IMMUNE-RESPONSE TO MYCOBACTERIUM-BOVIS BACILLE CALMETTE-GUERIN INFECTION IN MAJOR HISTOCOMPATIBILITY COMPLEX CLASS I-DEFICIENT AND II-DEFICIENT KNOCK-OUT MICE - CONTRIBUTION OF CD4 AND CD8 T-CELLS TO ACQUIRED-RESISTANCE

Knock-out mice with defined major histocompatibility complex (MHC) def iciencies were infected intravenously with Mycobacterium bovis bacille Calmette Guerin (M. bovis BCG) to assess the relative impact of MHC c lass I- and II-dependent immune responses. Heterozygous control mice w ere capable of controlling growth of M. bovis BCG, although infection progressed chronically, as assessed by determination of colony-forming units. Furthermore, infected controls developed granulomatous lesions at the site of mycobacterial growth and delayed-type hypersensitivity (DTH) reactions;after challenge with purified protein derivative of t uberculin. In vitro, spleen cells from heterozygous control mice produ ced high concentrations of interferon-gamma (IFN-gamma) after restimul ation with mycobacterial antigens. In contrast, the MHC class II-defic ient A beta(-/-) mice, which are virtually devoid of functional CD4 T cells, succumbed to M. bovis BCG infection. Furthermore, A beta(-/-) m ice lacked DTH reactions to tuberculin and only few minute picnotic le sions were formed in livers of infected mice. Finally, spleen cells fr om infected A beta(-/-) mice failed to produce measurable IFN-gamma co ncentrations after restimulation in vitro with various mycobacterial a ntigen preparations. The capacity of beta Z-microglobulin (beta 2m)-de ficient mice, which are devoid of CD8 alpha/beta T cells, to inhibit g rowth of M. bovis BCG was only slightly affected at low inocula, altho ugh significantly higher colony-forming units were detected in spleens . These knock-out mice developed strong DTH responses to tuberculin an d their spleen cells produced high levels of IFN-gamma once reactivate d by mycobacterial antigens. Furthermore, in livers of infected beta 2 m-deficient mice, extravascular infiltrates developed which were more diffuse than those in infected control littermates. Remarkably, the be ta 2m-deficient mice were substantially more susceptible to higher ino cula of M. bovis BCG than their control littermates. Our data formally prove the essential role of MHC class II-dependent immune mechanisms in all relevant aspects of immunity to M. bovis BCG. In addition, our findings emphasize an important contribution of MNC class I-dependent immunity to effective anti-mycobacterial protection. We assume that CD 4 T cells are highly effective in containing M.bovis BCG within distin ct granulomatous lesions, but fail to eradicate their intracellular pa thogens. It appears most likely that CD8 T cells are also required to achieve this goal.