Differential cell reaction upon Toll-like receptor 4 and 9 activation in human alveolar and lung interstitial macrophages

BACKGROUND: Investigations on pulmonary macrophages (MΦ) mostly focus on alveolar MΦ (AM) as a well-defined cell population. Characteristics of MΦ in the interstitium, referred to as lung interstitial MΦ (IM), are rather ill-defined. In this study we therefore aimed to elucidate differences between AM and IM obtained from human lung tissue. METHODS: Human AM and IM were isolated from human non-tumor lung tissue from patients undergoing lung resection. Cell morphology was visualized using either light, electron or confocal microscopy. Phagocytic activity was analyzed by flow cytometry as well as confocal microscopy. Surface marker expression was measured by flow cytometry. Toll-like receptor (TLR) expression patterns as well as cytokine expression upon TLR4 or TLR9 stimulation were assessed by real time RT-PCR and cytokine protein production was measured using a fluorescent bead-based immunoassay. RESULTS: IM were found to be smaller and morphologically more heterogeneous than AM, whereas phagocytic activity was similar in both cell types. HLA-DR expression was markedly higher in IM compared to AM. Although analysis of TLR expression profiles revealed no differences between the two cell populations, AM and IM clearly varied in cell reaction upon activation. Both MΦ populations were markedly activated by LPS as well as DNA isolated from attenuated mycobacterial strains (M. bovis H37Ra and BCG). Whereas AM expressed higher amounts of inflammatory cytokines upon activation, IM were more efficient in producing immunoregulatory cytokines, such as IL10, IL1ra, and IL6.CONCLUSION: AM appear to be more effective as a non-specific first line of defence against inhaled pathogens, whereas IM show a more pronounced regulatory function. These dissimilarities should be taken into consideration in future studies on the role of human lung MΦ in the inflammatory response

An early history of T cell-mediated cytotoxicity.

After 60 years of intense fundamental research into T cell-mediated cytotoxicity, we have gained a detailed knowledge of the cells involved, specific recognition mechanisms and post-recognition perforin-granzyme-based and FAS-based molecular mechanisms. What could not be anticipated at the outset was how discovery of the mechanisms regulating the activation and function of cytotoxic T cells would lead to new developments in cancer immunotherapy. Given the profound recent interest in therapeutic manipulation of cytotoxic T cell responses, it is an opportune time to look back on the early history of the field. This Timeline describes how the early findings occurred and eventually led to current therapeutic applications

Splenic macrophage precursor cells from Leishmania donovani infected mice as cytotoxic effectors against pro- and amastigotes

The most important effectors of natural- as well as lymphokine-mediated cytotoxicity against microbicidal and fungal targets and protozoa such as Leishmania donovani are represented by cells of the monocyte-macrophage lineage. We recently described the bone marrow-derived macrophage precursor which is able to spontaneously and extracellularly kill protozoa of the genus Leishmania. These nonadherent, nonphagocytic macrophage precursor cells are present in the spleen of healthy mice only in a small quantity; however, high nmumbers have been isolated from the spleen of L. donovani infected mice. Macrophage precursors from spleen of diseased animals are able to kill spontaneously the promastigote as well as the amastigote form of L. donovani. the mechanism of the spontaneous leishmanicidal activity of macrophage precursor cells derived from spleens of L. donovani infected mice was investigated. This effector function could be defined in part as an antibody-dependent cellular cytotoxicity ( ADCC). In addition we assessed the role of CSFI containing L-cell donditioned supernatant at the leishmanicidal activity of these immature cells of the macrophage lineage. For that purpose, nonadherent cells from healthy mice were cocultivated with this CSFI containing medium for four days. These in vitro proliferated macrophage precursor cells from untreated mice showed an increased leishmanicidal activity. (-y-

Functional heterogeneity of macrophage precursor cells from spleen of Leishmania donovani-infected and untreated mice

Cells belonging to the monocyte-macrophage lineage are known to be among the most important effectors of natural - as well as lymphokine - mediated cytotoxicity against tumor cells, microbial and fungal targets and protozoa. Recent observations (1) pressented evidence that macrophage precursor cells are not confined to the bone marrow compartment, but can also be found in a peripheral organ such as the spleen. Only a very small quantity of these cells is present in the spleens of normal, untreated mice. In contrast, large numbers of splenic macrophage precursors can be isolated from Leishmania donovani-infected C57BL/6 mice in the early stage of infection as well as three months post infectionem. We demonstrate the capability of these highly purified population of nonadherent, nonphagocytic macrophage precursors, derived from spleen parasitized with Leishmania donovani, to spontaneously kill the promastigote form of Leishmania donovani and Leishmania enriettii. These effector functions , however, are not found in healthy control C57BL/6 mice. The functional heterogeneity displayed by splenic macrophage precursors from Leishmania donovani-infected C57BL/6 mice and untreated animals is dicussed