of T h 2 differentiation in the pathology of a mice. Itch fl/fl CD4 Cre mice were found to accumulate memory phenotype CD8+ cells in their secondary lymphoid organs. The inflammatory pathology of Itch fl/fl CD4 Cre 1 mice was not required for accumulation of Itch deficient memory-like C D 8 + cells. The cause for this accumulation remains unclear, although an increase in homeostatic proliferation of the memory-like cells is considered unlikely. The findings of this thesis provide definitive support for several speculations regarding the function of Itch. In addition, they provide novel venues of study for the role of Itch in the immune system. Collectively, they argue that further study of this E3 ligase will be a fruitful endeavor for immunologi.

Comments

A thesis presented to the faculty of The Rockefeller University in partial fulfillment of the requirements for the degree of Doctor of Philosophy.

Permanent URL

http://hdl.handle.net/10209/198

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