Abstract
A recent report in Nature describes investigations into interactions between dendritic cells and T-cells in lymph nodes. The studies were performed using two-photon microscopy in anesthetized mice under physiologic conditions of blood and lymph flow; T-cell entry into lymph nodes was synchronized. The studies showed three sequential phases of interaction between dendritic cells and T-cells. During the first 8 hours in the lymph node, T-cells engaged in multiple short interactions with dendritic cells; over time, T-cell motility decreased and expression of activation markers increased. Over the next 12 hours, stable dendritic cell-T-cell complexes were formed and T-cells began to express the activation marker CD25 and to produce interleukin-2 and interferon-γ. This was apparently the period when immunologic synapses between dendritic cells and T-cells were formed. During the final phase of interaction, T-cells and dendritic cells separated and T-cells began to proliferate and to migrate from the lymph node. The mechanisms underlying the spatial and temporal patterns of this interaction are largely unknown.
Mempel TR, Henrickson SE, Von Andrian UH: T-cell priming by dendritic cells in lymph nodes occurs in three distinct phases. Nature 427:154–159, 2004
Transforming growth factor-β (TGF-β) binds to the TGF-β type II receptor to stimulate a variety of intracellular signaling pathways. In some situations, TGF-β inhibits neoplasia, while in others, it enhances tumor growth. When the TGF-β type II receptor was specifically deleted from interstitial fibroblasts throughout the body in conditional knockout mice, TGF-β signaling was abrogated in the target cells, leading to increased numbers of non-neoplastic stromal fibroblasts throughout the body. Furthermore, intraepithelial neoplasia and invasive squamous cell carcinoma were seen in associated prostate and forestomach epithelia, respectively. TGF-β type II receptors in epithelia were expressed normally; neoplasia was associated with activation of paracrine hepatocyte growth factor signaling in epithelial cells. These results indicate that TGF-β negatively regulates proliferation both in fibroblasts and adjacent epithelia and suggest one mechanism by which stromal cells can modulate tumor development in nearby epithelia.
Bhowmick NA, Chytil A, Plieth D, Gorska AE, Dumont N, Shappell S, Washington MK, Neilson EG, Moses HL: TGF-beta signaling in fibroblasts modulates the oncogenic potential of adjacent epithelia. Science 303:848–851, 2004
Unlike other members of the interleukin-1 (IL-1) family, IL-1α is found primarily within cells or anchored in cell membranes rather than free in the extracellular compartment. Moreover, the precursor form of IL-1α translocates to the nucleus in some cells. To test if this nuclear translocation serves a signaling function, investigators overexpressed precursor forms of IL-1α in a variety of cell types and simultaneously blocked the receptor-mediated activities of Il-1α by adding IL-1 receptor antagonist to the medium. After these cells were treated with inflammatory stimuli, the precursor form of IL-1α translocated to the nucleus where it activated a variety of transcription factors, including NF-κB and AP-1, upregulated its own synthesis, and stimulated production of IL-6 and IL-8. Thus, the precursor form of IL-1α can act in an intracrine fashion to enhance the cellular response to inflammatory stimuli.
Werman A, Werman-Venkert R, White R, Lee JK, Werman B, Krelin Y, Voronov E, Dinarello CA, Apte RN: The precursor form of IL-1α is an intracrine proinflammatory activator of transcription. Proc Natl Acad Sci U S A. 101:2434–2439, 2004
Japanese investigators have developed a multiplex-immunostain chip (MI chip) that allows simultaneous application of 50 different antibodies to a single tissue section or layer of cultured cells. The MI chip is a 5-mm-thick silicon rubber plate the same size as a glass slide. There are 50 wells on the plate; each well contains 4 µl of antibody at the appropriate dilution. The slide to be tested is clamped to the MI chip, and the apparatus is inverted to begin the incubation. Immunoreactivity is detected with an enzyme-linked universal anti-mouse and anti-rabbit secondary antibody and the appropriate chromagen system. Useful antibody panels include panels of solid tumor markers, such as intermediate filaments, and panels of lymphoma markers. This system allows simultaneous comparison of immunoreactivity with a wide array of antibodies on a single slide. Moreover, spaces between the wells serve as negative controls.
Furuya T, Ikemoto K, Kawauchi S, Oga A, Tsunoda S, Hirano T, Sasaki K: A novel technology allowing immunohistochemical staining of a tissue section with 50 different antibodies in a single experiment. J Histochem Cytochem 52:205–210, 2004
Although large animal models of myocardial infarction (MI) have been used for many years, there is increasing interest in genetically altered mice as experimental tools for studying MI. To determine how mouse models of MI differ from the more commonly used canine models, scientists at Baylor compared closed chest models of infarction and reperfusion in the two species. In both models there was a marked inflammatory response, but species differences were apparent. Replacement of injured cardiac myocytes by inflammatory cells occurred more rapidly in the mouse than in the dog, and this inflammatory response resolved more quickly in the mouse. Myofibroblast and macrophage infiltration of the infarct was more transient in the mouse. Furthermore, mast cells infiltrated canine but not murine infarcts. These differences in inflammatory response were associated with different patterns of cytokine, chemokine, and adhesion molecule expression. If these species-specific differences are taken into consideration, the mouse can serve as an informative model of MI.
Dewald O, Ren G, Duerr GD, Zoerlein M, Klemm C, Gersch C, Tincey S, Michael LH, Entman ML, Frangogiannis NG: Of mice and dogs: species-specific differences in the inflammatory response following myocardial infarction. Am J Pathol 164:665–677, 2004
Neutrophils are an important component of the innate immune response to microorganisms such as Salmonella enterica. While neutrophils are clearly able to migrate through the gut epithelium to attack Salmonella in the gut lumen, the role of neutrophils in protection against systemic Salmonella infection is less clear. To investigate this, German scientists used a mouse model of oral infection with virulent Salmonella. The extent of neutrophil infiltration into affected organs (Peyer's patches, mesenteric lymph nodes, spleen, and liver) was dependent on the bacterial burden. Despite massive neutrophil influx, however, systemic infection was not cleared. Moreover, studies with attenuated Salmonella strains revealed that neutrophil depletion did not restore the virulence of these organisms. Taken together, these findings suggest that neutrophils are unable to protect against systemic salmonellosis, probably because the organisms are sequestered intracellularly and are not accessible to neutrophil attack.
Cheminay C, Chakravortty D, Hensel M. Role of neutrophils in murine salmonellosis. Infect Immun 72:468–477, 2004