bluuebunny/crossref_metadata_2025_split huggingface dataset:
Interaction of HIV gp120 and anti‐CD4 antibodies with the CD4 molecule on human CD4+ T cells inhibits the binding activity of NF‐AT, NF‐χB and AP‐1, three nuclear factors regulating interleukin‐2 gene enhancer activity
Authors: Jabado Nada , Le Deist Françoise , Fischer Alain , Hivroz Claire 
Published: March 2007

AbstractThe membrane glycoprotein CD4 is required for optimal antigen‐mediated activation of CD4+ T cells restricted by class II molecules of the major histocompatibility complex (MHC). CD4 cross‐linking by anti‐CD4 antibodies or binding by human immunodeficiency virus (HIV) gp120 has been shown to inhibit antigen‐dependent and ‐independent T cell activation, abrogating T cell proliferation, IL‐2 synthesis and the increase in the intracellular calcium concentration. The molecular basis of these opposing phenomena is ill‐defined. To characterize further the inhibitory role of the CD4 molecule, we investigated the effects of CD4 ligands on the transcription factors regulating the IL‐2 gene enhancer and IL‐2 synthesis. We first confirmed that pre‐treatment of peripheral human CD4+ T lymphocytes by CD4 ligands, HIV gp120 or anti‐CD4 monoclonal antibodies inhibited IL‐2 production and cell proliferation, which was normally induced by an anti‐CD3 antibody (UCHT1) plus a protein kinase C activator (PMA). Moreover, these CD4 ligands inhibited the proliferation and synthesis of IL‐2 induced by activators bypassing membrane events, i.e. PMA and calcium ionophore, pointing to an active signaling pathway triggered by the CD4 molecule. Gp120 and anti‐CD4 antibodies induced a specific, significant decrease in the binding activity of NF‐AT, NF‐χB and AP‐1, three transcription factors regulating IL‐2 gene enhancer activity, as demonstrated by electrophoretic mobility shift assays. Inhibition was similarly observed following cell activation by activators involving membrane events and those bypassing them. These results strongly suggest that the inhibition mediated by cross‐linking of the CD4 molecule is at least partly due to a negative signal down‐regulating the availability of nuclear factors necessary for the regulation of IL‐2 gene transcription.
Activation of 70‐kDa S6 kinase, induced by the cytokines interleukin‐3 and erythropoietin and inhibited by rapamycin, is not an absolute requirement for cell proliferation
Authors: Calvo Victor , Wood Michael , Gjertson Carl , Vik Terry , Bierer Barbara E. 
Published: March 2007

AbstractThe cytokines interleukin (IL)‐3 and erythropoietin (EPO) are critical regulators of the proliferation and differentiation of cells of the hematopoietic system, but their intracellular mechanisms of action are not fully understood. Binding of IL‐3 to the IL‐3 receptor (IL‐3R) and binding of EPO to the EPOR both induce changes in intracellular tyrosine and serine/threonine phosphorylation; the phosphorylation of a number of polypeptides appears to be a shared response upon cytokine stimulation. We have previously shown that binding of IL‐2 to the IL‐2R activates the 70‐kDa (p70) S6 kinase, a serine/threonine kinase whose activity is regulated by serine/threonine phosphorylation; the immunosuppressant rapamycin inhibits IL‐2‐dependent proliferation and IL‐2‐triggered activation of p70 S6 kinase. We, therefore, sought to examine whether induction of p70 S6 kinase activity is a conserved response upon cytokine triggering, and whether this activity is essential for cell proliferation. Proliferation of the IL‐3‐dependent pro‐B cell line Ba/F3 transfected with the EPOR (Ba/F3‐EPOR) can be supported by either IL‐3 or EPO. In this cell line, both IL‐3 and EPO induced p70 S6 kinase activity; rapamycin inhibited both the IL‐3 and EPO‐induced activation of the 70‐kDa S6 kinase as well as cellular proliferation. Thus, p70 S6 kinase activation appears to be a common intermediate triggered by the stimulation of IL‐3, EPO, and IL‐2 receptors. The Friend spleen focus‐forming virus gp55 renders the EPOR constitutively active, and confers growth factor independence on cells expressing EPOR. Ba/F3‐EPOR cotransfected with gp55 (Ba/F3‐EpoRgp55) and the erythroleukemia cell line MEL, which also expresses both the EPOR and gp55, were analyzed. Rapamycin inhibited the activation of p70 S6 kinase in both cell lines. However, rapamycin inhibited proliferation of Ba/F3‐EpoRgp55 but not of MEL cells despite inhibition of p70 S6 kinase activity in both cells. Thus, p70 S6 kinase activation is not an absolute requirement for cell proliferation. These results are discussed in relation to the role of the activation of the 70‐kDa S6 kinase activation pathway in the regulation of cell cycle progression.
Properties of mouse CD40: the role of homotypic adhesion in the activation of B cells via CD40
Authors: Klaus Gerry G. B. , Holman Mary , Hasbold Jhagvaral 
Published: March 2007

