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Title page for ETD etd-08072013-164449


Type of Document Dissertation
Author Erickson, John Joseph
Author's Email Address john.erickson@vanderbilt.edu
URN etd-08072013-164449
Title CD8+ T cells are impaired during viral acute respiratory infection by coordinated inhibitory pathways
Degree PhD
Department Microbiology and Immunology
Advisory Committee
Advisor Name Title
Sebastian Joyce Committee Chair
James Crowe Committee Member
John V. Williams Committee Member
Ray S. Peebles Committee Member
Terence Dermody Committee Member
Keywords
  • PD-1
  • impairment
  • CD8+ T cell
  • influenza virus
  • human metapneumovirus
Date of Defense 2013-08-01
Availability unrestricted
Abstract
My thesis project explores mechanisms controlling CD8+ T cell impairment in the lung during viral acute lower respiratory infection. I show that viral infection is required for lung T cell impairment and that cognate viral antigen recognized by the T cell receptor drives this process through the upregulation of inhibitory receptors. One such receptor, programmed death-1 (PD-1), is a key mediator of impairment during both primary infection and reinfection and prevents effective anti-viral immunity. Therapeutic blockade of the PD-1 pathway results in restored lung CD8+ T cell effector functions and enhances viral clearance without exacerbating lower airway pathology. Additionally, I show that PD-1 mediates CD8+ T cell dysfunction in a cell-intrinsic manner and further identify three additional inhibitory receptors that contribute to impairment. In particular, lymphocyte-activation gene 3 (LAG-3) rapidly compensates for loss of PD-1 signaling to return lung CD8+ T cells to an impaired state. In sum, I have elucidated mechanisms controlling lung CD8+ T cell impairment during viral acute lower respiratory infection, which have important implications for design of novel therapeutics and vaccine strategies against respiratory viruses.
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