Date of Award

2013

Degree Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Graduate Group

Immunology

First Advisor

Paula M. Oliver

Abstract

Without the ability to suppress its responses, the immune system, instead of being advantageous to the individual, would elicit deleterious consequences. Thus, mechanisms to contain the activity of immune cells are necessary to prevent immune responses against non-pathogenic antigens and the severe immunopathology that would otherwise result. In T cells, these mechanisms are termed T cell tolerance. T cell tolerance is defined as the collection of T cell intrinsic and extrinsic processes that suppress T cell responses to these non-pathogenic antigens. A breach in T cell tolerance could have fatal results, as evidenced in several autoimmune syndromes. Many of these mechanisms of tolerance occur during T cell development (central T cell tolerance), whereas, others exist in mature T cells (peripheral T cell tolerance). This thesis is focused on the involvement of the adaptor protein Ndfip1 in mechanisms of peripheral T cell tolerance.

Ndfip1 is an adaptor for E3 ubiquitin ligases of the Nedd4 family. In Th2 cells, Ndfip1 is necessary for the degradation of JunB by the Nedd4 family E3 ligase Itch. Consequently, Ndfip1 limits IL-4 expression in Th2 cells. Here we present evidence that Ndfip1 also limits IL-4 expression during the differentiation of inducible Tregs (iTregs), promoting their suppressive program. Thus, by promoting iTreg differentiation, Ndfip1 enforces the proper balance between effector and tolerogenic T cell responses. Ndfip1 also promotes T cell tolerance by regulating T cell activation. Ndfip1 constrains T cell activation by limiting IL-2 mRNA expression. Ndfip1 is part of a negative regulatory system in which factors that induce IL-2 expression downstream of T cell receptor engagement also induce the expression of Ndfip1 to limit the extent of IL-2 production and, thus, control T cell activation. By regulating these two processes, Ndfip1 favors peripheral T cell tolerance and prevents the development of a T cell mediated fatal inflammatory disease.

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