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FUNCTION OF MYELOID DENDRITIC CELLS

  • Author / Creator
    Zhao,Li
  • Approximately 70% of patients infected with hepatitis C virus (HCV) develop chronic infection, which has been reported to be due to impaired specific T cell responses. Myeloid dendritic cells (mDCs) are potent antigen-presenting cells that regulate T cell responses, however their role during chronic hepatitis C (CHC) is not fully understood. My hypothesis was that the activity of mDCs to regulate T-cell response against HCV might be changed during CHC infection, and this change might contribute to the impaired T-cell responses that lead to the persistence of HCV infection. The objectives of my thesis were to compare the immunogenic activity (which stimulates T-cell proliferation), tolerogenic activity (which kills T cells), and apoptosis of mDCs from CHC patients and healthy donors. In this thesis, I found that mDCs from CHC patients expressed lower level of activating molecules, HLA-DR and CD86, compared to mDCs from healthy volunteers. When mDCs were cocultured with T cells, there were fewer T cells proliferating in the patient group than in the healthy group. This result indicated that the ability of mDCs to stimulate T cell proliferation was impaired in CHC patients. Moreover, mDCs from CHC patients underwent spontaneous apoptosis at a higher rate than mDCs from healthy donors. Nuclear factor-kappa B (NF-κB) activity, which is critical for mDC function and prevention of apoptosis, was diminished in mDCs from CHC patients. I further studied the tolerogenic activity of mDCs during CHC infection. mDCs from CHC patients expressed up-regulated levels of Fas ligand and the ligand 2 of PD-1 compared to mDCs from healthy volunteers. mDCs from CHC patients can kill T cells, while mDCs from healthy volunteers could not. This result indicated that the tolerogenic activity of mDCs was up-regulated in CHC patients. In conclusion, mDCs from CHC patients demonstrated functional changes with increased apoptosis, and diminished NF-κB activity. mDCs from CHC patients have impaired immunogenic activity to stimulate T-cell proliferation, and have up-regulated tolerogenic activity to kill T cells. These changes might be additional novel mechanisms of immune evasion by HCV, and contribute to the impaired specific T-cell responses observed in CHC patients.

  • Subjects / Keywords
  • Graduation date
    2012-11
  • Type of Item
    Thesis
  • Degree
    Doctor of Philosophy
  • DOI
    https://doi.org/10.7939/R3C411
  • License
    This thesis is made available by the University of Alberta Libraries with permission of the copyright owner solely for non-commercial purposes. This thesis, or any portion thereof, may not otherwise be copied or reproduced without the written consent of the copyright owner, except to the extent permitted by Canadian copyright law.
  • Language
    English
  • Institution
    University of Alberta
  • Degree level
    Doctoral
  • Department
    • Department of Medical Microbiology and Immunology
  • Specialization
    • Immunology
  • Supervisor / co-supervisor and their department(s)
    • D. Lorne Tyrrell
  • Examining committee members and their departments
    • Evans, David (Medical Microbiology and Immunology)
    • Adamko, Darryl (Pediatrics)
    • Kane, Kevin (Medical Microbiology and Immunology)
    • Schang, Luis (Biochemistry)
    • Michalak, Thomas (Memorial university)