High bacillary burden and the ESX-1 type VII secretion system promote MHC class I presentation by <i>Mycobacterium tuberculosis</i> infected macrophages to CD8 T-cells

Abstract Mycobacterium tuberculosis (Mtb) subverts host defenses to persist in macrophages despite immune pressure. CD4 T-cells can recognize macrophages infected with a single bacillus in vitro . Under identical conditions, CD8 T-cells inefficiently recognize infected macrophages and fail to restrict Mtb growth, although they can inhibit Mtb growth during high burden intracellular infection. We show that high intracellular Mtb numbers cause macrophage death, leading other macrophages to scavenge cellular debris and cross-present the TB10.4 antigen to CD8 T-cells. Presentation by infected macrophages requires Mtb to have a functional ESX-1 type VII secretion system. These data indicate that phagosomal membrane damage and cell death promote class I MHC presentation of the immunodominant antigen TB10.4 by macrophages. Although this mode of antigen-presentation stimulates cytokine production that we presume would be host beneficial; killing of uninfected cells could worsen immunopathology. We suggest that shifting the focus of CD8 T-cell recognition to uninfected macrophages would limit the interaction of CD8 T-cells with infected macrophages and impair CD8 T-cell mediated resolution of tuberculosis.