CD8+ T-cell responses in a Th2-polarized inflammatory setting

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+ Tcell 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. Degree Type Dissertation Degree Name Doctor of Philosophy (PhD) Graduate Group Cell & Molecular Biology First Advisor Paula M. Oliver Subject Categories Allergy and Immunology | Cell Biology | Immunology and Infectious Disease | Medical Immunology | Microbiology This dissertation is available at ScholarlyCommons: http://repository.upenn. edu/edissertations/884 CD8 T-CELL RESPONSES IN A TH2-POLARIZED INFLAMMATORY SETTING Vanessa C. Kurzweil A DISSERTATION in Cell and Molecular Biology Presented to the Faculties of the University of Pennsylvania in Partial Fulfillment of the Requirements for the Degree of Doctor of Philosophy 2013 Supervisor of Dissertation _____________________ Paula M. Oliver, Ph.D. Associate Professor of Pathology and Laboratory Medicine Graduate Group Chairperson _____________________ Daniel S. Kessler, Ph.D. Associate Professor of Cell and Developmental Biology Dissertation Committee: Michael R. Betts, Ph.D. Associate Professor of Microbiology Christopher A. Hunter, Ph.D. Professor of Pathobiology Gary Koretzky, M.D., Ph.D. Francis C. Wood Professor of Medicine Phillip Scott, Ph.D. Professor of Pathobiology E. John Wherry (Chair), Ph.D. Associate Professor of Microbiology