Natural Killer T Cell-Mediated Control Of Francisella Tularensis-Induced Cytokine Storm Syndrome

Inflammation is critical for the effective clearance of viral and bacterial challenges, while simultaneously a mechanism utilized by many highly infectious pathogens to cause disease. The bacterium Francisella tularensis, the causative agent of human tularemia, elicits a cytokine storm, wherein the immune system over-responds to the presence of the bacterium causing a dysregulated release of proinflammatory and regulatory cytokines. Without treatment, tularemia mortality can be as high as 30%, with inhalation of as few as 10 CFUs inducing respiratory tularemia. Natural Killer T (NKT) cells are innate-like T lymphocytes with a diverse array of regulatory functions. Unlike conventional T cells, NKT cells recognize lipid and glycolipid antigens, rather than peptides, which are presented by MHC class I-like CD1d molecules. NKT cells are activated very early following Francisella infection suggesting a critical role in the innate immune response in tularemia. NKT cells are categorized into two distinct subtypes, types I and II, with an unresolved understanding of their individual characteristics in regulating inflammation. This study aims to elucidate the regulatory role of NKT subtypes in response to Francisella tularensis infection and identify the mechanisms utilized in their response. Through ex-vivo and in-vivo techniques, we observed a moderate suppression of inflammation when both subtypes of NKT cells are present. This phenotypic suppression is disrupted when each subtype responds individually to infection. We have characterized the mechanism of NKT suppression of Francisella induced inflammation to be mediated by secreted factors. Our findings suggest that type I NKT cells strongly suppress inflammation, with interleukin-22 (IL-22) playing a crucial role in this inhibition. The results of this study suggest that NKT cells, particularly type I, could be leveraged for therapeutic applications in inflammatory diseases like tularemia and other NIH priority infectious diseases.