Antigen-specific CD4+ T cells promote monocyte recruitment and differentiation into glycolytic lung macrophages to control Mycobacterium tuberculosis.

Although lung myeloid cells provide an intracellular niche for Mycobacterium tuberculosis (Mtb), CD4+ T cells limit Mtb growth in these cells to protect the host. Here, we show that monocyte-derived macrophages (MDMs), instead of phenotypically similar dendritic cells, are preferentially infected with Mtb in murine lungs. Mtb-specific CD4+ T cells recruited monocyte precursors of MDMs into the lungs via interferon-? (IFN-?). Although the CD4+ T cells increased the number of Mtb-infectable cells in the lungs, they then attenuated Mtb growth by engaging in MHC class II (MHCII)-mediated cognate interactions with monocyte-derived cells to promote their disinfection. Specifically, cognate CD4+ T cell help via MHCII enhanced MDM expression of glycolytic genes independently of IFN-?. These results indicate that CD4+ T cells recruit infectable MDMs to the lungs and trigger glycolysis-dependent bacterial control within them by engaging MHCII-bound Mtb peptides on their surfaces. Overall design: Tamoxifen-fed Cre negative, H2-Ab1-flox/flox (samples 1 and 2, 2 biological replicates) and Ccr2-CreERT2, H2-Ab1-flox flox mice (samples 3 and 4, 2 biological replicates) were infected with Mycobacterium tuberculosis strain H37Rv via standard low-dose aerosol inoculation (~100 colony forming units/mouse). At 3 weeks post-infection, lung single cell suspensions were generated, sorting was performed to enrich for monocytes, macrophages and dendritic cells, and single cell RNA sequencing was performed using the 10X Genomics 3' Single Cell Gene Expression kit.