Border patrol gone awry: lung NKT cell activation by F. tularensis exacerbates tularemia-like disease (MUC1P.908)

Abstract

The respiratory mucosa is a major site for pathogen invasion and, hence, a site requiring constant immune surveillance. The semi-invariant natural killer T (NKT) cells are enriched within the lung vasculature. Despite optimal positioning for border patrol, the role of NKT cells in respiratory infectious diseases remains poorly understood. Hence, we assessed their function in a murine model of pulmonary tularemia—because tularemia is a sepsis-like proinflammatory disease and NKT cells are known to control the cellular and humoral responses underlying sepsis. Here we show for the first time that respiratory infection with Francisella tularensis live vaccine strain results in rapid recruitment of NKT cells to the lung interstitium. Interstitial NKT cell activation resulted in protective interferon-γ production, and affected both local and systemic proinflammatory responses. Hence, NKT cell-deficient mice showed reduced inflammatory cytokine and chemokine response yet survived the infection whilst their wild type counterparts did not. Strikingly, NKT cell-deficient mice had increased lymphocytic infiltration in the lungs that organized into structures resembling induced bronchus-associated lymphoid tissue (iBALT) at the peak of infection. Thus, NKT cell activation by F tularensis infection hampers iBALT formation, which in conjunction with NKT cell-dependent proinflammatory response causes severe pulmonary tularemia-like disease in mice.