Single-cell resolution map of innate-like lymphocyte response to Francisella tularensis infection reveals protection by interleukin-17-producing MAIT cells

Early immune dynamics during the initiation of fatal tularemia caused by Francisella tularensis infection remain largely unknown. To this 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 1 and interleukin-17-producing type 3 innate-like lymphocytes expand in the infected lungs. Natural killer (NK) and NKT cells drove the type 1 response, whereas mucosal-associated invariant T (MAIT) and gd 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 are enriched in MAIT17 cells, was sufficient to protect LVS-susceptible, immunodeficient RAG2-/- mice from severe LVS-inflicted pathology. Collectively, our findings position MAIT cells as key mediators of interleukin-17-dependent protection from pulmonary tularemia-like disease.