bluuebunny/crossref_metadata_2025_split huggingface dataset:
Fcγ receptor‐mediated phagocytosis requires tyrosine kinase activity and is ligand independent
Authors: Hutchinson M. J. , Harrison Patrick T. , Floto R. Andres , Allen Janet M. 
Published: March 2007

AbstractReceptors for the invariant chain of immunoglobulins (FcR) define the cellular response to specific antigens. FcγR recognize IgG and so elicit a variety of effector functions including phagocytosis. We are interested in the structural determinants for FcγR‐mediated phagocytosis, specifically FcγRI(p135) and FcγRIIa isoforms. The low‐affinity receptor, FcγRIIa, is found on macrophages and its cytoplasmic domain contains a tyrosine activation motif which has previously been shown to regulate endocytosis. In contrast, FcγRI has no known signaling motifs, though a functional interaction has recently been demonstrated with the γ chain of the high‐affinity receptor for IgE, FcεRI. This accessory molecule has a cytoplasmic tyrosine activation motif implicated in signal transduction. Here we demonstrate that although FcγRI transiently expressed on COS‐7 cells is able to rosette opsonized SRBC, it cannot phagocytose them. If the cytoplasmic domain of either γ chain or FcγRIIa replaces that of FcγRI in a chimeric receptor, efficient phagocytosis occurs. This particle ingestion is sensitive to the tyrosine kinase inhibitor genistein. Chimeric receptors where the extracellular domain of either FcγRI or FcγRIIa is replaced with that of CD2, a T cell antigen, indicate that FcγR‐mediated phagocytosis is ligand independent. We conclude that phagocytosis is dependent upon close particle apposition, tyrosine kinase activity, and that the process is ligand independent.
Antibody ligation of CD7 leads to association with phosphoinositide 3‐kinase and phosphatidylinositol 3,4,5‐trisphosphate formation in T lymphocytes
Authors: Ward Stephen G. , Parry Richard , Lefeuvre Catherine , Sansom David M. , Westwick John , Lazarovits Andrew I. 
Published: March 2007

AbstractThe CD7 40‐kDa glycoprotein is present on a major subset of human T cells and in the presence of phorbol esters mediates an accessory pathway of T cell activation. Hitherto, the intracellular events elicited by CD7 have been ill‐defined. This report demonstrates that cross‐linking of CD7 results in the formation of phosphatidic acid in the absence of phosphatidylinositol‐4,5‐bisphosphate metabolism and also the formation of D‐3 phosphoinositides lipids which have been postulated to act as intracellular regulatory molecules. The magnitude of D‐3 phosphoinositidé formation was similar to that induced by CD3. Both the CD7‐ and CD3‐induced elevation of phosphatidylinositol 3,4,5‐trisphosphate approximately 5–10 fold less than that elicited by ligation of the costimulatory molecule CD28 by its counter receptor CD80. The formation of D‐3 phosphoinositides following ligation of CD7 coincided with the co‐association of CD7 with phosphoinositide 3‐kinase, the enzyme which mediates the formation of D‐3 phosphoinositide lipids. In contrast, ligation of another reported T cell accessory molecule CD5, failed to elicit formation of D‐3 phosphoinositides, implying that phosphoinositide 3‐kinase is not coupled to all T cell molecules with accessory functions. Since D‐3 phosphoinositides have been suggested to play a pivotal role in T cell costimulatory signals induced by CD28, the results presented in this study suggest that CD7 may also influence T cell activation via this pathway.
CD28 activation promotes Th2 subset differentiation by human CD4+ cells
Authors: King Christopher L. , Stupi Robert J. , Craighead Nancy , June Carl H. , Thyphronitis George 
Published: March 2007

