Single-cell resolution map of innate-like lymphocyte response to Francisella tularensis infection reveals MAIT cell role in protection from tularemia-like disease

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-γ-producing type 1 and interleukin-17-producing type 3 innate-like lymphocytes expanded in the infected lungs. Natural killer (NK) and NKT cells drove the type 1 response, whereas mucosal-associated invariant T (MAIT) and γδ T cells drove the type 3 response. Furthermore, tularemia-like disease-resistant NKT cell-deficient, Cd1d - /- mice accumulated more MAIT1 cells, MAIT17 cells, and cells with a hybrid phenotype between MAIT1 and MAIT17 cells than wild-type mice. Critically, adoptive transfer of LVS-activated MAIT cells from Cd1d - /- mice, which were enriched in MAIT17 cells, was sufficient to protect LVS-susceptible, immunodeficient RAG2 -/- mice from severe LVS infection-inflicted pathology. Collectively, our findings position MAIT cells as potential mediators of interleukin-17-dependent protection from pulmonary tularemia-like disease. HIGHLIGHTS Pulmonary F. tularensis LVS infection induces type 1 & type 3 immune responses. NK and NKT cells drive type 1, whilst MAIT and γδT cells drive type 3 responses. Increased MAIT17 cell accumulation is associated with resistance to TID. Adoptive transfer of MAIT17-enriched cells protect immunodeficient mice from TID.