Differential Effects of Control and Antigen-Specific T Cells on Intracellular Mycobacterial Growth

Abstract

It is estimated that one-third of the world's population is infected with Mycobacterium tuberculosis and that tuberculosis (TB) kills more than 2 million people each year (4). Intradermal vaccination of infants with the currently available TB vaccine Mycobacterium bovis bacillus Calmette-Guérin (BCG) can induce partial protection against TB disease (7) but does not prevent initial or latent infection with M. tuberculosis. Once infected, individuals are at chronic risk for TB disease progression and secondary transmission, especially when vaccine immunity wanes or is suppressed. Therefore, the development of a more efficacious TB vaccine strategy capable of preventing or eliminating chronic infection is an important goal.Mycobacteria replicate within macrophages in the human host, and defects in cell-mediated immunity result in increased susceptiblity to these intracellular pathogens. Therefore, it can be predicted that memory-immune T cells capable of inhibiting the intracellular growth of mycobacteria are important for in vivo protection against TB. Mycobacteria-specific CD4 ϩ ␣␤ T cells, CD8 ϩ ␣␤ T cells, and ␥␦ T cells develop in individuals with partial resistance against TB disease, such as healthy purified protein derivative (PPD)-positive persons latently infected with M. tuberculosis and BCG-vaccinated individuals

Hepatitis C Virus Inhibits Cell Surface Expression of HLA-DR, Prevents Dendritic Cell Maturation, and Induces Interleukin-10 Production

“…The experimental design for the experiment was similar to that of work previously described (15,49). For each condition, 4 ϫ 10 4 DCs were resuspended in a total volume of 200 l RPMI medium, RPMI medium plus recombinant human IL-10 (BD Biosciences), control hepatocyte culture medium, or supernatants from HCV-infected hepatocytes.…”

Characterization of Bovine Homologues of Granulysin and NK-lysin

“…Perforin appears to be required for granulysin to enter infected cells and lyse intracellular organisms (1). Despite the cytoplasmic association in granules and cooperative mechanism of action, the levels of protein expressed in infected tissue and mRNA detected after Ag-specific recall indicate that granulysin expression may be regulated separately from perforin upon T cell activation (16,17). Currently, one of the most interesting antimicrobial activities associated with granulysin is the ability to directly kill mycobacteria (18).…”

“…Mycobacterium tuberculosis can be lysed extracellularly by granulysin or NK-lysin (1,5,7), and lysed intracellularly by granulysin following permeation of the cellular membrane by perforin (1). Granulysin-dependent killing of M. tuberculosis-infected targets by CD4 ϩ , CD8 ϩ , and ␥␦ T cells has been inferred from in vitro studies in which granule-dependent killing occurred despite blocking perforin and/or granzyme activity (1,3,16,21,22). Cytotoxic activity by T lymphocytes against Mycobacterium bovis bacillus Calmette-Guérin (BCG) 3 -infected macrophages correlates to increased expression of granulysin in human T cells isolated from peripheral blood of subjects reactive to purified protein derivative (16).…”

“…Granulysin-dependent killing of M. tuberculosis-infected targets by CD4 ϩ , CD8 ϩ , and ␥␦ T cells has been inferred from in vitro studies in which granule-dependent killing occurred despite blocking perforin and/or granzyme activity (1,3,16,21,22). Cytotoxic activity by T lymphocytes against Mycobacterium bovis bacillus Calmette-Guérin (BCG) 3 -infected macrophages correlates to increased expression of granulysin in human T cells isolated from peripheral blood of subjects reactive to purified protein derivative (16). In that study, cytotoxicity against M. bovis-infected targets could be exacted by populations enriched for CD4 ϩ , CD8 ϩ , or ␥␦ TCR-bearing cells.…”

Granzyme A as a potential biomarker of Mycobacterium tuberculosis infection and disease

“…Worku and Hoft have previously demonstrated that increased mRNA expression of perforin, granzyme and granulysin contribute to a protective host response in human TB [27]. This improved mechanism of protection has also been demonstrated using antibody blockage of the granule exocytosis pathway, that dramatically reduced the lytic activity of T cells against Mtb-infected macrophages and the increase of intracellular growth of bacteria [28].…”