A Delicate Balance: Elucidating the Dynamics of the Immune Landscape in Response to Pulmonary Francisella Tularensis Infection

Abstract

Early immune dynamics during the initiation of fatal tularemia caused by Francisella tularensis infection remain unknown. Unto that end, we generated a transcriptomic map at single-cell resolution of the innate-like lymphocyte responses to F. tularensis live vaccine strain (LVS) infection of mice. We found that both interferon-g-producing type I and interleukin-17-producing type III innate-like lymphocytes expanded in the infected lungs. Natural killer (NK) and NKT cells drove the type I response, whereas mucosal-associated invariant T (MAIT) and gd T cells drove the type III response. Furthermore, tularemia-like disease-resistant, NKT cell-deficient Cd1d-/- mice accumulated more MAIT1 cells and MAIT17 cells, than wild-type mice. Critically, adoptive transfer of LVS-activated MAIT17- but not MAIT1-enriched MAIT cells, was sufficient to protect LVS-susceptible, immunodeficient mice from severe LVS infection-inflicted pathology. These MAIT17 cells expressed factors that promote iBALT formation suggesting a potential mechanism of MAIT-mediated protection from severe LVS-induced disease. Moreover, mice deficient in IL-21 signaling accumulated significantly less MAIT17 cells and were more susceptible to LVS-induced disease. Finally, depletion of S100a9-expression from neutrophils increased accumulation of MAIT17 cells, which was accompanied by reduced neutrophil accumulation. Collectively, these findings position MAIT cells as key mediators of interleukin-17-dependent protection from pulmonary tularemia-like disease