AbstractStimulation of human B cells via CD40 is known to induce their homotypic aggregation. We show here that anti‐mouse CD40 monoclonal antibodies (mAb) also induce B cells to form large, spherical, extremely stable clusters. This clustering is markedly enhanced by co‐stimulation with either interleukin‐4 (IL‐4) or anti‐immunoglobulin (Ig). The aggregation is slow in onset, and is largely (but not completely) abrogated by anti‐LFA‐1 mAb, but not by mAb directed against other potentially important adhesion molecules on B cells. Anti‐LFA‐1 mAb also partially suppressed DNA synthesis induced by anti‐CD40, but not by other B cell mitogens, suggesting that clustering is an important component of B cell activation via CD40. This concept is supported by analyses of the phenotype of clustered B cells: the cells within clusters express higher levels of various activation markers, and also more of them are in cell cycle than non‐clustered cells. These results therefore suggest that CD40 stimulation may either induce B cells to secrete soluble factors which act in an autocrine way to promote Bcell activation, or that clustering generates cell contact‐mediated signals which are important in the activation cascade.
CD28 signal transduction: tyrosine phosphorylation and receptor association of phosphoinositide‐3 kinase correlate with Ca2+‐independent costimulatory activity
Authors: Lu Yiling , Phillips Catherine A. , Bjorndahl Jay M. , Trevillyan James M. 
Published: March 2007

AbstractThe interaction of CD28 with its counter‐receptor, B7, induces a cosignal in T cells required to prevent clonal anergy and to promote antigen‐dependent interleukin‐2 production. The molecular basis of the CD28 cosignal is not well understood but involves the activation of protein tyrosine kinase(s) (PTK). In this report we demonstrate that CD28 cross‐linking on Jurkat T leukemic cells causes the activation of at least two PTK pathways. A CD28‐induced, p56lck kinase‐independent pathway causes tyrosine‐phosphorylation of a 110‐kDa substrate while recruitment of p56lck kinase activity is apparently required for CD28‐induced tyrosine‐phosphorylation of 97‐ and 68‐kDa substrates as well as CD28‐induced increases in intracellular calcium. The tyrosine phosphorylation of p110, but not p97 or p68, correlated with CD28 calcium‐independent costimulatory activity. The pp110 molecule was tentatively identified as the catalytic subunit of phosphoinositide (PI)‐3 kinase based upon its coimmunoprecipitation with the p85 regulatory subunit of PI‐3 kinase. PI‐3 kinase protein and catalytic activity were found complexed with the CD28 receptor if the receptor was “activated” by cross‐linking on the surface of intact cells prior to detergent solubilization. The kinetics of association of PI‐3 kinase with the “activated” CD28 receptor was rapid, occurring within 30 s of receptor cross‐linking and was stable for at least 30 min. Analysis of the CD28 cytoplasmic peptide sequence revealed a putative PI‐3 kinase src homology 2 binding motif and CD28 tyrosine phosphorylation site, DYMNM. Tyrosine phosphorylation of CD28 was detected in pervanadate‐treated Jurkat B2.7 cells, but not untreated cells. Pervanadate‐induced tyrosine phosphorylation of CD28 correlated with receptor association of PI‐3 kinase in the absence of CD28 cross‐linking, suggesting that CD28 association with PI‐3 kinase uses a tyrosine phosphorylation‐dependent mechanism. These data provide a model for CD28 signal transduction and support a role for PI‐3 kinase in mediating the CD28 calcium‐independent, cyclosporin A‐insensitive costimulatory signal.
Surface immunoglobulins mediate efficient transport of antigen to lysosomal compartments resulting in enhanced specific antigen presentation by B cells
Authors: Liu Ko‐Jiunn , Parikh Vandana S. , Tucker Philip W. , Kim Byung S. 
Published: March 2007

