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*
Department of Immunohematology and Blood Transfusion, Leiden University Medical Center, Leiden, The Netherlands;
Department of Mycobacterial Immunology, Pasteur Institute of Brussels, Brussels, Belgium; and
Immunotech, Marseille, France
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-
and TNF-
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.
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