High bacillary burden and the ESX-1 type VII secretion system promote MHC class I presentation to CD8 T-cells during Mycobacterium tuberculosis infection

Abstract

T-cell mediated immunity is required for optimal protection against Mycobacterium tuberculosis (Mtb) infection, but often fails to completely clear the pathogen. Mtb has evolved strategies to subvert host immunity so it can persist in host cells despite pressure from innate and adaptive immunity. While cytotoxic CD8 T-cells should recognize and clear infected host cells, eliminating Mtb’s intracellular niche, previous findings have demonstrated otherwise [1]. In fact, we have shown that CD8 T-cells specific to the immunodominant antigen TB10.4 poorly recognize Mtb infected macrophages in vitro. Here we extend our initial findings to show that class I MHC-restricted epitopes other than TB10.44-11 are inefficiently presented by Mtb-infected macrophages to CD8 T cells. The only exception we find is for heavily infected macrophages. During high burden infections, macrophages cross-present TB10.4 antigen to CD8 T-cells. These high burden infections result in considerable cell death, and we find that uninfected macrophages effectively scavenge dead cellular debris and cross-present this antigen to CD8 T cells. Furthermore, we find that cross-presentation by heavily infected cells is dependent on the ESX-1 type VII secretion system, suggesting that phagosomal membrane damage and host cell death are crucial for effective class I MHC cross-presentation during Mtb infection.