The role of B7 molecules in the cell contact-mediated suppression of T cell mitogenesis by immunosuppressive macrophages induced with mycobacterial infection

We found previously that immunosuppressive macrophages (Mφs) induced by Mycobacterium intracellulare infection (MI-Mφs) transmitted their suppressor signals to target T cells through cell contact with target T cells. In this study, we examined what kinds of Mφ surface molecules are required for such cell–to–cell interaction. First, it was found that a B7-1-like molecule (B7–1LM) recognizable with one of three test clones of anti-B7-1 monoclonal antibodies (mAbs) was required for expression of the Mφ suppressor activity. Neither anti-B7-2, anti-ICAM-1, nor anti-VCAM-1 mAb blocked the Mφ suppressor activity. Second, MI-Mφs increased the expression of B7–1LM in parallel with the acquisition of the suppressor activity. Moreover, MI-Mφs bound with target T cells in a B7–1LM-dependent fashion. Third, mAb blocking of CTLA-4 on target T cells did not reduce the suppressor activity of MI-Mφs, suggesting the role of a putative molecule on target T cells other than CTLA-4 as the receptor for B7–1LM of MI-Mφs. Fourth, concanavalin A (Con A) stimulation of MI-Mφs was needed for effective cell contact with target T cells and subsequent expression of the suppressor activity of MI-Mφs. Fifth, the Con A-induced increase in the suppressor activity of MI-Mφs was inhibited by KN-62 but not by herbimycin A, H-7, nor H-88, indicating that Con A-induced up-regulation of MI-Mφ function is mediated by calmodulin-dependent protein kinase II or ATP/P2Z receptors, but independent of protein tyrosine kinase, protein kinase C, and protein kinase A. These findings indicate that a B7/CTLA-4-independent mechanism is needed for the transmission of the suppressor signals from MI-Mφs to target T cells

Additional file 2: of Which strategies might improve local primary healthcare in Germany? An explorative study from a local government point of view

Questionnaire county administrators. The translated questionnaire for the survey of county administrators in Lower Saxony. (PDF 484 kb

Interleukin-6 regulates the phenotype of the immune response to a tuberculosis subunit vaccine

We investigated the role of interleukin-6 (IL-6) in the development of the immune response to a subunit vaccine against tuberculosis consisting of the culture filtrate proteins of Mycobacterium tuberculosis emulsified in the adjuvant dimethyldioctadecylammonium bromide (DDA). C57Bl/6 mice immunized with this vaccine developed a strong T helper 1 (Th1) response characterized by an increased production of interferon-γ (IFN-γ) secreted by CD4(+) T cells. Neutralization of IL-6 during in vivo priming resulted in marked reduction in the ability of T cells to secrete IFN-γ and IL-2 and to proliferate. IL-6 gene-disrupted mice primed with the vaccine showed a decrease in the number of IFN-γ-producing cells and an increase in IL-4-secreting cells as compared to control mice. In contrast, neutralization of IL-6 during a boost of the vaccine in previously primed mice did not affect the development of IFN-γ-producing cells but still increased the number of IL-4-producing cells. Our work shows that IL-6 plays a major role in the priming but not in the later expression of a Th1 response to a tuberculosis vaccine

Activation of macrophages and interference with CD4(+) T-cell stimulation by Mycobacterium avium subspecies paratuberculosis and Mycobacterium avium subspecies avium

Mycobacterium avium subspecies paratuberculosis (M. ptb) and M. avium subspecies avium (M. avium) are closely related but exhibit significant differences in their interaction with the host immune system. The macrophage line, J774, was infected with M. ptb and M. avium and analysed for cytokine production and stimulatory capacity towards antigen-specific CD4(+) T cells. Under all conditions J774 cells were activated to produce proinflammatory cytokines. No influence on the expression of major histocompatibility complex (MHC) class II, intracellular adhesion molecule-1 (ICAM-1), B7.1, B7.2 or CD40 was found. However, the antigen-specific stimulatory capacity of J774 cells for a CD4(+) T-cell line was significantly inhibited after infection with M. ptb, but not with M. avium. When a T-cell hybridoma expressing a T-cell receptor identical to that of the T-cell line was used, this inhibition was not observed, suggesting that costimulation which is essential for the CD4(+) T-cell line is influenced by the pathogenic bacterium M. ptb

Reduced T-cell receptor CD3ζ-chain protein and sustained CD3ε expression at the site of mycobacterial infection

Control of mycobacterial infection by the cellular immune system relies both on antigen-presenting cells and on T lymphocytes. The quality of an effective cellular immune response is dependent on functional signal transduction residing in the cytoplasmic tails of the T-cell receptor CD3 components. In order to investigate potential effects of mycobacteria on T-cell receptor signalling, we examined the protein expression of T-cell signal transduction molecules (CD3ζ, ZAP-70, p59(fyn), p56(l ck)). In Western blots of peripheral blood mononuclear cells of Mycobacterium tuberculosis infected patients, only the CD3ζ-chain showed a marked reduction in protein expression. To investigate the situation in situ, immunoenzymatic and immunofluorescence stainings for CD3ε and CD3ζ expression were performed on sections of normal lymphoid tissue, M. leprae infected and sarcoid tissue. CD3ε and CD3ζ expression were similar with respect to intensity, localization and the number of cells stained in normal lymphoid tissue and in sarcoid granulomas. In contrast, the granulomas of M. leprae infected tissues showed a significantly reduced expression of CD3ζ compared to CD3ε. Using double immunofluorescence analysis, virtually no CD3ζ expression could be detected in comparison to the CD3ε expression in the lesions. Apparently, mycobacteria are capable of significantly reducing CD3ζ-chain expression, which may be restored by cytokines. IL-2-enhanced ζ-chain expression and T-cell effector functions, defined by interferon-γ release, in M. tuberculosis-specific and human leucocyte antigen-DR restricted CD4(+) T cells isolated from granuloma lesions from patients with pulmonary tuberculosis. Because CD3ζ is essential for CD3 signalling and for eliciting T-cell effector functions, reduced CD3ζ protein expression could result in altered signal transduction and inefficient T-cell effector functions. Alternatively, reduced CD3ζ-chain expression may protect T cells from repetitive TCR stimulation associated with anergy or apoptosis