Because tuberculosis (TB) cause two - three million deaths annually, development of a vaccine to control and eradicate the infection is an important unmet medical need. Analysis of the mechanisms of protective immunity in mouse models has
indicated
that
both MHC class Ⅰ- and MHC class Ⅱ-restricted T cells contribute to immunity against TB. MHC class Ⅱ-restricted CD4+ T cells release lymphokines such as IFN-γ and tumor necrosis factor-α that result in macrophage activation. More
importantly,
β2-microglobulin (β2m)-deficient mice are unable to develop MHC class Ⅰ-restricted cytotoxic T lymphocytes (CTL) and rapidly succumb to Mycobacterium tuberculosis (MTB) infection. This pathway of protective immunity
appears
to
involve CD8+ T cells and transporters associated with antigen processing (TAP)-dependent presentation of peptide antigen. Thus, studies of mouse models of tuberculosis (TB) infection have indicated a central role for MHC class Ⅰ-restricted CD8+
T
cells
in protective immunity. Furthermore, CD8+ T cells not only are able to lyse MTB infected cells but also can simultaneously kill intracellular bacteria by the release of the antimicrobial peptide granulysin.
To define antigens and epitopes of Mycobacterium tuberculosis (MTB) proteins that are presented by infected cells to CD8+ T cells, we screened 40 MTB proteins for HLA class ⅠA*0201-binding motifs. Peptides that bound with high
affinity
to
purified HLA molecules were subsequently analyzed for recognition by CD8+ cytotoxic T lymphocytes. We identified three epitopes recognized by CD8+ T cells from patients recovering from TB infection. Those three epitopes were derived from three
different
antigens: thymidylate synthase (ThyA30-38), RNA polymerase β-subunit (RpoB127-135), and a putative phosphatge transport system permease protein A-1 (PstA175-83). In addition, CD8+ T cell lines specific for three
peptides (ThyA30-38, PstA175-83, and 85B15-23) were generated from peripheral blood mononuclear cells of normal HLA-A1*0201 donors. These CD8+ T cell lines specifically recognized MTB-infected
macrophages, as
demonstrated by production of IFN-γ and lysis of the infected target cells. Finally, CD8+ cytotoxic T lymphocytes reduced the viability of the intracellular MTB, providing evidence that CD8+ T cell recognition of MHC class Ⅰ-restricted epitopes
of
these MTB antigens can contribute to effective immunity against tuberculosis. Currently, the frequencies of circulating CD8+ T cells specific for each epitope peptide are being investigated in TB patients, normal PPD+ and PPD- donors in order to
evaluate the relationship of epitope-specific CD8+ T cell population to the immune responses to MTB infection.
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