Korean Lepr Bull.  2002 Jul;35(1):3-10.

Protective Immune Mechanism against Mycobacterial tuberculosis Infection

• Cho S

Abstract

Because tuberculosis (TB) causes 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 class II-restricted T cells contribute to immunity against TB. MHC class II-restricted CD4+ T cells release lymphokines such as IFN-gamma and tumor necrosis factor-alpha that result in macrophage activation. More importantly, beta(2)-microglobulin (beta(2)m)-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 I A(*)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 (ThyA(30-38)), RNA polymerase beta-subunit (RpoB(127-135)), and a putative phosphate transport system permease protein A-1 (PstA1(75-83)). In addition, CD8+ T cell lines specific for three peptides (ThyA(30-38), PstA1(75-83), and 85B(15-23)) were generated from peripheral blood mononuclear cells of normal HLA-Al(*)0201 donors. These CD8+ T cell lines specifically recognized MTB-infected macrophages, as demonstrated by production of IFN-gamma 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.

MeSH Terms

Animals
Antigen Presentation
Bacteria
Cell Line
DNA-Directed RNA Polymerases
Epitopes
Humans
Lymphokines
Macrophage Activation
Macrophages
Mice
Mycobacterium tuberculosis
Peptides
T-Lymphocytes
T-Lymphocytes, Cytotoxic
Thymidylate Synthase
Tissue Donors
Tuberculosis*
Tumor Necrosis Factor-alpha
DNA-Directed RNA Polymerases
Epitopes
Lymphokines
Peptides
Thymidylate Synthase
Tumor Necrosis Factor-alpha