Professor Vanderbilt University Medical Center Nashville, Tennessee, United States
Disclosure(s):
Sebastian Joyce, PhD: No financial relationships to disclose
Introduction/Rationale: Here we demonstrate that respiratory infection with Francisella tularensis induces the formation of induced bronchus-associated lymphoid tissue (iBALT) as a protective mechanism against pulmonary tularemia-like disease in mice. While semi-invariant natural killer T (NKT) cells and mucosal-associated invariant T (MAIT) cells are abundant at the lung mucosa, their roles in infectious diseases remain poorly understood. Pulmonary tularemia, the most severe form of tularemia, arises from respiratory infection with F. tularensis. Using C57BL/6 mice infected with the live vaccine strain (LVS) of F. tularensis to model tularemia-like disease, we previously showed that NKT cells exacerbate disease, as NKT-deficient CD1d⁻/⁻ mice were protected. Notably, protected CD1d⁻/⁻ mice developed iBALT structures in the lungs, which were absent in C57BL/6 mice.
Methods: Molecular immunology methods.
Results: Respiratory LVS infection in CD1d⁻/⁻ mice induced a robust expansion of IL-17-producing MAIT17 cells and a decrease in regulatory T cells in the lungs compared to C57BL/6 mice. Single-cell RNA sequencing revealed a gene signature in MAIT cells linked to factors that drive iBALT formation. Supporting this notion, adoptive transfer of LVS-activated lung MAIT cells from infected CD1d⁻/⁻ mice conferred protection against tularemia-like disease in RAG2⁻/⁻ recipients, while splenic MAIT cells did not despite the fact that both populations homed to the lungs after transfer. Lung-derived MAIT cells were enriched in IL-17-producing MAIT17 cells, whereas splenic MAIT cells predominantly consisted of interferon-gamma-producing MAIT1 cells. Last, IL-17 was identified as critical for iBALT development during respiratory LVS infection in CD1d⁻/⁻ mice.
Conclusion: In summary, our findings establish MAIT cells as central mediators of IL-17-dependent protection against pulmonary tularemia-like disease and underscore the potential protective role of iBALT in disease resistance.
