Mycobacterium tuberculosis (Mtb) resides within a phagosome that resists maturation, yet Mtb antigens are presented on Class I molecules through poorly understood mechanisms. This dissertation characterizes the processing pathways of ten Mtb epitopes presented by both classical and nonclassical Class I molecules in dendritic cells. We show that Mtb antigens access the cytosol via phagosomal retrotranslocation, where they undergo proteasomal or alternative cytosolic protease degradation before TAP-dependent peptide transport. While most epitopes require ER–Golgi processing, HLA‑E–restricted antigens are loaded within the phagosome independent of ER transport. These findings establish cytosolic cross-presentation as the dominant pathway for Mtb antigen presentation.
