Tuberculosis uses secretion system to control MHC-I antigen presentation

Tuberculosis, caused by Mtb, remains one of the world's leading infectious killers, and scientists are still piecing together how the immune system recognizes infected cells. CD8 T cells are part of that response because they detect short fragments of proteins, called peptides, presented on MHC-I molecules at the surface of infected cells. But for bacterial peptides to appear on MHC-I, they must reach the cellular machinery that loads and displays them, and the routes by which Mtb antigens access MHC-I have been unclear. In work led by Bryan D. Bryson, researchers set out to define those routes. They combined sensitive protein-detection techniques with genetic changes in both the host cell and the bacteria, and they tested whether the peptides that appeared on MHC-I could activate T cells. The team focused on whether a particular Mtb secretion system influences which peptides reach MHC-I, aiming to move beyond assumptions that host cell damage or general membrane rupture are the primary ways bacterial material reaches antigen-presenting pathways.

To follow peptides that end up on MHC-I, the researchers used quantitative immunopeptidomics along with host and bacterial genetic perturbations and T cell activation assays. They found that presentation of Mtb-derived peptides on MHC-I requires the ESX-1 type VII secretion system. This presentation proceeded in a manner dependent on the transporter associated with antigen processing (TAP) but was independent of host cell mechanisms such as autophagy or MPEG1-mediated pore formation. The team also tested whether breaking the phagosomal membrane by chemical induction of phagosomal membrane damage could substitute for ESX-1, and it could not restore antigen presentation when ESX-1 activity was absent. Together, the methods and results show that a pathogen-encoded secretion system specifically governs access to MHC-I antigen processing pathways, rather than nonspecific membrane rupture or the host processes tested.

These findings reveal a secretion system-driven route for bacterial antigens to reach MHC-I, changing how we think about the interface between mycobacteria and host antigen presentation. By identifying ESX-1 and TAP as key players, the study suggests that some bacterial proteins are intentionally secreted into host pathways that lead to CD8 T cell recognition. That helps explain why certain Mtb peptides are seen by the immune system and points to new avenues for vaccine research: vaccine design strategies might benefit from mimicking or harnessing secretion-dependent delivery to the MHC-I pathway. Beyond tuberculosis, the work highlights a potential route for synthetic antigen delivery to the cytosol that could be exploited in therapeutics and vaccination strategies where controlled access to MHC-I is desirable.