AbstractA BCL1 immunoglobulin (Ig) transfectant, expressing wild‐type surface (s)IgM with the TEPC‐15 idiotype (T15‐Id) and anti‐phosphorylcholine (PC) specificity, was previously shown to present PC‐conjugated hen egg‐white lysozyme (PC‐HEL) to a HEL‐specific T cell hybridoma at a lower antigen (Ag) concentration than that required for native HEL. Two variant Ig transfectants, expressing T15‐Id sIgM with substitutions either in the entire spacer, transmembrane (TM) domain and cytoplasmic tail (B186 variant) or in the NH2‐terminal third of TM domain only (TM2 variant), failed to display this sIgM‐mediated, enhanced presentation of PC‐HEL at low concentrations. However, prolonged treatment with anti‐T15‐Id monoclonal antibody (mAb) led to a reduction of surface expression of the T15‐Id sIgM in the wild‐type and TM2 variant, but not in the B186 variant sIgM transfectants. Treatment with anti‐T15‐Id mAb also resulted in an increased intracellular accumulation of T15‐Id sIgM in the wild‐type transfectant, but not in the B186 variant. Subcellular fractionation analysis revealed that the ligands bound to the T15‐Id sIgM are not efficiently transported to the dense lysosomal compartments in both B186 and TM2 transfectants, as compared to the wild‐type sIgM transfectant. A significant increase in tyrosine phosphorylation after cross‐linking of the T15‐Id sIgM was observed only in the wild‐type sIgM transfectant. These results suggest that, while the NH2‐terminal third of the TM region is not involved in the process responsible for the ligand‐induced reduction of surface expression of sIgM, it appears to be essential for subsequent transport of sIgM/ligand complexes to the lysosomal compartments, as well as efficient activation of tyrosine kinases. These results strongly suggest that sIg‐mediated enhancement of specific antigen presentation reflects the ability of sIg to efficiently transport antigen to the lysosomal compartments, and possibly the activation of protein tyrosine kinases.
T cell regulation of collagen‐induced arthritis in mice. III. Is T cell vaccination a valuable therapy?
Authors: Chiocchia Gilles , Manoury‐Schwartz Bénédicte , Boissier Marie‐Christophe , Gahery Hanne , Marche Patrice N. , Fournier Catherine 
Published: March 2007

AbstractSince T cells play a critical role in collagen‐induced arthritis (CIA), CD4+ T cell hybridomas were derived from DBA/1 mice immunized with bovine type II collagen (CII). The hybrid clones selected were Thy‐1‐2+, CD4+, CD8−, T cell receptor (TcR) αβ+ and produced interleukin‐2 in response to CII peptides presented by I‐Aq molecules. The clones were collagen type‐specific and recognized CII from many species except the mouse. More precisely, the reactivity was directed against the immunodominant cyanogen bromide‐cleaved fragment CB11(II). Analysis of the TcR carried by the T cell hybridomas showed that they used identical Vα and Jα (VαBMB, Jα20) gene segments and two distinct Vβ (Vβ1 and Vβ4) associated with the Jβ2.5 gene segment. Interestingly, the junctional regions were highly conserved in structure and length. These findings may indicate a strong in vivo selection by the antigen for a particular combination of both α and β chains of the TcR. Inoculation of irradiated anti‐CII T cell hybrids into DBA/1 mice, before priming with CII, altered the course of the disease resulting in either a long‐lasting suppression or an exacerbation of CIA whereas a control CD4+ hybridoma with an unrelated specificity did not influence the development of arthritis. However, the regulatory effect of anti‐CII T cell clones was unpredictable, suggesting that the TcR structure may not solely account for the modulation of CIA and that T cell vaccination is not a reliable method for inducing suppression of CIA.
The mixotope: a combinatorial peptide library as a T cell and B cell immunogen
Authors: Estaquier Jérǒme , Gras‐Masse Hélène , Boutillon Christophe , Ameisen Jean‐Claude , Capron André , Tartar André , Auriault Claude 
Published: March 2007

AbstractWe report a new approach in peptide vaccine strategy based on combinatorial synthesis. A library of 7.5 × 105 related peptides, termed mixotope, was derived from the sequence of the third hypervariable domain (V3 loop) of the human immunodeficiency virus (HIV) envelope protein.This preparation induced a strong immune response in all syngeneic and outbred rodents tested. The response directed against the mixotope included antibodies, CD4+ T helper cells (TH1 and TH2) and CD8+ T cells. In rodents immunized with the mixotope, the T cell response directed against individual V3 peptide sequences (BRU, MN, RF, SF2, and ELI) as measured by T cell proliferation and interleukin (IL)‐2 production, was found to be major histocompatibility complex haplotype‐dependent. However, additional experiments performed in mice indicated that selectivity was less restrictive when using IL‐3 secretion to explore T cell activation.This combinatorial antigen could be considered as a series of agretopic motifs framing a multiplicity of closely related epitopes for T cell recognition and able to elicit a T cell and B cell repertoire. This new construct may therefore provide a basis for the design of future vaccine strategies.
Distinct structural and functional epitopes of the αEβ7 integrin
Authors: Russell Gary J. , Parker Christina M. , Cepek Karyn L. , Mandelbrot Didier A. , Sood Arvind , Mizoguchi Emiko , Ebert Ellen C. , Brenner Michael B. , Bhan Atul K. 
Published: March 2007

