bluuebunny/crossref_metadata_2025_split huggingface dataset:
Virus or a hapten‐carrier complex can activate autoreactive B cells by providing linked T help
Authors: Steinhoff Ulrich , Burkhart Christoph , Arnheiter Heinz , Hengartner Hans , Zinkernagel Rolf 
Published: March 2007

AbstractWe investigated the mechanism leading to an IgG autoantibody response in two transgenic mouse lines expressing the glycoprotein of vesicular stomatitis virus (VSV‐G). Previous experiments have shown that these animals do not mount a transgene‐specific IgG response upon stimulation with purified VSV‐G or infection with recombinant vaccinia virus expressing VSV‐G. However, infection of VSV‐G transgenic animals with wild‐type vesicular stomatitis virus, serotype Indiana, readily induced VSV‐G‐specific, neutralizing IgG autoantibodies. We have tested whether this labile state of tolerance reflected differential availability of VSV‐G‐specific T help. For this, we immunized transgenic mice with the self‐antigen VSV‐G covalently coupled to sperm‐whale myoglobulin (VSV‐G‐SWM), to provide new T helper epitopes that are linked to the B cell epitope; co‐injected uncoupled VSV‐G and SWM served as control. High titers of VSV‐G specific IgG autoantibodies were detected in serum of mice immunized with VSV‐G‐SWM but not after co‐injection of uncoupled VSV‐G and SWM. Transgenic animals depleted of CD4+ T cells prior to injection of VSV‐G‐SWM failed to mount an IgG response. Priming of transgenic mice with the foreign carrier did not accelerate the IgG autoantibody response to VSV‐G‐SWM, suggesting that B cells were limiting the rate of the response. Thus, self‐reactive B cells could be triggered to produce IgG, if they received linked T help specific for a foreign carrier determinant provided either by a classical carrier determinant or a virus.
T helper type 1 development of naive CD4+ T cells requires the coordinate action of interleukin‐12 and interferon‐γ and is inhibited by transforming growth factor‐β
Authors: Schmitt Edgar , Hoehn Petra , Huels Christoph , Goedert Sigrid , Palm Norbert , Rüde Erwin , Germann Tieno 
Published: March 2007

AbstractIt was observed in vitro and in vivo that both interferon (IFN)‐γ and interleukin (IL)‐12 can promote the development of T helper type 1 (TH1) cells. Since IL‐12 was shown to be a costimulator for the production of IFN‐γ by T or natural killer (NK) cells, IL‐12 might play only an indirect role in TH1 differentiation by providing IFN‐γ which represents the essential differentiation factor. Using anti‐CD3 monoclonal antibody (mAb) for activation of naive CD4+ T cells in the absence of accessory cells we could demonstrate that costimulation by IFN‐γ alone results only in marginal TH1 development. Similarly, IL‐12 in the absence of IFN‐γ is only a poor costimulator for inducing differentiation towards the TH1 phenotype. Our data indicate that both cytokines are required to allow optimal TH1 development and that IL‐12 has a dual role, it promotes differentiation by direct costimulation of the T cells and also enhances the production of IFN‐γ which serves as a second costimulator by an autocrine mechanism. Another cytokine that was reported to favor TH1 differentiation in certain experimental systems is transforming growth factor (TGF)‐β. With naive CD4+ T cells employed in this study TGF‐β strongly inhibited the production of IFN‐γ triggered by IL‐12 as well as the IL‐12‐induced TH1 development. When TGF‐β was combined with anti‐IFN‐γ mAb for neutralization of endogenous IFN‐γ the TH1‐inducing capacity of IL‐12 was completetly suppressed.
A directory of human germ‐line Vχ segments reveals a strong bias in their usage
Authors: Cox Jonathan P. L. , Tomlinson Ian M. , Winter Greg 
Published: March 2007

AbstractFrom the genomic DNA of a single individual, we have amplified, cloned and sequenced 37 human germ‐line Vχ segments. Four of these segments were new. We then compiled a comprehensive directory of all germ‐line Vχ segments and identified 50 different sequences with open reading frames. Comparison with 236 rearranged sequences revealed that no more than 24 of these germ‐line sequences could be assigned rearranged counterparts, that some of these were rarely used, and that only about 11 sequences are used frequently. This suggests that the expressed Vχ repertoire is mainly derived from a limited number of segments. Most surprisingly, the Jχ‐distal region of the locus appears to be rarely used: we could unambiguously assign 162 rearranged sequences to Vχ segments of the Jχ‐proximal region, but only 5 to segments of the Jχ‐distal region.
Engagement of the CD4 receptor inhibits the interleukin‐2‐dependent proliferation of human T cells transformed by Herpesvirus saimiri
Authors: Bröker Barbara M. , Tsygankov Alexander Y. , Fickenscher Helmut , Chitaev Nikolai A. , Müller‐Fleckenstein Ingrid , Fleckenstein Bernhard , Bolen Joseph B. , Emmrich Frank 
Published: March 2007