AbstractLigation of CD28 provides a costimulatory signal to T cells necessary for their activation resulting in increased interleukin (IL)‐2 production in vitro, but its role in IL‐4 and other cytokine production and functional differentiation of T helper (Th) cells remains uncertain. We studied the pattern of cytokine production by highly purified human adult and neonatal CD4+ T cells activated with anti‐CD3, phorbol 12‐myristate 13‐acetate (PMA) and ionomycin, or phytohemagglutinin (PHA) in the presence or absence of anti‐CD28 in repetitive stimulation‐rest cycles. Initial stimulation of CD4+ cells with anti‐CD3 (or the mitogens PHA or PMA+ionomycin) and anti‐CD28 monoclonal antibodies induced IL‐4, IL‐5 and interferon‐γ (IFN‐γ) production and augmented IL‐2 production (6‐ to 11‐fold) compared to cells stimulated with anti‐CD3 or mitogen alone. The anti‐CD28‐induced cytokine production corresponded with augmented IL‐4 and IL‐5 mRNA levels suggesting increased gene expression and/or mRNA stabilization. Most striking, however, was the progressively enhanced IL‐4 and IL‐5 production and diminished IL‐2 and IFN‐γ production with repetitive consecutive cycles of CD28 stimulation. The enhanced Th2‐like response correlated with an increased frequency of IL‐4‐secreting cells; up to 70% of the cells produced IL‐4 on the third round of stimulation compared to only 5% after the first stimulation as determined by ELISPOT. CD28 activation also promoted a Th2 response in naive neonatal CD4+ cells, indicating that Th cells are induced to express a Th2 response rather than preferential expansion of already established Th2‐type cells. This CD28‐mediated response was IL‐4 independent, since enhanced IL‐5 production with repetitive stimulation cycles was not affected in the presence of neutralizing anti‐IL‐4 antibodies. These results indicate that CD28 activation may play an important role in the differentiation of the Th2 subset in humans.
Linked in vivo expression of soluble interleukin‐4 receptor and interleukin‐4 in murine schistosomiasis
Authors: Fernandez‐Botran Rafael , Wynn Thomas A. , Hieny Sara , Caspar Patricia , Chilton Paula M. , Sher Alan 
Published: March 2007

AbstractSoluble interleukin‐4 receptors (sIL‐4R) are truncated IL‐4R molecules that are secreted into biological fluids. To gain an insight into the mechanisms that control sIL‐4R synthesis in vivo and their role in the regulation of immune responses, the expression and secretion of sIL‐4R in mice infected with Schistosoma mansoni was studied. Splenocytes from infected animals responded to schistosomal antigen preparations with increased production of both IL‐4 and sIL‐4R. The synthesis of sIL‐4R by spleen cells peaked at 8 weeks following infection and coincided with maximum levels of sIL‐4R in serum and sIL‐4R‐specific mRNA in the liver of infected mice. The expression of IL‐4‐specific mRNA in the liver was different from that of IL‐4R, reaching its peak approximately 2 weeks earlier. A relationship between sIL‐4R production and the development and activation of Th2 cells was suggested by the findings that: (a) in vivo administration of anti‐IL‐4 antibodies (11B11) impaired the ability of splenic cells to secrete either IL‐4 or sIL‐4R; and (b) splenic cells from mice vaccinated with irradiated cercariae, which tend to develop much weaker Th2 responses than mice injected with live cercariae, expressed reduced levels of sIL‐4R when challenged with schistosomal antigens. Moreover, a direct role for IL‐4 in regulating the expression of sIL‐4R was suggested by the ability of anti‐IL‐4 antibodies to inhibit sIL‐4R synthesis in vitro. These data provide the first evidence demonstrating that the production of sIL‐4R in vivo is up‐regulated during immune responses, especially during those characterized by the development and activation of Th2 cells and IL‐4 secretion. The association between sIL‐4R and IL‐4 syntheses is consistent with a potential role for sIL‐4R in the regulation of IL‐4 activity in vivo.
Modulation of Fcγ receptor‐mediated early events by the tyrosine phosphatase CD45 in primary human monocytes. Consequences for interleukin‐6 production
Authors: Corvaïa Nathalie , Reischl Ilona G. , Kroemer Elisabeth , Mudde Geert C. 
Published: March 2007

