Bacillus anthracis causes high-level bacteremia, strongly suggesting paralysis of the innate immune system. We have examined the effects of anthrax lethal toxin (LT) on human neutrophil chemotaxis, a process that requires actin filament assembly. Polymorphonuclear neutrophils (PMNs) treated with a sublethal concentration of LT (50 ng/mL) for 2 h demonstrated insignificant apoptosis or necrosis. However, this same concentration slowed human PMN formylmethionylleucylphenylalanine (FMLP)-stimulated chemokinesis by >60%, markedly reduced polar morphology, and rendered PMNs incapable of responding to a chemotactic gradient. These changes were accompanied by a >50% reduction in FMLP-induced actin filament assembly. One hour of exposure to LT failed to impair polarity or actin assembly, and the effects of LT were independent of mitogen-activated protein kinase kinase 1 inhibition. We conclude that 2 h of exposure to LT markedly impairs PMN actin assembly, and reductions in actin filament content are accompanied by a profound paralysis of PMN chemotaxis.
Apoptosis mediates neutrophil (PMN) phagocytosis and is influenced by cytokines and the Fas/Fas ligand pathway. To determine whether apoptosis of cord blood PMN differs from those of adults, cultured PMN were evaluated by morphological analysis, flow cytometry (TUNEL assay), and DNA gel electrophoresis. In addition, we studied the effect of anti-Fas IgM or cycloheximide on induction of PMN apoptosis. Spontaneous apoptosis (24 h) was less in cord blood PMN (mean ؎ SD; 29 ؎ 9 vs. adults, 56 ؎ 14%, P F 0.001). Treatment (6 h) with anti-Fas IgM induced less apoptosis in cord blood PMN (24 ؎ 6 vs. adults, 63 ؎ 7%, P F 0.001), as did treatment with cycloheximide (13 ؎ 10 vs. adults, 55 ؎ 16%, P F 0.01). These data suggest the pre-existence of proteins that inhibit apoptosis or the absence of those that promote apoptosis in cord blood PMN. J. Leukoc. Biol. 64: 331-336; 1998.
Despite an era of marked success with universal screening, Group B Streptococcus (GBS) continues to be an important cause of early-onset sepsis, and thus remains a significant public health issue. Improved eradication of GBS colonization and disease may involve universal screening in conjunction with rapid diagnostic technologies or other novel approaches. Given the complications and potential limitations associated with maternal intrapartum prophylaxis, however, vaccines may be the most effective means of preventing neonatal GBS disease. The global utility of conjugated GBS vaccines may be hampered by the variability of serotypes in diverse populations and geographic locations. Modern technologies, such as those involving proteomics and genomic sequencing, are likely to hasten the development of a universal vaccine against GBS.
Accumulating evidence suggests that Th17 cells and Tregs may exhibit development plasticity and that CD41 Tregs can differentiate into IL-17-producing T cells; however, whether Th17 cells can reciprocally convert into Tregs has not been described. In this study, we generated Th17 clones from tumor-infiltrating T lymphocytes (TILs). We showed that Th17 clones generated from TILs can differentiate into IFN-c-producing and FOXP3 1 cells after in vitro stimulation with OKT3 and allogeneic peripheral blood mononuclear cells. We further demonstrated that T-cell receptor (TCR) engagement was responsible for this conversion, and that this differentiation was due to the epigenetic modification and reprogramming of gene expression profiles, including lineage-specific transcriptional factor and cytokine genes. In addition to expressing IFN-c and FOXP3, we showed that these differentiated Th17 clones mediated potent suppressive function after repetitive stimulation with OKT3, suggesting that these Th17 clones had differentiated into functional Tregs. We further demonstrated that the Th17-derived Tregs, unlike naturally occurring CD4 1 CD25 1 Tregs, did not reconvert back into Th17 cells even under Th17-biasing cytokine conditions. These results provide the critical evidence that human tumor-infiltrating Th17 cells can differentiate into Tregs and indicate a substantial developmental plasticity of Th17 cells.Keywords: IL-17 . Treg . T-cell development . Th17Supporting Information available online IntroductionRecent discovery of two novel T-cell subsets, Th17 and Tregs, has resulted in an explosion of immunological research that has markedly enhanced our understanding of human T-cell-mediated immunity under both physiological and pathological conditions [1,2]. It is now widely accepted that Tregs have a broad immunosuppressive capacity and play a central role in controlling immune tolerance and homeostasis of the immune system [3,4], whereas Th17 cells are important contributors to the pathogenesis of a wide array of inflammatory and autoimmune diseases [5]. 