ABSTRACTDespite the extensive research on CD4 T cells within the context ofMycobacterium tuberculosis(Mtb) infections, few studies have focused on identifying and investigating the profile of Mtb-specific T cells within lung granulomas. To facilitate the identification of Mtb-specific CD4 T cells, we identified immunodominant epitopes for two Mtb proteins, namely, Rv1196 and Rv0125, using a Mauritian cynomolgus macaque model of Mtb infection, thereby providing data for the synthesis of MHC class II tetramers. Using tetramers, we identified Mtb-specific cells within different immune compartments, postinfection. We found that granulomas were enriched sites for Mtb-specific cells and that tetramer+cells had increased frequencies of the activation marker CD69 as well as the transcription factors T-bet and RORγT, compared to tetramer negative cells within the same sample. Our data revealed that while the frequency of Rv1196 tetramer+cells was positively correlated with the granuloma bacterial burden, the frequency of RORγT or T-bet within tetramer+cells was inversely correlated with the granuloma bacterial burden, thereby highlighting the importance of having activated, polarized, Mtb-specific cells for the control of Mtb in lung granulomas.