A Subset of Mycobacteria-Specific CD4 + IFN-γ + T Cell Expressing Naive Phenotype Confers Protection against Tuberculosis Infection in the Lung.

Failure of the most recent tuberculosis (TB) vaccine trial to boost bacillus Calmette-Guerin-mediated anti-TB immunity despite the induction of Thl-specific central memory cell and effector memory cell responses highlights the importance of identifying optimal T cell targets for protective vaccines. In this study, we describe a novel, Mycobacterium tuberculosis-specific IFN-gamma(+)CD4(+) T cell population expressing surface markers characteristic of naive-like memory T cells (T-NLM), which were induced in both human (CD45RA(+)CCR7(+)CD27(+)CD95(-)) and murine (CD62L(+)CD44(-)Sca-1(+)CD122(-)) systems in response to mycobacteria. In bacillus Calmette-Guerin-vaccinated subjects and those with latent TB infection, T-NLM were marked by the production of IFN-gamma but not TNF-alpha and identified by the absence of CD95 expression and increased surface expression CCR7, CD27, the activation markers T-bet, CD69, and the survival marker CD74. Increased tetramer-positive T-NLM frequencies were noted in the lung and spleen of ESAT-6(1-20)-specific TCR transgenic mice at 2 wk postinfection with M. tuberculosis and progressively decreased at later time points, a pattern not seen with TNF-alpha(+)CD4(+) T cells expressing naive cell surface markers. Importantly, adoptive transfer of highly purified T-NLM alone, from vaccinated ESAT-6(1-20)-specific TCR transgenic mice, conferred equivalent protection against M. tuberculosis infection in the lungs of Rag(-/-) mice when compared with total memory populations (central and effector memory cells). Thus, T-NLM may represent a memory T cell population that, if optimally targeted, may significantly improve future TB vaccine responses.