An essential role for endogenous interferon-gamma in the generation of protective T cells against Mycobacterium bovis BCG in mice

Protective CD4(+) T cells against Mycobacterium bovis bacillus Calmette-Guerin (BCG), which are characterized by the ability to produce interferon-gamma (IFN-gamma), could be induced by immunization of mice with viable BCG but not with killed BCG. A high level of IFN-gamma mRNA was observed when normal spleen cells were stimulated with viable bur not killed BCG. By comparing mice immunized with either viable or killed M. bovis BCG, it was found that a high level of IFN-gamma mRNA was expressed only after immunization with viable BCG. This finding prompted us to investigate the effect of neutralizing the IFN-gamma on the final generation of protective T cells against M. bovis BCG. When endogenous IFN-gamma was neutralized by administration of anti-IFN-gamma monoclonal antibody in mice immunized with viable BCG, the generation of protective T cells was significantly impaired, as revealed by the adoptive transfer of spleen T cells. The generation of BCG-specific, IFN-gamma-producing T cells was also abolished. These results clearly demonstrate that endogenous IFN-gamma actually plays a critical role in the generation of protective T cells against M. bovis BCG in vivo. Moreover, this study suggests that the lack of IFN-gamma-inducing ability is responsible for the inability of killed M. bovis BCG to induce protective T cells in mice.