Heterogeneity of lung mononuclear phagocytes enables M. tuberculosis evasion of IFN-γ responses 2773

Abstract Description Mycobacterium tuberculosis (Mtb) can reside in distinct lung phagocyte subsets. We previously found that, in the presence of adaptive immunity, alveolar macrophages (AM) control Mtb, while monocyte-derived phagocytes (permissive MNC1 and less permissive MNC2) allow the bacteria to survive during chronic infection. However, the underlying mechanisms of functional heterogeneity in these subsets are incompletely understood. Using RNA sequencing, flow sorting, immunofluorescence imaging, and functional assays, we determined that MNC1 cells express lower levels of IFN-γ-induced proteins and are hyporesponsive to IFN-γ ex vivo compared to AM and MNC2. MNC1 cells also exhibit impaired Mtb antigen presentation to CD4 T cells. We further show that prior immunity mediated by contained Mtb infection (CoMtb) not only increases IFN-γ responsiveness of MNC cells, but also reduces the bacterial burden in MNC subsets and the infected lungs. Our findings provide evidence that heterogeneity in IFN-γ responsiveness is a novel evasion mechanism employed by Mtb to establish persistence in specific lung mononuclear phagocytes. Overcoming or bypassing limited IFN-γ responsiveness are potential strategies to improve Mtb control, and our findings have implications for the design of TB vaccines. Funding Sources Supported by NIH/NIAID U01AI166309; Tuberculosis Research and Mentoring Program; Mentored Scientist Award in Tuberculosis Topic Categories Microbial, Parasitic, and Fungal Immunology (MPF)