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. The CD4+ T cell activities including
interferon-γ (IFN-γ) production that account for this protection are
poorly understood. Using intravenous antibody labeling and lineage-tracing
reporter mice, we show that monocyte-derived macrophages (MDMs), rather
than phenotypically similar monocytes or dendritic cells, are
preferentially infected with Mtb in murine lungs. MDMs were recruited to
the lungs by Mtb-specific CD4+ T cells via IFN-γ, which promoted the
extravasation of monocyte precursors from the blood. It was possible that
CD4+ T cells recruited infectable MDMs because these cells are uniquely
poised to receive cognate MHCII-mediated help to control intracellular
bacteria. Mice with MHCII deficiency in monocyte-derived cells had normal
Mtb-specific CD4+ T cell activation, expansion and differentiation but the
CD4+ T cells were unable to attenuate Mtb growth. Using single cell RNA
sequencing, we showed that MDMs receiving cognate MHCII-mediated help from
CD4+ T cells upregulated glycolytic genes associated with Mtb control.
Overall, the results indicate that CD4+ T cells recruit
infectable MDMs to the lungs then trigger glycolysis-dependent bacterial
control in the MDMs by engaging their MHCII-bound Mtb peptides. Moreover,
the results suggest that cognate MHCII-mediated help to promote MDM
glycolysis is an essential, IFN-γ-independent effector function of
Mtb-specific CD4+ T cells.