AbstractStimulation of primary human monocytes from several donors by cross‐linking of Fcγ receptor type I (FcγRI) and FcγRII gave rise to calcium mobilization and protein tyrosine phosphorylation. These early events were not observed without cross‐linking. CD45, a transmembrane tyrosine phosphatase, when co‐cross‐linked with either FcγRI or FcγRII, could prevent FcγRI and FcγRII‐mediated calcium mobilization and protein tyrosine phosphorylation. When interleukin (IL)‐6 production was measured, we noted a strong IL‐6 production after activation of primary human monocytes by cross‐linking of FcγRI or FcγRII. In contrast to calcium mobilization and tyrosine phosphorylation of proteins, IL‐6 production was not affected by co‐cross‐linking of CD45 with either FcγRI or FcγRII. Interestingly, cross‐linking of the CD45 itself was sufficient to induce IL‐6 production. Our results show that the CD45 molecule is important in modulating early events following stimulation of primary human monocytes by cross‐linking of FcγRI or FcγRII. However, triggering of CD45 alone can also induce IL‐6 production, indicating that CD45 ligation itself can give signals and may have an important role in cytokine induction pathways.
Induction of Bax‐α precedes apoptosis in a human B lymphoma cell line: potential role of the bcl‐2 gene family in surface IgM‐mediated apoptosi
Authors: Bargou Ralf C. , Bommert Kurt , Weinmann Pamela , Daniel Peter T. , Wagener Christian , Mapara Markus Y. , Dörken Bernd 
Published: March 2007

AbstractThe members of the bcl‐2 gene family are major regulators of programmed cell death, but their role in sIg‐triggered apoptosis remains unclear. Using sensitive and resistant variants of the human B cell line BL‐41, we studied the expression of the bcl‐2 gene family during surface IgM‐mediated apoptosis. We found constitutive Bcl‐2 and Bcl‐x expression, which remained unaltered after sIg cross‐linking, in both resistant and sensitive cells. This and other experiments suggest that constitutive expression of Bcl‐2 or Bcl‐x alone is not sufficient to protect from activation‐induced cell death in B cells. We therefore investigated Bax‐α, the death‐promoting splice variant of Bax, and found strong induction of both mRNA and protein upon sIg stimulation in sensitive cells. However, resistant subclones showed only weak expression, which was not inducible by sIg cross‐linking. We provide evidence that up‐regulation of Bax‐α and the resulting imbalance of Bcl‐2/Bax might be a major regulator of sIg‐mediated apoptosis. Additionally, we found strong constitutive expression of Bcl‐xs, the death promoting variant of Bcl‐x, in sensitive cells, whereas resistant cells showed only weak Bcl‐xs expression. Thus, we observed a much stronger expression of the death‐promoting proteins Bax‐α (inducible) and Bcl‐xs (constitutive) in sensitive cells than in resistant cells. We therefore propose a potential role of the novel bcl‐2 gene family members bcl‐x and bax in surface IgM‐triggered apoptosis.
Recombinant chicken interferon: a potent antiviral agent that lacks intrinsic macrophage activating factor activity
Authors: Schultz Ursula , Kaspers Bernd , Rinderle Conny , Sekellick Margaret J. , Marcus Philip I. , Staeheli Peter 
Published: March 2007

