NKT cells exacerbate pulmonary tularemia-like disease in mice by suppressing protective IL-17-mediated MAIT cell immunity 3578

Abstract Description Both semi-invariant natural killer T (NKT) and mucosal associated invariant T (MAIT) cells are enriched at the lung mucosa but their roles in respiratory diseases are not fully understood. Pulmonary tularemia, caused by Francisella tularensis (Ft) is associated with most severe form of the disease with significantly enhanced mortality. We have found a pro-inflammatory role for NKT cells in tularemia-like disease caused by intranasal (i.n.) LVS infection of C57BL/6 (B6) mice. By contrast, NKT cell deficient CD1d-/- mice were protected from tularemia-like disease caused by i.n. LVS infection. Protected CD1d-/- mice showed increased iBALT structures in the lungs which were absent in NKT-cell sufficient B6 mice. While IL-17 is known to promote iBALT formation, Tregs are known to suppress them. We have found significantly enhanced IL-17 producing MAIT17 cells and reduced Treg numbers in lungs of CD1d-/- mice when compared to B6 mice 7 days post inoculation (dpi) with LVS. In a preliminary experiment we found that adoptive transfer of LVS-activated MAIT cells sorted from the lungs of infected CD1d-/- mice protected Rag2-/- recipients from developing tularemia-like disease while splenic MAIT cells did not. Lung MAIT cells are enriched in MAIT17 in comparison to splenic MAIT cells, which are enriched in interferon (IFN)-g producing MAIT1 cells. Thus, enhanced protection in CD1d-/- mice compared to B6 mice is due to MAIT17-cell-associated qualitative and quantitative differences. Funding Sources Supported by VA merit awards BX001444 & BX001610 and BX000915; NIH grants AI137082, AI139046 and HL136664. GDO and NUC were supported by T32GM007347 and NUC by F30HL159941. Topic Categories Innate Immune Responses and Host Defense: Cellular Mechanisms (INC)