"Border Patrol Gone Awry: Lung NKT Cell Activation by Francisella tularensis Exacerbates Tularemia-Like Disease".

Hill T.M. et al, PLoS Pathogens 2015, Jun 11;11(6):e1004975

• In this work  from the Joyce lab, Hill et al. provide insights into the role of NKT cells in mediating the response to infection by the live vaccine strain of Francisella tularensis, in a mouse model of infection. 
  
  
• Type I, semi-invariant natural killer T (NKT) cells are innate-like lymphocytes with a demonstrated role in a wide range of diseases.
  
  
• NKT cells express an invariant TCR α-chain (Vα14-Jα18 in mice and Vα24-Jα18 in humans) and one of a restricted set of TCR β-chains and, hence, called semi-invariant. Their name also reflects their hybrid nature, in that they co-express markers of both NK cells and conventional T cells.
   
  
• Often cited for their ability to rapidly produce a variety of cytokines upon activation, NKT cells  have long been appreciated for their ability to “jump-start” the immune system and to shape the quality of both the innate and adaptive response. 
  
  
• NKT cells are enriched within the lung vasculature where they are optimally positioned for early antigen encounter. 
  
  
• Hill et al., challenged mice intranasally with the live vaccine strain (LVS) of Francisella tularensis to probe the role of lung NKT cells in pulmonary tularemia. In pulmonary tularemia, patients typically show signs of systemic illness, which may be accompanied by immediate signs of respiratory disease and can result in death in 30–60% of cases if left untreated. Although the exact cause of death is unclear, it is likely due to an overwhelming systemic inflammatory response.  
  
  
• In their mouse models of infection, Hill and colleagues discovered that LVS infection activated iNKT cells which produced interferon (IFN)-γ and propagated a sepsis-like proinflammatory response that led to a lethal phenotype in wild type mice. This proinflammatory response was much tempered in CD1d-deficient mice that lacked NKT cells.
  
  
• Strikingly, however, the mutant mice had increased lymphocytic infiltration in the lungs that organized into tertiary structures resembling induced bronchus-associated lymphoid tissue (iBALT) at the peak of infection.
  
  
• iBALT are typically associated with chronic conditions and have been described in the lung for some viral infections.
  
  
• Such early iBALT formation is suggestive of a more vigorous and effective adaptive immune response resulting in reduced systemic inflammation and therefore less severe disease. These findings suggest a suppressive/regulatory role for pulmonary NKT cells.
  

• The regulatory function of NKT cells is just beginning to be elucidated and much of what we know derives from studies utilizing model antigens. The findings from the Joyce lab  provide a model in which to study the potentially detrimental functions of iNKT cells in a natural infection.