AbstractCrude preparations of chicken interferon (ChIFN) from various sources contain both antiviral and macrophage‐activating factor (MAF) activity. Previous serological data indicated that unlike mammals, birds might express only a single type of IFN in response to viruses and mitogens that exhibits both activities. We have now expressed a complementary DNA for virus‐induced ChIFN in transfected COS cells and in Escherichia coli. Purified recombinant ChIFN is a powerful antiviral agent and has high Mx promoter‐inducing activity. However, as the sole agent, recombinant ChIFN lacks MAF activity: it does not induce the secretion of nitric oxide in primary monocyte‐derived chicken macrophages. A neutralizing antiserum prepared against cloned ChIFN blocks most of the antiviral and Mx promoter‐inducing activity present in preparations of natural ChIFN, but does not inhibit the MAF activity. These results demonstrate that chicken cells can be induced to secrete a novel cytokine which probably represents the avian homolog of mammalian IFN‐γ.
In the absence of major histocompatibility complex class II molecules, invariant chain is translocated to late endocytic compartments by autophagy
Authors: Chervonsky Alexander , Sant Andrea J. 
Published: March 2007

AbstractIt has been suggested that the cytoplasmic amino‐terminal tail of invariant chain (Ii) contains a sorting signal that directs trafficking of the major histocompatibility complex (MHC) class II: Ii oligomeric complex to endocytic compartments. This model is based, in part, on the observation that in the absence of MHC class II molecules, Ii is detectable in lysosomal structures, a phenotype that is dependent on an intact NH2 terminus. However, the route by which Ii gains access to endosomal compartments in the absence of class II molecules remains uncertain. Here we report a mechanism that localizes Ii in lysosomal compartments independently of class II. We show that murine Ii can be detected by immunofluorescence within late endocytic compartments of stably transfected Ltk− mouse fibroblasts. Immunochemical studies indicate that degradation of Ii in these cells is sensitive to the lysosomotropic agent ammonium chloride, yet the majority of Ii that undergoes this apparent lysosomal degradation is sensitive to the enzyme endoglycosidase H. This finding suggests that Ii may reach the lysosomal compartment by a route that bypasses the Golgi complex. Consistent with this possibility, we found that in contrast to Ii which is complexed to class II molecules, transport of free Ii to lysosomes is prevented by 3‐methyladenine, an inhibitor of the autophagic pathway of protein degradation, a process which involves direct transport from the endoplasmic reticulum to lysosomes. These data suggest the route of transport that leads to endosomal localization of Ii in the absence of class II is distinct from that taken when expressed with class II. This forces a re‐evaluation of the concept that the cytosolic tail of Ii contains a dominant Golgi‐to‐endosomal sorting signal.
Nitric oxide up‐regulates the release of inflammatory mediators by mouse macrophages
Authors: Marcinkiewicz Janusz , Grabowska Agnieszka , Chain Benjamin 
Published: March 2007

AbstractNitric oxide (NO) plays a key role in mediating macrophage cytotoxicity towards different targets, including tumoral cells and intracellular pathogens. However, its role in macrophage immunoregulation is less well defined. In this study, we have investigated the effect of altering NO levels on the production by mouse macrophages of cytokines, and reactive oxygen intermediates as measured by luminol‐dependent chemiluminescence. Our results demonstrate that NO can enhance the release of both tumor necrosis factor‐α and interleukin‐1α, and chemiluminescence. Thus, in addition to acting as a powerful effector molecule in mediating cytotoxic activities of mouse macrophages, NO can play a role in enhancing the production of a variety of other inflammatory mediators, and thus can contribute both directly and indirectly to the immunopathology of macrophage‐dependent inflammation.
Co‐ligation of mouse complement receptors 1 and 2 with surface IgM rescues splenic B cells and WEHI‐231 cells from anti‐surface IgM‐induced apoptosis
Authors: Kozono Yuko , Duke Richard C. , Schleicher Mary S. , Holers V. Michael 
Published: March 2007

