Comparative Analysis of T Lymphocytes Recovered from the Lungs of Mice Genetically Susceptible, Resistant, and Hyperresistant toMycobacterium tuberculosis-Triggered Disease

Abstract

Genetic control of susceptibility to tuberculosis (TB) is being intensively studied, and immune responses to mycobacteria are considerably well characterized. However, it remains largely unknown which parameters of response distinguish resistant and susceptible TB phenotypes. Mice of I/St and A/Sn inbred strains and (A/Sn × I/St)F1 hybrids were previously categorized as, respectively, susceptible, resistant, and hyperresistant to Mycobacterium tuberculosis-triggered disease. In the present work we compared parameters of lung T cell activation and response following M. tuberculosis challenge. In all mice, the disease progression was accompanied by a marked accumulation in the lungs of activated CD4+ (CD44high/CD45RBlow) and CD8+ (CD44high/CD45RB+) T cells capable of secreting IFN-γ and of activating macrophages for NO production and mycobacterial growth inhibition. However, significantly more CD8+ T cells were accumulated in the lungs of resistant A/Sn and F1 compared with I/St mice. About 80% A/Sn and F1 CD8+ cells expressed CD44high/CD45RB+ phenotype, while about 40% I/St CD8+ cells did not express CD45RB marker at week 5 of infection. In contrast, in susceptible I/St mice lung CD4+ cells proliferated much more strongly in response to mycobacterial sonicate, and a higher proportion of these cells expressed CD95 and underwent apoptosis compared with A/Sn cells. Unseparated lung cells and T cells of I/St origin produced more IL-5 and IL-10, respectively, whereas their A/Sn and F1 counterparts produced more IFN-γ following infection. F1 cells overall expressed an intermediate phenotype between the two parental strains. Such a more balanced type of immune reactivity could be linked to a better TB defense.

Increased Susceptibility of Mice Lacking T-bet to Infection withMycobacterium tuberculosisCorrelates with Increased IL-10 and Decreased IFN-γ Production

“…By enrichment of the T cell population from M. tuberculosis-infected lung, we were able to demonstrate that PPD-reactive lung resident T cells, in the absence of T-bet, produced elevated levels of IL-10 at 5 and 9 wk postinfection. In agreement with Turner Many studies have reported the immunosuppressive activities of IL-10 on the control of mycobacterial disease (12,(43)(44)(45)(46)(47). Macrophages are deactivated in the presence of IL-10 and down-regulate production of inflammatory cytokines such as TNF-␣ and IL-12-p40, resulting in increased organ mycobacterial burden (45,48).…”

Influence of ESAT-6 Secretion System 1 (RD1) of Mycobacterium tuberculosis on the Interaction between Mycobacteria and the Host Immune System

“…infection of mice with M. tuberculosis have been well characterized (22,23). Indeed, percentages of both CD4 ϩ and CD8 ϩ T cells peak at 3-4 wk postinfection, which correlates with the end of the acute phase of infection.…”

“…Indeed, percentages of both CD4 ϩ and CD8 ϩ T cells peak at 3-4 wk postinfection, which correlates with the end of the acute phase of infection. Even if the expression of the adhesion molecule CD44 is not essential for the proper trafficking of T cells into the lungs (24), the presence of both CD4 ϩ and CD8 ϩ T cells with CD44 high phenotype in the lungs is a hallmark of activated antimycobacterial T cells (22,23). The CD44 high phenotype of T cells is further associated with low expression of CD62L and CD45RB.…”

Chronic pneumonia despite adaptive immune response to Mycobacterium bovis BCG in MyD88-deficient mice

“…31,32 In brief, mice were deeply anaesthetised with xylazine-ketamine, bronchoalveolar lavage with NaCl 0.9% was performed and the mice were perfused with 0.02% EDTA-PBS until the tissue turned white. After removal, lung tissue was sliced into 1-2 mm 3 pieces and was incubated in RPMI 1640 (Gibco, Paisley, Scotland, UK) containing 5% foetal calf serum, antibiotics (Penicillin 100 U/ml-streptomycin 100 mg/ml), 10 mM HEPES (Gibco) and collagenase (150 U/ml), DNase (50 U/ml; Sigma, St Louis, MO, USA).…”