Item Details

Regulation of the Intrahepatic CD8+ T Lymphocyte

Dolina, Joseph
Format
Thesis/Dissertation; Online
Author
Dolina, Joseph
Advisor
Hahn, Young
Abstract
The liver is a tolerogenic environment exploited by persistent infections such as hepatitis B (HBV) and C (HCV) viruses. Using murine models of intravenous (IV) adenovirus and mouse cytomegalovirus (MCMV) infections, I establish that antiviral CD8+ T cells primed directly in the liver acquire a dysfunctional phenotype characterized by a decreased ability to produce pro-inflammatory cytokines and cytolytically kill target cells. During the onset of intrahepatic viral infection, CD8+ T cell infiltration/expansion are accompanied by the upregulation of three core immunoregulatory pathways: IL-10, PD-1/PD-L1, and Tim-3. To examine the role of hepatic myeloid PD-L1 expression during the early phase of viral infection, I administered PD-L1 siRNA encapsulated in lipidoid nanoparticles (LNP) in mice. My studies indicate that Kupffer cells (KC) preferentially engulfed PD-L1 LNP within a short period of time and silenced Pdl1 during adenovirus and MCMV infections leading to enhanced natural killer (NK) and CD8+ T cell intrahepatic accumulation, effector function, CD8+ T cell-mediated viral clearance, and memory. Without application of PD-L1 LNP, if the dysfunctional liver-primed CD8+ T cells were allowed to expand in the natural setting, these cells also acquired a late phase T regulatory (Treg) cell function on the in vitro and in vivo priming of naïve CD8+ OT-I T cells. Liver-primed CD8+ T cell (herein renamed CD8+ Treg cells) regulatory activity was independent of PD-1/PD-L1 interaction, IL-10 production, and expression of the canonical Tim-3 ligand, Gal-9. I discovered that CD8+ Treg cell surface Tim-3 controls the expansion of antiviral CD8+ Teff cells by binding to a novel ligand, HMGB-1. HMGB-1, originally identified as a DNA binding protein, may therefore act as a potent cytokine controlling the outcome of acute and chronic viral infections in the liver. Although PD-L1 did not appear to directly play a functional role in CD8+ Treg cell suppression at the late phase antiviral immune response, PD-1/PD-L1 signaling from KCs during the early phase promoted the development of CD8+ Treg cells. Overall, KC specific PD-1/PD-L1 negative signaling was central in diminishing the early antiviral immune response, whereas Tim-3 limited late phase CD8+ T cell antiviral immunity in the liver. The presence of IL-10-producing, PD-1+PD-L1+Tim-3+CD8+ T cells in the livers of chronic HCV patients raises the possibility that liver-primed CD8+ T cells could play a pivotal role in dampening hepatic T cell responses in the local tissue microenvironment.
Language
English
Date Received
20130801
Published
University of Virginia, Department of Microbiology, Immunology, and Cancer Biology, PHD (Doctor of Philosophy), 2013
Published Date
2013-07-31
Degree
PHD (Doctor of Philosophy)
Collection
Libra ETD Repository
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