AbstractIntestinal intraepithelial lymphocytes (iIEL) are predominantly CD3+, CD8+ T lymphocytes located above or adjacent to the mucosal basement membrane. Although they are positioned to interact with intercellular luminal antigen or with enterocytes, the function of iIEL remains unknown. Most (> 85%) of the iIEL express the αEβ7 integrin which appears to be involved in the adhesion of lymphocytes to epithelial cells. We report the characterization of three monoclonal antibodies (mAb) termed αE7‐1, αE7‐2, and αE7‐3, that react with the αEβ7 integrin recognized by the previously described mAb HML‐1 as demonstrated by identical sodium dodecyl sulfate – polyacrylamide gel electrophoresis mobility and charge. Flow cytometric analysis of antibody cross‐blocking indicated that these mAb recognize distinct epitopes of αEβ7. While all of the mAb were capable of blocking the adhesion of cultured iIEL to a breast epithelial cell line, only HML‐1 and αE7‐1 (which recognize an identical or closely related epitope) were co‐stimulatory with suboptimal concentrations of anti‐CD3 mAb in inducing proliferation of cultured iIEL. Thus, these mAb appear to recognize functionally distinct epitopes of αEβ7 and will be useful to study relationships between the structure and function of this integrin.
Genetic control of the human Vβ13.2 T cell repertoire: importance of allelic variation outside the coding regions of the TCRBV13S2 gene
Authors: Kay Richard A. , Snowden Neil , Hajeer Ali H. , Boylston Art W. , Ollier William E. R. 
Published: March 2007

AbstractIn humans, the T cell repertoire is influenced by HLA, T cell receptor null alleles and antigen. Here, we describe a novel mechanism, independent of superantigen or T cell receptor structure which influences the T cell repertoire in a Vβ‐dependent manner. We have identified a biallelic locus, the TCRBV13S2 T cell receptor gene, where allelic differences predominate in the non‐coding regions including transitions, transversions and frameshift deletions. The expressed protein is non‐polymorphic at this locus. The TCRBV13S2 genotype profoundly influences the circulating levels of Vβ13.2 CD4 T cells but does not affect T cell receptor expression or function.
Selective regulation of ICAM‐1 and major histocompatibility complex class I and II molecule expression on epidermal Langerhans cells by some of the cytokines released by keratinocytes and T cells
Authors: Chang Chung‐Hsing , Furue Masutaka , Tamaki Kunihiko 
Published: March 2007

AbstractEpidermal Langerhans cells (LC) are major histocompatibility complex (MHC) class II (Ia)‐positive dendritic cells that act as potent antigen‐presenting or accessory cells for primary and secondary T cell‐dependent immune responses. Recent studies have disclosed that the morphological, functional, and phenotypic characteristics of LC are variably and drastically modulated by external stimuli both in vivo and in vitro. However, little is known of the biological significance of diverse cytokines in regulating the surface molecules of LC. To determine the regulatory properties of ICAM‐1, Ia, and MHC class I (H‐2K) molecules in LC, we have examined the effects of interleukin (IL)‐1α, IL‐1β, IL‐2, IL‐3, IL‐4, IL‐5, IL‐6, IL‐7, IL‐10, interferon‐γ (IFN‐γ), tumor necrosis factor‐α (TNF‐α), and granulocyte‐macrophage colony‐stimulating factor (GM‐CSF) on the expression of these molecules. Among the cytokines examined, IFN‐γ markedly and reproducibly up‐regulates the expression of H‐2K, but not ICAM‐1, in Ia+ LC in a time‐ and dose‐dependent manner. TNF‐α consistently up‐regulates the expression of ICAM‐1, but not H‐2K, in a time‐ and dose‐dependent manner. IL‐10 slightly but reproducibly inhibits the expression of ICAM‐1, but not H‐2K, in a time‐ and dose‐dependent manner. IL‐10 potently inhibits the TNF‐α‐induced ICAM‐1 up‐regulation, but not the IFN‐γ‐induced H‐2K up‐regulation. Moreover, no cytokine consistently affects the Ia expression of LC. In addition, slight enhancing effects have been observed on H‐2K expression by IL‐4, and on ICAM‐1 expression by IL‐1α, IL‐1β, or GM‐CSF. The present data suggest that the selective regulation is operative in a certain cell surface moiety of LC by various cytokines. These results further facilitate our understanding of immunobiology of LC.
CD8high(CD57+) T cells in normal, healthy individuals specifically suppress the generation of cytotoxic T lymphocytes to Epstein‐Barr virus‐transformed B cell lines
Authors: Wang Eddie Chung Yern , Lehner Paul Joseph , Graham Shek , Borysiewicz Leszek Krysztof 
Published: March 2007

