Protective CD4 T Cells Targeting Cryptic Epitopes of Mycobacterium tuberculosis Resist Infection-Driven Terminal Differentiation

CD4 T cells are crucial to the control of Mycobacterium tuberculosis infection and are a key component of current vaccine strategies. Conversely, immune-mediated pathology drives disease, and recent evidence suggests that adaptive and innate responses are evolutionarily beneficial to M. tuberculosis. We compare the functionality of CD4 T cell responses mounted against dominant and cryptic epitopes of the M. tuberculosis 6-kDa early secreted Ag (ESAT-6) before and postinfection. Protective T cells against cryptic epitopes not targeted during natural infection were induced by vaccinating mice with a truncated ESAT-6 protein, lacking the dominant epitope. The ability to generate T cells that recognize multiple cryptic epitopes was MHC-haplotype dependent, including increased potential via heterologous MHC class II dimers. Before infection, cryptic epitope-specific T cells displayed enhanced proliferative capacity and delayed cytokine kinetics. After aerosol M. tuberculosis challenge, vaccine-elicited CD4 T cells expanded and recruited to the lung. In chronic infection, dominant epitope-specific T cells developed a terminal differentiated KLRG1(+)/PD-1(lo) surface phenotype that was significantly reduced in the cryptic epitope-specific T cell populations. Dominant epitope-specific T cells in vaccinated animals developed into IFN-γ- and IFN-γ,TNF-α-coproducing effector cells, characteristic of the endogenous response. In contrast, cryptic epitope-specific CD4 T cells maintained significantly greater IFN-γ(+)TNF-α(+)IL-2(+) and TNF-α(+)IL-2(+) memory-associated polyfunctionality and enhanced proliferative capacity. Vaccine-associated IL-17A production by cryptic CD4 T cells was also enhanced, but without increased neutrophilia/pathology. Direct comparison of dominant/cryptic epitope-specific CD4 T cells within covaccinated mice confirmed the superior ability of protective cryptic epitope-specific T cells to resist M. tuberculosis infection-driven T cell differentiation.