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

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-gamma (IFN-gamma) after restimulation with mycobacterial antigens. In contrast, the MHC class II-deficient A beta-/- mice, which are virtually devoid of functional CD4 T cells, succumbed to M. bovis BCG infection. Furthermore, A beta-/- mice lacked DTH reactions to tuberculin and only few minute picnotic lesions were formed in livers of infected mice. Finally, spleen cells from infected A beta-/- mice failed to produce measurable IFN-gamma concentrations after restimulation in vitro with various mycobacterial antigen preparations. The capacity of beta 2-microglobulin (beta 2m)-deficient mice, which are devoid of CD8 alpha/beta 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-gamma once reactivated by mycobacterial antigens. Furthermore, in livers of infected beta 2m-deficient mice, extravascular infiltrates developed which were more diffuse than those in infected control littermates. Remarkably, the beta 2m-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.

Human CD8+ CTL Specific for the Mycobacterial Major Secreted Antigen 85A

“…The activation of CD4 ϩ T cells has been known for some time to be important for protection against TB; however, there is now mounting evidence from animal models that CD8 ϩ T cells may also be required (10,11). Nevertheless, the existence of CD8 ϩ T cells specific for M. tuberculosis in human disease has only recently come to light (9 -15).…”

Host Responses and Antigens Involved in Protective Immunity to Mycobacterium tuberculosis

“…for the normal generation of protective granulomas and the lack of this subset leads to diffuse and badly organized cellular infiltrates [81].…”

Control of Mycobacterium fortuitum and Mycobacterium intracellulare infections with respect to distinct granuloma formations in livers of BALB/c mice

“…T cell-deficient mice do not form granulomas and form loose inflammatory lesions incapable of controlling bacterial growth. The adoptive transfer of CD4 + T cells reconstitutes granuloma formation in RAG-deficient mice infected with Mycobacterium (Ladel et al 1995). The T cell repertoire of a single granuloma is very diverse and similarly sized granulomas in the same organ from the same animal can have different T cell contents in Mycobacterium-infected mice (Hogan et al 2001).…”

“…On the other hand, compromised granuloma formation is accompanied by dissemination. In addition, the course of the infection in individuals that develop compromised granulomas changes from chronic to acute, leading to high morbidity and mortality from mycobacterial infections (Ladel et al 1995).…”