Immune response to Mycobacterium bovis bacille Calmette Guérin infection in major histocompatibility complex class I‐ and II‐deficient knock‐out mice: contribution of CD4 and CD8 T cells to acquired resistance

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Abstract
Knock‐out mice with defined major histocompatibility complex (MHC) deficiencies were infected intravenously with Mycobacterium bovis bacille Calmette Guérin (M. bovis BCG) to assess the relative impact of MHC class I‐ and II‐dependent immune responses. Heterozygous control mice were 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 tuberculin. In vitro, spleen cells from heterozygous control mice produced high concentrations of interferon‐γ (IFN‐γ) after restimulation with mycobacterial antigens. In contrast, the MHC class II‐deficient Aβ−/− mice, which are virtually devoid of functional CD4 T cells, succumbed to M. bovis BCG infection. Furthermore, Aβ−/− mice lacked DTH reactions to tuberculin and only few minute picnotic lesions were formed in livers of infected mice. Finally, spleen cells from infected Aβ−/− mice failed to produce measurable IFN‐γ concentrations after restimulation in vitro with various mycobacterial antigen preparations. The capacity of β2‐microglobulin (β2m)‐deficient mice, which are devoid of CD8α/β T cells, to inhibit growth of M. bovis BCG was only slightly affected at low inocula, although significantly higher colony‐forming units were detected in spleens. These knock‐out mice developed strong DTH responses to tuberculin and their spleen cells produced high levels of IFN‐γ once reactivated by mycobacterial antigens. Furthermore, in livers of infected β2m‐deficient mice, extravascular infiltrates developed which were more diffuse than those in infected control littermates. Remarkably, the β2m‐deficient mice were substantially more susceptible to higher inocula 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 MHC class I‐dependent immunity to effective anti‐mycobacterial protection. We assume that CD4 T cells are highly effective in containing M. bovis BCG within distinct granulomatous lesions, but fail to eradicate their intracellular pathogens. It appears most likely that CD8 T cells are also required to achieve this goal.