936that instruct a specific differentiation program [6][7][8]. It is now recognized that cytokines IL-12 and IFN-g are required for the polarization of Th1 cells, whereas signal transducer and activator of transcription 1 and 4 (Stat1 and Stat4) and T box transcription factor (T-bet) are critical for their regulation [6,7]. Th2-cell differentiation requires the cytokine IL-4 and the transcriptional factors GATA3 and Stat6 [6,7]. Th17-cell differentiation is dependent on the transcription factors retinoid-related orphan receptor (RORgt), Stat3 and interferon regulatory factor 4 (IRF-4) [9,10]. TGF-b and IL-6 or TGF-b and IL-21 are critical cytokines for the initiation of mouse Th17-cell differentiation [11][12][13]. Furthermore, IL-23 is critical for the in vivo function of pathogenic effectors of Th17-cells [14,15]. The differentiation and development of Tregs require TGF-b and the forkhead transcription factor, FOXP3 [16].Although different types of T-cell lineages have...
Apoptosis is critical to the resolution of inflammation, as it promotes the removal of neutrophils (PMN) by the reticuloendothelial system. In contrast, PMN persistence characterizes the early stages of chronic inflammation. Adult PMN with delayed senescence retain some functionality, although this has not been described for neonatal PMN. We hypothesized that neonatal PMN with prolonged survival retain cytotoxic and inflammatory function. To test one aspect of inflammatory function, we determined surface CD11b expression on 0-h and 24-h PMN after chemotactic formyl-methionine-leucine-phenylalanine (fMLP) stimulation. Although fMLP induced a greater percentage upregulation of CD11b on 0-h adult PMN, this was similar between nonapoptotic cord blood and adult PMN at 24 h. Furthermore, percentage up-regulation of CD11b was more robust for 24-h than for 0-h cord blood PMN. In contrast, there was no difference in responsiveness between 0-h and 24-h adult PMN. In studies of cytotoxic potential, we determined the expression of reactive oxygen intermediates (ROI) in phorbol 12-myristate 13-acetatestimulated cord blood and adult PMN at 0 h and in 24-h nonapoptotic PMN, using the dihydrorhodamine 123 assay.Stimulated cord blood PMN generated more ROI than did adult PMN at both 0 h and 24 h; in addition, ROI levels in 24-h cord blood PMN were similar to those of 0-h adult PMN. We conclude that PMN with prolonged survival retain specific cytotoxic and inflammatory functions, and these are enhanced in cord blood PMN. We speculate that neonatal PMN with prolonged survival have the functional capacity to contribute to the pathogenesis of inflammatory disorders. Abbreviations CLD, chronic lung disease DHR, dihydrorhodamine 123 fMLP, formyl-methionine-leucine-phenylalanine PE, phycoerythrin PMA, phorbol 12-myristate 13-acetate PMN, neutrophil(s) ROI, reactive oxygen intermediates 7-AAD, 7-aminoactinomycin PMN serve as the primary line of host defense during the early stages of sepsis and inflammation (1). After activation by systemic or local factors, primed endothelial cells interact with PMN through adhesion molecules that include selectins and integrins (2). These adhesive interactions initiate a process that allows the extravasation of PMN into inflamed tissue with the goal of neutralizing the inciting stimulus. In the case of inflammation mediated by bacterial or fungal microorganisms, phagocytosis and subsequent killing of these invaders occurs through mechanisms that partly involve ROI and proteases (3,4).The concept that apoptosis of inflammatory PMN and their timely removal by resident macrophages are critical to the resolution of inflammation has been well established (5,6). During the resolution phase, PMN typically undergo the phenotypic changes associated with apoptosis, which promotes their removal by resident macrophages (7). PMN can also undergo necrosis and lysis, a process that induces cytotoxicity in surrounding tissues (8), although apoptosis is the more common and physiologically preferable route. All cells a...
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