Journal
JOURNAL OF IMMUNOLOGY
Volume 192, Issue 7, Pages 3247-3258Publisher
AMER ASSOC IMMUNOLOGISTS
DOI: 10.4049/jimmunol.1300283
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Funding
- Marie Curie Actions Project [253706]
- Danish Research Council Project [10-094496]
- 7th Framework Programme for Research and Technological Development-HEALTH-2009 [241745]
- Danish National Advanced Technology Foundation [060-2009-3]
- Novo Nordisk Foundation [9686-3014]
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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-gamma- and IFN-gamma, TNF-alpha-coproducing effector cells, characteristic of the endogenous response. In contrast, cryptic epitope-specific CD4 T cells maintained significantly greater IFN-gamma+TNF-alpha+IL-2(+) and TNF-alpha(+) 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.
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