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

Abstract

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-1lo 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.