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Title page for ETD etd-11032015-123048

Type of Document Dissertation
Author Hill, Timothy Michael
URN etd-11032015-123048
Title Role of Invariant Natural Killer T Cells in Tularemia-like Disease in Mice
Degree PhD
Department Microbiology and Immunology
Advisory Committee
Advisor Name Title
Luc Van Kaer Committee Chair
Eric Sebzda Committee Member
Larry L. Swift Committee Member
Maria Hadjifrangiskou Committee Member
Sebastian Joyce Committee Member
  • NKT
  • inflammation
  • disease tolerance
Date of Defense 2015-08-03
Availability unrestricted
The respiratory mucosa is a major site for pathogen invasion and, hence, a site requiring constant immune surveillance. The type I, semi-invariant natural killer T (iNKT) cells are enriched within the lung vasculature. Despite optimal positioning, the role of iNKT cells in respiratory infectious diseases remains poorly understood. Hence, their function was assessed in a murine model of pulmonary tularemia—because tularemia is a sepsis-like proinflammatory disease and iNKT cells are known to control the cellular and humoral responses underlying sepsis. These studies show for the first time that respiratory infection with Francisella tularensis live vaccine strain resulted in rapid accumulation of iNKT cells within the lung interstitium. Activated iNKT cells produced interferon-gamma upon recognition of a Francisella-derived glycosphingolipid, and promoted both local and systemic proinflammatory responses. Consistent with these results, iNKT cell-deficient mice showed a reduced inflammatory cytokine and chemokine response yet they survived the infection better than their wild type counterparts. Strikingly, iNKT cell-deficient mice had increased lymphocytic infiltration in the lungs that organized into tertiary lymphoid structures resembling induced bronchus-associated lymphoid tissue (iBALT) at the peak of infection. Thus, iNKT cell activation by F. tularensis infection hampers iBALT formation and promotes a systemic proinflammatory response, which exacerbates severe pulmonary tularemia-like disease in mice.
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