Date of Award

2013

Degree Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Graduate Group

Cell & Molecular Biology

First Advisor

Paula M. Oliver

Abstract

A variety of external factors can affect the activation status, effector function, and memory differentiation of T cells. Such factors include resident microbiota and the cytokine milieu produced in a host. Loss of tolerance to commensal bacteria and excess inflammatory cytokines such as IL-4 have been implicated in the pathogenesis of many diseases, including inflammatory bowel disease (IBD) and allergy. Although these diseases are traditionally associated with CD4+ T cells, it is increasingly appreciated that CD8+ T cells in these settings may either contribute to or reduce pathology. This work explores the influence of various factors on CD8+ T-cell responses in an inflammatory setting, mice deficient in Nedd4-family interacting protein 1 (Ndfip1). Ndfip1 restricts IL-4 production in CD4+ T cells by facilitating degradation of the transcription factor JunB. Ndfip1-deficient CD4+ T cells have increased JunB levels and consequently overproduce IL-4. This excess IL-4 impairs Th17 and iTreg differentiation. Mice lacking Ndfip1 develop severe TH2-mediated inflammation at sites of environmental antigen exposure, including skin, GI tract, and lung, and develop IBD-like symptoms. We first tested the role of bacterial antigens in triggering this phenotype by treating mice lacking Ndfip1 in T cells with a cocktail of antibiotics to deplete intestinal bacteria. We then analyzed T cells for activation markers and examined tissues for signs of inflammation in the GI tract. Next, we analyzed whether exposure to the high levels of IL-4 in Ndfip1KO mice affects CD8+ T cell differentiation. We concluded that IL-4, but not intestinal bacteria, is required for the increase in activated/memory phenotype CD8+ T cells observed in Ndfip1KO mice. These findings add to the growing body of literature describing the importance of extrinsic cytokines to the development of memory-phenotype CD8+ T cells, and raise the possibility that such cells may be clinically relevant in diseases which are characterized by local increases in IL-4.