Poster Presentation Lorne Infection and Immunity 2013

Novel insights into the in vivo regulation of IFN-γ secretion during Salmonella Typhimurium infection (#135)

Andreas Kupz 1 , Timothy Scott 1 , Sammy Bedoui 1 , Richard Strugnell 1
  1. University of Melbourne, Parkville, VIC, Australia

IFN-γ secretion constitutes a critical element in the host defense against experimental and clinical Salmonella infections. However, the exact cellular sources and mechanisms that regulate these responses still remain poorly resolved. Using a mouse model of systemic Salmonella Typhimurium infection, we observed that only a lack of either all lymphocytes, or Thy1+ cells, but not the absence of T, NK, NKT, RORγt+ and/or B cells alone replicated the highly susceptible phenotype of IFN-γ-deficient mice to systemic disease. Subsequently we identified antigen-independent memory CD8+ T cells and Thy1+ NK cells as important sources of host-protective IFN-γ during Salmonella infections. These responses were regulated through a complex in vivo mechanism that involved intracellular sensing of flagellin and provided robust protection against bacterial replication.

Inspired by recent reports of Thy1+ NK cells contributing to immunological memory, we also analyzed the role of Thy1+ NK cells in secondary protection against otherwise lethal wild-type SL1344 Salmonella infections. Intriguingly, we observed that a vaccine strain carrying mutations in the Entner-Doudoroff and Embden-Meyerhoff-Parnas metabolic pathways not only conferred superior protection when compared to conventional vaccination regimens, but also that this enhanced efficiency was afforded through involvement of Thy1+ NK cells in the secondary response. Taken together, these findings provide a comprehensive mechanistic framework for the regulation of antigen-independent IFN-γ secretion during Salmonella infections and ascribe a critical role for Thy1-expressing NK cells in immunity against Salmonella infections. More braoadly these findings have important implications for our understanding of non-cognate and cognate anti-bacterial immunity.