H2 complex controls CD4/CD8 ratio, recurrent responsiveness to repeated stimulations, and resistance to activation-induced apoptosis during T cell response to mycobacterial antigens

Abstract

Genetic variation in the major histocompatibility complex (MHC) influences susceptibility and immune responses to Mycobacterium tuberculosis in mice and humans, but connections among the severity of tuberculosis (TB), dynamic changes in T cell responses to mycobacteria, and MHC genetic polymorphisms are poorly characterized. The overall effect of the MHC genes on TB susceptibility and cellular responses to mycobacteria is moderate; thus, such studies provide reliable results only if congenic mouse strains bearing a variety of H2 haplotypes on an identical genetic background are analyzed. Using a panel of H2-congenic strains on the B10 background, we demonstrate that T cells from mice of three different strains, which are resistant to TB infection, readily respond by proliferation to repeated stimulations with mycobacterial sonicate, whereas T cells from three susceptible mouse strains die after the second stimulation with antigen. This difference is specific, as T cells from TB-susceptible and -resistant mouse strains do not differ in response to irrelevant antigens. The CD4/CD8 ratio in immune lymph nodes correlates strongly and inversely with TB susceptibility, being significantly lower in resistant mice as a result of an increased content of CD8+ cells. These differences between the two sets of mouse strains correlate with an elevated level of activation-induced T cell apoptosis in TB-susceptible mice and a higher proportion of activated CD44+ CD62 ligand- T cells in TB-resistant mice. These results may shed some light on the nature of the cellular basis of MHC-linked differences in susceptibility to TB.

Immune responses in the lungs of patients with tuberculous pleural effusion without pulmonary tuberculosis

“…Another study has demonstrated that the CD4+/CD8+ ratio was higher in susceptible TB mice [34]. In the present study, we showed that the CD4+/CD8+ ratio of T lymphocytes changes in patients without active TB infection.…”

H-2 alleles contribute to antigen 85-specific interferon-gamma responses during Mycobacterium tuberculosis infection

“…H-2 genes control multiple aspects of the anti- M.tb immune response, including the generation of antibodies [12], survival of mycobacterial antigen-specific T cells in vitro [13, 14], and in vitro IFN-γ levels produced by T cells [16]. Here, we focused our analysis to identify H-2 k -dependent (comparison of C57BL/6 and C57BL/6 H-2 k data) and -independent (comparison of C57BL/6 H-2 k , CBA/J, C3H/HeJ data) contributions to the anti- M.tb immune response during early M.tb infection in vitro and in vivo .…”

Are mouse models of human mycobacterial diseases relevant? Genetics says: ‘yes!’

“…There is ample evidence that polymorphisms in the MHC region in both species have modest effects on TB susceptibility (reviewed in refs. 22,59), and profound effects on the immune response to mycobacterial antigens 73–75 . However, the number of polymorphic genes located within the MHC region and potentially involved in the anti‐mycobacterial immune response is very large, even if classical Class I and Class II antigen‐presenting molecules and TNF‐like products are left aside.…”