Cd8+ T-Cell Responses in a Th2-Polarized Inflammatory Setting

Loading...
Thumbnail Image
Degree type
Doctor of Philosophy (PhD)
Graduate group
Cell & Molecular Biology
Discipline
Subject
Allergy and Immunology
Cell Biology
Immunology and Infectious Disease
Medical Immunology
Microbiology
Funder
Grant number
License
Copyright date
2014-08-22T00:00:00-07:00
Distributor
Related resources
Contributor
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.

Advisor
Paula M. Oliver
Date of degree
2013-01-01
Date Range for Data Collection (Start Date)
Date Range for Data Collection (End Date)
Digital Object Identifier
Series name and number
Volume number
Issue number
Publisher
Publisher DOI
Journal Issue
Comments
Recommended citation