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CCR7 controls CD8+ T cell splenic localization
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SOCS-mediated cross-talk between signaling pathways
The chemoattractants IL-8 and fMLP induce migration of neutrophils to sites of inflammation where they release growth factors such as G-CSF. Suppressor of cytokine signaling (SOCS) proteins negatively regulate the action of G-CSF by a feedback mechanism. To date, the effects of IL-8 and fMLP on G-CSF signaling have not been established. Stevenson et al. (p. 3243 ) detected IL-8-stimulated or fMLP-stimulated up-regulation of SOCS1 and SOCS3 mRNA and protein in established human monocyte lines and in primary neutrophils, monocyte-derived dendritic cells and PBMCs from healthy donors. The response of all of the cells to fMLP was rapid (<1 h), whereas the response to IL-8 was delayed by several hours. G-CSF and IL-6 induced phosphorylation of STAT1, STAT3, or STAT5, but fMLP and IL-8 did not. Pretreatment of neutrophils with fMLP or IL-8 prevented subsequent STAT3 phosphorylation by G-CSF; the fMLP block to G-CSF signaling remained after removal of the chemoattractant. The authors conclude that the chemoattractants IL-8 and fMLP induce SOCS proteins that mediate cross-talk between G-protein-coupled receptor signaling and cytokine receptor signaling in a STAT-independent manner in myeloid cells.
Neonatal vs adult CD4+ T cell responses
Development of IgE-mediated allergic diseases has increased over the past several decades. It is possible that the fetal immune system is primed before birth; however, there is scant information on the response of human cord blood mononuclear cells (MNC) to allergens. Thornton et al. (p. 3084 ) determined that CD4+ T cells in MNC purified from human umbilical cord blood were required for proliferative responses to OVA and other allergens. Culturing in the presence of OVA for 5 days resulted in a population of highly apoptotic cells expressing a low level of CD4 (CD4low) in cord blood MNC but not in adult peripheral blood MNC. Treatment of the cultured cord blood MNC preparations with IL-4 and IL-7 prevented the emergence of the CD4low cells. Cord blood MNC proliferated in response to GST but not a self-Ag. CFSE-labeling of CD25+ T cells in cord blood MNC at day 0 demonstrated that all of the CD4high CD25+ T cells detected after 5 days of OVA stimulation were present in the starting population. CD4+CD25+ T cells from neonates were CD45RO–/CD45RA+/CD38+, whereas those from adults were CD45RO+/CD45RA–/CD38–. Neonatal CD4+CD25+ T cells became anergic to PHA and suppressive in MLR after 5 days of culture with OVA. Addition of autologous mature dendritic cells to cord blood MNC decreased CD4+ T cell apoptosis. The data highlight the differences between neonatal and adult T cell responses to allergens and challenge the concept of transplacental priming of neonatal allergic responses.
Multiple infections increase mortality in mice
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levels in coinfected animals were lower than with T. gondii infection alone, whereas H. felis infection alone did not produce IFN- levels above uninfected controls. Replication of parasites in spleen and in small bowel and anti-parasite IgG responses were increased by T. gondii infection of mice chronically infected with H. felis compared with controls. The presence of T. gondii increased the anti-H. felis IgG2 response, reduced the anti-H. felis IgG1 response and decreased bacterial loads. Histological changes in the gastric mucosa of dually infected mice were severe, including diffuse glandular epithelial atrophy and mucosal inflammation. Coinfection increased levels of IFN-, IL-12, and IL-1
and decreased IL-4 and IL-10 expression compared with H. felis infection alone. The authors conclude that concurrent infection of BALB/c mice with both T. gondii and H. felis alters the immune responses to both organisms and increases morbidity and mortality. Regulatory T cells block pancreatic islet infiltration
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cells but which lacked Treg cells. Prior injection of recipient mice with wild-type Treg cells protected against OVA-induced diabetes, whereas prior injection with CD4+CD25– T cells did not. Pancreata stained with a clonotypic Ab specific for the injected cells showed less islet infiltration by Treg cells than by CD4+CD25– T cells. OVA-T cells produced high levels of IFN- in OVA-immunized mice that had received the CD4+CD25– T cells, whereas prior injection of Treg cells inhibited the IFN- response; anti-IFN- Ab prevented CD4+CD25– T cell islet infiltration. Treg cells or anti-IFN- Ab reduced expression of the chemokine receptor CXCR-3 on the OVA-T cells transferred into the OVA-immunized mice. Wild-type mice injected with OVA-T cells and a second population of OVA-Treg cells had a reduced number of cells positive for IFN- and CXCR3 following OVA immunization. The independent manipulation of Treg and pathogenic T cells (OVA-T) show that Treg cells control diabetes induction by inhibiting IFN- production and chemokine receptor CXCR3 expression, resulting in a blockade of islet infiltration by T cells. Induction of lung fibrosis
FIZZ1 (found in inflammatory zone), which is highly induced in type II alveolar epithelial cells (AECs) in bleomycin (BLM)-treated lung fibrosis, can induce myoblast differentiation in vitro. IL-4 and IL-13, both of which stimulate fibroblast proliferation of pulmonary vascular smooth muscle cells, also are implicated in lung fibrosis. Liu et al. (p. 3425 ) showed that the two Th2 cytokines stimulated rapid FIZZ1 gene expression in AECs in vitro. Using the mouse model of BLM-induced lung injury, they demonstrated that lung tissue from mice lacking either IL-4 or IL-13 had a 50% reduction in BLM-induced FIZZ1 mRNA compared with wild-type mice; mice deficient for both IL-4 and IL-13 had no increase in BLM-induced FIZZ1 mRNA compared with saline-treated controls. The decreased FIZZ1 mRNA levels were accompanied by decreased lung fibrosis as measured by lower levels of hydroxyproline. Treatment of AECs with either cytokine induced STAT6 phosphorylation and increased the protein level of janus family tyrosine kinase-1. IL-4-induced FIZZ1 mRNA expression was enhanced by transfection of AECs with a STAT6 expression plasmid; cotransfection with an antisense STAT6 plasmid reduced the FIZZ1 mRNA level to that of negative controls. Lung tissue from BLM-treated STAT6 knockout mice had no increase in FIZZ1 mRNA over that seen in saline-treated animals. The authors suggest that IL-4 and IL-13 use a STAT6 pathway to induce FIZZ1, a molecule that mediates cross-talk between epithelial cells and fibroblastic cells in the development of fibroblastic foci.
Cytosine deamination in class switch recombination
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, and anti-CD40 mAb for 24 h, isolated the genomic DNA and subjected it to ligation-mediated PCR. Sequence-specific primers 5' of S
, one of which created a blunt end, generated a specific ladder of bands of PCR products on denaturing PAGE. The same pattern was detected for the three stimulating reagents in all combinations and each alone. No specific ladder was seen by direct ligation of primers to the DNA, by ligation of primers to DNA trimmed of 5' or 3' overhangs, or by the use of primers 3' of S in the PCR. Cloning and sequencing of PCR products revealed that cleavage had occurred only in the lower strand of S between the C and the A in a CAG consensus sequence. The authors suggest that conversion of C to U by activation induced deaminase occurs at CAG consensus sequences within the template DNA strand of unstable S region RNA:DNA hybrids and that the deaminated DNA is then cleaved by uracil DNA glycosylase. Summaries written by Dorothy L. Buchhagen, Ph.D.
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