Identification of Major Epitopes ofMycobacterium tuberculosisAG85B That Are Recognized by HLA-A*0201-Restricted CD8+ T Cells in HLA-Transgenic Mice and Humans

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Abstract
CD8+ T cells are thought to play an important role in protective immunity to tuberculosis. Although several nonprotein ligands have been identified for CD1-restricted CD8+ CTLs, epitopes for classical MHC class I-restricted CD8+ T cells, which most likely represent a majority among CD8+ T cells, have remained ill defined. HLA-A*0201 is one of the most prevalent class I alleles, with a frequency of over 30% in most populations. HLA-A2/Kb transgenic mice were shown to provide a powerful model for studying induction of HLA-A*0201-restricted immune responses in vivo. The Ag85 complex, a major component of secreted Mycobacterium tuberculosis proteins, induces strong CD4+ T cell responses in M. tuberculosis-infected individuals, and protection against tuberculosis in Ag85-DNA-immunized animals. In this study, we demonstrate the presence of HLA class I-restricted, CD8+ T cells against Ag85B of M. tuberculosis in HLA-A2/Kb transgenic mice and HLA-A*0201+ humans. Moreover, two immunodominant Ag85 peptide epitopes for HLA-A*0201-restricted, M. tuberculosis-reactive CD8+ CTLs were identified. These CD8+ T cells produced IFN-γ and TNF-α and recognized Ag-pulsed or bacillus Calmette-Guérin-infected, HLA-A*0201-positive, but not HLA-A*0201-negative or uninfected human macrophages. This CTL-mediated killing was blocked by anti-CD8 or anti-HLA class I mAb. Using fluorescent peptide/HLA-A*0201 tetramers, Ag85-specific CD8+ T cells could be visualized in bacillus Calmette-Guérin-responsive, HLA-A*0201+ individuals. Collectively, our results demonstrate the presence of HLA class I-restricted CD8+ CTL against a major Ag of M. tuberculosis and identify Ag85B epitopes that are strongly recognized by HLA-A*0201-restricted CD8+ T cells in humans and mice. These epitopes thus represent potential subunit components for the design of vaccines against tuberculosis.