Alveolar and monocyte-derived macrophages differentially engage antibacterial programs during adaptive immunity to Mycobacterium tuberculosis.

Abstract

Abstract Cognate interactions between antigen-specific CD4 T cells and Mycobacterium tuberculosis (Mtb)-infected cells are critical for mucosal immunity to tuberculosis (TB). However, Mtb resides intracellularly within a variety of myeloid cell populations, and the relative impact of CD4 T cells on distinct infected cell types remains unknown. Here we report that intratracheally-transferred, Mtb-specific T cells are unable to reduce the bacterial burden in the first week after aerosol infection, when Mtb resides almost exclusively within alveolar macrophages (AMs). However, transferred T cells do mediate protection by day 14, at which point Mtb has disseminated to monocyte-derived macrophages (MDMs). Using an Mtb “replication clock” strain, which loses plasmid at a fixed rate with bacterial division, we observe that Mtb continues to replicate in AMs even after the onset of adaptive immunity, whereas replication in MDMs is curtailed. We also find that MDMs are less reliant on oxidative metabolism and express more NOS2 than AMs, which may explain their superior antibacterial activity. Finally, RNA-Seq analysis of these two macrophage populations reveals enriched expression of proinflammatory pathways (i.e. NFkB signaling) in Mtb-infected MDMs compared to AMs. Together, our results indicate that AMs may serve as a privileged niche for Mtb, despite the presence of Mtb-specific T cells. As many current TB vaccine candidates seek to induce lung-resident T cells that can recognize and control Mtb early after aerosol infection, the relative resistance of Mtb-infected AMs to T cell-mediated immunity could represent a previously unappreciated barrier to this strategy.