AbstractRecent studies have shown that complement receptors play important roles in both T‐dependent and T‐independent B lymphocyte responses to low doses of antigen (Ag) in vivo. Complement activation by either the classical or alternative pathway results in the covalent binding of C3 molecules to Ag in forms that ligate complement receptors type 1 (CR1) and 2 (CR2). We hypothesized that C3‐bound Ag might cross‐link CR2 and/or CR1 with surface (s)IgM and alter the signal that would be transduced through sIgM by Ag binding alone. One result of the altered signal could be the rescue of B lymphocytes from apoptosis that would otherwise be induced by the binding of certain types of Ag alone. We find that co‐cross‐linking of mouse CR2 and CR1 with sIgM rescues both resting B cells and WEHI‐231.7 cells from apoptosis induced by sIgM ligation in a fashion similar to that found using soluble mouse CD40 ligand (mCD40L). Anti‐CR2/CR1‐mediated rescue requires co‐cross‐linking of the receptors with sIgM, and has an additive effect on mCD40L‐mediated apoptosis rescue. Based on these results, it is likely that the CR2/CR1‐derived signal is cooperative with T cell‐derived signals such as CD40L and interleukiin‐4.
T cell antigen CD28 binds to the GRB‐2/SOS complex, regulators of p21ras
Authors: Schneider Helga , Cai Yun‐Cai , Prasad K. V. S. , Shoelson Steven E. , Rudd Christopher E. 
Published: March 2007

AbstractThe T cell molecule CD28 provides a co‐stimulatory signal that is required for T cell proliferation, and has been implicated in the control of T cell anergy. An important clue to the signaling mechanism of CD28 is the finding that CD28 can bind to phosphatidylinositol 3‐kinase (PI 3‐kinase) by means of a cytoplasmic phospho‐YMNM (pYMNM) motif. A remaining issue concerns whether CD28 can recruit other intracellular signaling molecules. In this study, we show that CD28 uses the same pYMNM motif to recruit a second intracellular protein, GRB‐2. CD28‐associated GRB‐2, as detected by anti‐GRB‐2 immunoblotting, was found in human peripheral T cells, HPB‐ALL and Jurkat cells. As in the case of PI 3‐kinase, antibody‐induced cross‐linking of CD28 induces a time‐dependent recruitment of GRB‐2. Likewise, mutation of the pY‐191 residue within the pYMNM motif reduces GRB‐2 binding. Peptide binding studies show that the SH2 domain of GRB‐2 binds to the pYMNM motif with an affinity comparable to GRB‐2/SHC, but some 10‐ to 100‐fold lower than the CD28/PI 3‐kinase. Despite this, CD28/GRB‐2 and CD28/PI 3‐kinase complexes are found to co‐exist in peripheral T cells. Finally, immunoblotting shows that CD28 also associates with the gene product of the human homolog of the Drosophila Son of sevenless gene (SOS), a GRB‐2‐complexed guanine nucleotide exchange factor responsible for converting p21ras to a GTP‐bound active state. CD28‐associated GRB2/SOS is likely to serve an important link in the regulation of p21ras and lymphokine expression mediated by CD28.
Epitope specificity, cytokine production profile and diabetogenic activity of insulin‐specific T cell clones isolated from NOD mice
Authors: Daniel Dylan , Gill Ronald G. , Schloot Nanette , Wegmann Dale 
Published: March 2007

AbstractT cells are known to play an important role in beta cell destruction in the nonobese diabetic (NOD) mouse model of Type I diabetes and islet‐specific T cell clones have been demonstrated to be capable of adoptive transfer of diabetes. One important issue involves the identity of beta cell antigens that are recognized by nominally islet cell‐specific T cell clones. We have previously reported that insulin‐specific T cells are a predominant component of islet‐specific T cells isolated from islet infiltrates of pre‐diabetic NOD mice. In this report we examine six independently derived insulin‐specific T cell clones established from islet infiltrates of pre‐diabetic NOD mice in detail. All six clones were found to be specific to a region of the insulin molecule defined by a synthetic peptide encompassing residues 9–23 of the B chain. Despite this restricted specificity, each member of this panel exhibited a distinct receptor specificity defined either by Vβ usage or antigen fine specificity. Five clones produced interferon (IFN)‐γ but not interleukin (IL)‐4, placing them in the T helper type 1 (TH1)‐like category whereas one clone produced both IL‐4 and IFN‐γ, a characteristic of TH0 cells. All six clones were capable of either acceleration of diabetes in young NOD mice or adoptive transfer to NODscid mice. Taken together, these results suggest that spontaneously arising insulin‐specific T cells participate in beta cell destruction during development of diabetes in NOD mice.
Reciprocal regulation of the nitric oxide synthase/arginase balance in mouse bone marrow‐derived macrophages by TH 1 and TH 2 cytokines
Authors: Modolell Manuel , Corraliza Ines M. , Link Franz , Soler Germán , Eichmann Klaus 
Published: March 2007

