Identification and characterization of murine cytotoxic T cells that kill Mycobacterium tuberculosis

As we seek to develop and evaluate new vaccines against tuberculosis, it is desirable that we understand the mechanisms of protective immunity in our models. Adoptive transfer of protection with hsp65-specific T-cell clones from infected or vaccinated mice into naïve mice had indicated that cytotoxic T cells can make a major contribution to protection. We characterized 28 CD4(+) CD8(-) and 28 CD4(-) CD8(+) hsp65-specific T-cell clones derived from infected or vaccinated mice. Half of the CD4(+) CD8(-) and 64% of the CD4(-) CD8(+) clones were cytotoxic. Cytotoxicity was associated with high expression of CD44 and gamma interferon production. Most (86%) of the cytotoxic CD4(+) CD8(-) clones lysed target cells via the Fas-FasL pathway, and most (83%) of the cytotoxic CD4(-) CD8(+) clones lysed target cells via cytotoxic granules. Only the clones using the granule-mediated pathway caused substantial loss of viability of virulent Mycobacterium tuberculosis during lysis of infected macrophages, and the degree of killing closely correlated with the availability of granule marker enzyme activity. Granule-mediated cytotoxicity thus may have a key role in protection against tuberculosis by delivering mycobactericidal granule contents.