The Major Histocompatibility Complex Haplotype Affects T-Cell Recognition of Mycobacterial Antigens but Not Resistance to Mycobacterium tuberculosis in C3H Mice

Abstract

Both innate and adaptive immunity play an important role in host resistance to Mycobacterium tuberculosis infection. Although several studies have suggested that the major histocompatibility complex (MHC) haplotype affects susceptibility to infection, it remains unclear whether the modulation of T-cell immunity by the MHC locus determines the host's susceptibility to tuberculosis. To determine whether allelic differences in the MHC locus affect the T-cell immune response after M. tuberculosis infection, we infected inbred and H-2 congenic mouse strains by the respiratory route. The H-2 locus has a profound effect on the antigen-specific CD4؉ -T-cell response after M. tuberculosis infection. The public health threat caused by tuberculosis is worsening because of the spread of multidrug resistant strains of Mycobacterium tuberculosis, the continued human immunodeficiency virus epidemic, and the demise of the public health infrastructure in many areas of the world. T-cell-mediated immunity and the production of cytokines are critical for the control of infection in humans and in rodent models of the disease (13). Both CD4 ϩ and CD8 ϩ T cells participate in the immune response, and their production of cytokines, including gamma interferon (IFN-␥), is critical for the activation of macrophages, which ultimately kill intracellular bacteria (15,34). A successful immune response can contain the infection, although a few mycobacteria may remain viable in a latent phase within the host's tissue for decades (16,18,36). Most individuals develop immunity to M. tuberculosis, and epidemiological studies indicate that only 5 to 10% of infected individuals will develop tuberculosis during their lifetime. Interestingly, studies comparing individuals that develop protective immunity to people who develop active disease have suggested that genetic factors are important for the development of host resistance to M. tuberculosis (6, 24).The major histocompatibility complex (MHC) locus is known to play a key role in the control of susceptibility to infection. In humans, HLA-DR2 and -DR3 have been associated with susceptibility to pulmonary tuberculosis (38) and tuberculoid leprosy (12). The H-2 genes of mice control the clearance of many pathogens, such as retroviruses (25), protozoa (2, 21), and bacteria (35). Although various studies during the last 20 years have shown that the murine H-2 locus affects immune responsiveness (as measured by the antibody repertoire) or susceptibility (as measured by survival), it is not yet clear whether the modulation of immunity by the MHC locus determines the susceptibility of the host to tuberculosis. The purpose of this study was to determine how allelic differences in the MHC locus affect T-cell immunity to M. tuberculosis infection. Using congenic and inbred mouse strains, we show that the T-cell recognition of M. tuberculosis antigens is determined in part by the MHC haplotype; however, the susceptibility of C3H mice to M. tuberculosis is MHC independent. We found that both C57BL/6 (B6) mice an...

Genetic architecture of tuberculosis resistance in a mouse model of infection

“…However on the susceptible C3H background, the effect of the H-2 b allele on survival after infection with MTB was negligible. 34 Our data are in agreement with findings of Kamath et al in that the H-2-encoded polymorphism(s) is not a major determinant of extreme susceptibility of C3HeB/FeJ to tuberculosis. Indeed, if a major effect of the H-2 locus is on activation of MTBspecific IFN-g producing Th1 cells, as suggested by Kamath et al, it is reasonable to expect that the overall impact of MHC on host resistance would depend on epistatic interactions with other polymorphic gene(s) that determine macrophage responsiveness to the Th1-mediated activation.…”

“…31,32 In mice, different alleles at specific H-2 loci affected survival after i.v. infection with virulent MTB, the level of delayed type hypersensitivity (DTH), T cell proliferative response to mycobacterial antigens, and efficacy of antituberculosis vaccination with live attenuated Mycobacterium bovis (BCG), 31 production of IFN-g by mycobacteria-specific T cells, 33,34 as well as production of mycobacteria-specific antibodies. 9,26 Mouse MHC complex contains several genes that participate in processing and presentation of antigenic peptides to cytokine-producing and cytotoxic T cells.…”

Antigen-Specific CD8+ T Cells and the Development of Central Memory during Mycobacterium tuberculosis Infection

“…4; data not shown) (12,14,15). The phenotype of these pulmonary TB10.4 20 -28 -specific CD8 ϩ T cells is consistent with either effector or effector memory T cells (16).…”

Progression of Pulmonary Tuberculosis and Efficiency of Bacillus Calmette-Guérin Vaccination Are Genetically Controlled via a Common sst1-Mediated Mechanism of Innate Immunity

“…Deficit of functionally active T cells in the tuberculosis lung lesions of the extremely susceptible C3HeB/ FeJ mice could provide a plausible explanation, as to why the adaptive immunity, although active systemically, failed to control tuberculosis progression in the lungs of the sst1 S mice. However, using the H-2 congenic mouse strains Kamath et al (30) have found that the greater number of the Th1-type T cells in the lungs was controlled by the MHC locus on chromosome 17 and associated with the H-2 b haplotype, which, nevertheless, did not correlate with protection. In contrast, we have shown that progression of tuberculosis infection in the lungs was controlled by the sst1 locus (18), although the sst1 polymorphism did not affect the recruitment of T cells to the lungs of the MTB-infected mice, nor the balance of Th1/Th2 cytokine production.…”