AbstractWe have previously identified two subsets of CD8+, CD57+ lymphocytes in normal peripheral blood: i) T cells expressing high levels [CD8high(CD57+)] and ii) natural killer cells expressing low levels of surface CD8 [CD8low(CD57+)]. We investigated the cytotoxic and suppressive function of CD8high(CD57+) T lymphocytes from normal, healthy individuals using standard chromium‐release assays and limiting dilution analysis. In normal, healthy subjects, this cell subset suppressed the generation of cytotoxic T lymphocytes (CTL) to autologous, Epstein‐Barr virus (EBV)‐transformed B cell lines (BCL). Depletion of CD8high(CD57+) T lymphocytes from peripheral blood mononuclear cells (PBMC) resulted in a three‐ to sevenfold rise in CTL precursor frequency to autologous EBV‐transformed BCL, but not allogeneic PBMC or BCL by LDA. Replacement of CD8high(CD57+) T lymphocytes in limiting dilution cultures led to the dose‐dependent suppression of EBV‐specific, but not allogeneic, CTL generation. Supernatant from CD8high(CD57+) T lymphocytes cultured with autologous BCL did not exhibit suppression, suggesting that soluble factors were not responsible. As CD8high(CD57+) T lymphocytes did not, themselves, exhibit cytotoxicity against autologous BCL, removal of BCL stimulator cells in co‐culture was not the mechanism of suppression. Furthermore, while the CD8high(CD57+) T lymphocytes from healthy subjects suppressed the generation of CTL to autologous BCL, they did not suppress the cytotoxic activity of established mixed lymphocyte reactions or peptide‐specific CTL clones, as has been reported in bone marrow transplant recipients and human immunodeficiency virus patients. This suggests that CD8high(CD57+) T lymphocytes from healthy subjects suppress the generation of, rather than killing by, CTL in a contact‐dependent manner. To our knowledge, this is the first identification of a phenotypically distinct subset of human CD8+ T cells that can suppress generation of antigen‐specific major histocompatibility complex class I‐restricted CTL.
Heterogeneity in P‐glycoprotein (multidrug resistance) activity among murine peripheral T cells: Correlation with surface phenotype and effector function
Authors: Bommhardt Ursula , Cerottini Jean‐Charles , MacDonald H. Robson 
Published: March 2007

AbstractP‐glycoprotein (P‐gly) is the transmembrane efflux pump responsible for multidrug resistance in tumor cells. Functional P‐gly activity can be conveniently assessed microfluorometrically using the fluorescent dye rhodamine 123 (Rh123), which is an artificial substrate for the P‐gly transporter. Here we assess P‐gly activity in subsets of mouse peripheral T lymphocytes using the Rh123 efflux assay. Our data indicate that virtually all CD8+ cells extrude Rh123 efficiently, whereas only a subset of CD4+ cells exhibit P‐gly activity. Correlation of P‐gly activity in CD4+ cells with the expression of a panel of surface markers revealed that cells bearing an “activated/memory” phenotype (CD45RB−, CD44hi, CD62L−, CD25+, CD69+) were exclusively found in the fraction that can extrude Rh123. In contrast “naive” phenotype CD4+ cells (CD45RB+, CD44lo, CD62L+, CD25−, CD69−) could be further subdivided into two major subsets based on P‐gly activity. In functional studies of sorted cell populations the Rh123‐extruding subset of “naive” CD4+ cells proliferated more strongly and secreted higher levels of interleukin (IL)‐2 than its Rh123‐retaining counterpart when activated by a variety of polyclonal stimuli. Furthermore, this subset produced detectable levels of interferon (IFN)‐γ upon stimulation but no IL‐4 or IL‐10. As expected, the Rh123‐retaining “naive” subset produced only IL‐2 after stimulation, whereas the “memory” subset produced IFN‐γ, IL‐4 and IL‐10 in addition to low levels of IL‐2. Collectively, our data indicate that P‐gly activity is a novel parameter that can be used to distinguish a subset of “preactivated” CD4+ cells that would be considered as naive on the basis of their surface phenotype.