AbstractActivation with lipopolysaccharide induces macrophages to produce the enzymes arginase and nitric oxide (NO) synthase. Both enzymes use as a substrate the amino acid L‐arginine, which can be either hydrolyzed by arginase to urea and ornithine or oxidized by NO synthase to NO and citrulline. NO is important in the bactericidal and cytotoxic activities of macrophages. An equivalent functional role of arginase and its products is not known. We tested the induction of arginase in bone marrow‐derived macrophages by endogenous mediators that are known to induce NO synthase, such as interferon‐γ (IFN‐γ), or suppress the induction of this enzyme, such as interleukin (IL)‐4, IL‐10, and prostaglandin E2 (PGE2). We find that PGE2 and the TH2 cytokines IL‐4 and IL‐10 are potent inducers of arginase. In contrast, the TH 1 cytokine IFN‐γ does not induce arginase. Simultaneous application of both types of mediators leads to reduced induction of both arginase and NO synthase. Exposure of macrophage cultures to inducers of NO synthase exhausts their ability to respond subsequently to inducers of arginase. Conversely, exposure of the cells to inducers of arginase exhausts their ability to respond subsequently to inducers of NO synthase. The results are consistent with a competition of both enzymes for their substrate, L‐arginine, with a reciprocal inhibition in the induction of both enzymes, or a combination of both phenomena. The enzymes NO synthase and arginase appear to define two alternate functional states of macrophages, induced by TH 1 and TH 2 cytokines, respectively.
Activation of murine epidermal γδ T cells through surface 2B4
Authors: Schuhmachers Georg , Ariizumi Kiyoshi , Mathew Porunelloor A. , Bennett Michael , Kumar Yinay , Takashima Akira 
Published: March 2007

AbstractDendritic epidermal T cells (DETC) are γδ T cells that normally reside in murine skin. They express on their surface the 2B4 molecule, a 66‐kDa glycoprotein of the immunoglobulin gene superfamily thought to be associated with anti‐tumor cytotoxicity by natural killer and lymphokine‐activated killer cells. Here, we show that ligation of surface 2B4 transduces cell activation signals in DETC. Treatment with anti‐2B4 monoclonal antibodies triggers the secretion of interferon‐γ and interleukin‐2 by DETC lines, induces proliferation of resting DETC lines, amplifies anti‐CD3‐dependent proliferation of DETC freshly isolated from mouse skin; and up‐regulates egr‐1 and c‐fos mRNA expression. These results indicate a unique pathway for DETC activation.
Activated T cells induce interleukin‐12 production by monocytes via CD40‐CD40 ligand interaction
Authors: Shu Uno , Kiniwa Mamoru , Wu Chang You , Maliszewski Charles , Vezzio Nadia , Hakimi John , Gately Maurice , Delespesse Guy 
Published: March 2007

AbstractPrevious studies on the production of interleukin‐12 (IL‐12) have shown that it is released, together with other proinflammatory cytokines, shortly after exposure of phagocytic cells to a variety of pathogens. We here report that IL‐12 is also released during the recall response to soluble antigen (Ag) devoid of intrinsic adjuvant activity. We show that activated T cells induce the production of IL‐12 by monocytes via a mechanism involving the interaction of T cell‐associated CD40 ligand with CD40 on monocytes. The data suggest that Ag presentation on monocytes favors the persistence of type 1 responses.