All ETDs from UAB

Advisory Committee Chair

Casey T Weaver

Advisory Committee Members

Peter D Burrows

David D Chaplin

Robin D Hatton

Chander Raman

Thomas M Ryan

Document Type

Dissertation

Date of Award

2009

Degree Name by School

Doctor of Philosophy (PhD) Heersink School of Medicine

Abstract

Maintenance of immune homeostasis involves a balance between T cell effector responses to antigen stimulus and reciprocal downregulation of this response through peripheral tolerance mechanisms. Upon exposure to pathogen, cytokine production and signaling serve to tightly coordinate cell-mediated clearance of antigen followed by contraction of the immune response. Interkeukin-2 (IL-2) is a type I family cytokine critical for expansion of activated T cells in vitro and enhancement of T cell memory responses in vivo. Deficiency of IL-2 in vivo also revealed a critical role for IL-2 in immune tolerance through the maintenance of T regulatory cell populations (Treg) in peripheral lymphoid tissues. Thus, regulation of Il2 gene expression and autocrine signaling are central to the balance of immune homeostasis. Defining the regulatory mechanisms associated with Il2 gene expression is crucial for defining the integral role for IL-2 in tolerance and effector immunity. In order to evaluate the role of IL-2 production during the immune response we have engineered a BAC transgenic as well as a gene-targeted knock-in reporter mouse model system to mark Il2 gene activation. Our studies indicate that both mouse models exhibit reporter expression with high fidelity to endogenous Il2 expression patterns while stably marking IL-2-producing cells. Using our Il2 BAC transgenic system (2BiT) system to model inhibition of IL-2 production in responder CD4 T cells by Tregs we describe a model in which Tregs prevent initial activation of Il2 transcription that also subsequently associates with increased responder cell death of non-IL-2 producers. Suppression of naïve activated CD4 T cells by Tregs followed a mechanism consistent with competition for co-stimulation and preventing a threshold of activation rather than cytokine deprivation. Utilizing an Il2 GFP knock-in model we show evidence that IL-21 enhances proliferation and the frequency of IL-2-producing cells in activated naïve CD4 T cells. These results are suggestive of a coordinate relationship between Il2 expression and IL-21 production and signaling in effector T cell function and fate. Future Il2< expression studies using our novel mouse reporter systems will enable a more in-depth understanding of the role of this cytokine in effector function and immune tolerance.

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