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*
Immunology Unit, Department of Infectious and Tropical Diseases, London School of Hygiene and Tropical Medicine, Keppel Street, London, United Kingdom;
Molecular Immunology Group, Nuffield Department of Clinical Medicine, University of Oxford, John Radcliffe Hospital, Oxford, United Kingdom;
Tuberculosis Research Programme, MRC Laboratories, Fajara, The Gambia; and
§
Glaxo-Wellcome Research and Development, Medicines Research Centre, Stevenage, United Kingdom
The role of CD8+ CTL in protection against tuberculosis
in human disease is unclear. In this study, we stimulated the
peripheral blood mononuclear cells of bacillus Calmette-Guérin
(BCG)-vaccinated individuals with live Mycobacterium
bovis BCG bacilli to establish short-term cell lines and then
purified the CD8+ T cells. A highly sensitive enzyme-linked
immunospot (ELISPOT) assay for single cell IFN-
release was used to
screen CD8+ T cells with overlapping peptides spanning the
mycobacterial major secreted protein, Ag85A. Three peptides
consistently induced a high frequency of IFN- responsive
CD8+ T cells, and two HLA-A*0201 binding motifs,
P48–56 and P242–250, were revealed within the
core sequences. CD8+ T cells responding to the 9-mer
epitopes were visualized within fresh blood by ELISPOT using free
peptide or by binding of HLA-A*0201 tetrameric complexes. The class
I-restricted CD8+ T cells were potent CTL effector cells
that efficiently lysed an HLA-A2-matched monocyte cell line pulsed with
peptide as well as autologous macrophages infected with
Mycobacterium tuberculosis or recombinant vaccinia virus
expressing the whole Ag85A protein. Tetramer assays revealed a 6-fold
higher frequency of peptide-specific T cells than IFN- ELISPOT
assays, indicating functional heterogeneity within the CD8+
T cell population. These results demonstrate a previously unrecognized,
MHC class I-restricted, CD8+ CTL response to a major
secreted Ag of mycobacteria and supports the use of Ag85A as a
candidate vaccine against tuberculosis.
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