AbstractInfection with Herpesvirus saimiri, a tumor virus of non‐human primates, transformed human CD4+ T cell clones to permanent interleukin (IL)‐2‐dependent growth without need for restimulation with antigen and accessory cells. The IL‐2‐dependent proliferation of these cells was dramatically inhibited by soluble anti‐CD4 whole antibodies, F(ab′)2 and Fab fragments, and also by gp 120 of human immunodeficiency virus. The inhibition was not due to cell death and could be overcome by high concentrations of exogenous IL‐2. Cell surface expression of CD4, and to a lesser degree the density of the IL‐2 receptor α chain, were reduced upon anti‐CD4 treatment. After long lasting (>12h) incubation with anti‐CD4, abundance and activity of CD4‐bound p56lck were diminished while the free fraction of p56lck remained unchanged. Since IL‐2 binding to its receptor activated only the CD4‐bound fraction of p56lck, the IL‐2‐induced p56lck activity was diminished after long‐term CD4 ligation. Taken together, our results suggest a cross talk between CD4‐ and IL‐2 receptor‐mediated signaling via p56lck.
Ca2+ mobilization in physiologically stimulated single T cells gradually increases with peptide concentration (analog signaling)
Authors: Røtnes Jan S. , Bogen Bjarne 
Published: March 2007

AbstractWe have investigated Ca2+ mobilization in single T cells stimulated with their physiological ligand, i.e. antigenic peptide bound to major histocompatibility complex (MHC) molecules on antigen‐presenting cells (APC). Fibroblasts expressing I‐Ed class II molecules were pulsed with a peptide derived from the λ2315 immunoglobulin light chain. Onto such antigen‐pulsed fibroblasts were sedimented cloned Th1 cells loaded with Fura‐2. Changes in cytosolic Ca2+ concentration in single T cells were continually monitored by use of an imaging system based on fluorometry. Ca2+ mobilization was both peptide‐specific and MHC‐restricted. Within seconds of the initial APC‐T cell contact, a Ca2+ spike could be observed. The Ca2+ response gradually declined over a 25‐min period, during which oscillations were noted. Various parameters characterizing the magnitude of the Ca2+ response (latency, increase rate, max and mean Ca2+ increase, frequency and period of oscillations) all correlated with the amount of peptide used for pulsing the fibroblasts. Thus, Ca2+ mobilization in single T cells appears not to be an all or none phenomenon. Rather, activation is incremental (analog signaling), the degree of Ca2+ mobilization probably being related to the number of stimulatory peptide‐MHC complexes on the surface of the APC. The extent of calcium mobilization and lymphokine production (interleukin (IL)‐2, IL‐3, interferon‐γ) correlated, at least at the population level.
The progressive differentiation of primed T cells is associated with an increasing susceptibility to apoptosis
Authors: Salmon Mike , Pilling Darrell , Borthwick Nicola J. , Viner Nick , Janossy George , Bacon Paul A. , Akbar Arne N. 
Published: March 2007

AbstractRecent studies have suggested that T cell memory for recall antigens resides in clones of primed T cells with a short inter‐mitotic half‐life. In humans such cells express an isoform of the leukocyte common antigen termed CD45RO. Nevertheless, little is known of the fate of these primed T cells after initial activation, since no markers are available to distinguish recently primed cells from long‐established clones. This report is focused on a spectrum of primed CD4+ T cells characterized by an inverse relationship between the expression of two CD45 epitopes: CD45RB and CD45RO. We show that primed CD4+ T cells progress through many cycles of division from a CD45RBbrightOdull to a CD45RBdullObright state, resulting in a highly skewed distribution of the T cell receptor variable region usage within this particular population. The progressive differentiation defined by the shift from CD45RBbright to CD45RBdull is paralleled by the gradual loss of bcl‐2 and gain of Fas expression, two features associated with an increased propensity for apoptosis. At the same time, the highly differentiated CD45RBdull cells selectively lose the capacity to synthesize interleukin (IL)‐2, a cytokine which is particularly effective in preventing T cell apoptosis, although they produce high levels of IL‐4. The inability to produce adequate levels of IL‐2 leads to the apoptosis of primed CD45RBdull cells, when they are stimulated in the absence of exogenous IL‐2. These observations show the crucial dependence of highly differentiated T cells on the availability of exogenous IL‐2, and suggest both a major constraint for the persistence of T cell memory maintained by continually cycling primed cells, and an important mechanism contributing to the maintenance of T cell homeostasis in vivo.
Lymphokine production induced by streptococcal pyrogenic exotoxin‐A is selectively down‐regulated by pooled human IgG
Authors: Skansén‐Saphir Ulrika , Andersson Jan , Björk Lars , Anderson Ulf 
Published: March 2007

AbstractThe influence of pooled human IgG preparations for intravenous use (IVIg) on cytokine production induced by streptococcal pyrogenic exotoxin‐A (SPE‐A) was studied at the single‐cell level using cytokine‐specific monoclonal antibodies and indirect immunofluorescence or immunohistochemical staining. Mononuclear cells from healthy adult blood donors were stimulated with SPE‐A alone or in the presence of IVIg. IVIg was added either prior to stimulation or 24 h after initiation of cultures, in an attempt to evaluate whether IVIg treatment could influence an already established systemic streptococcal disease. Cells were harvested after 48 or 72 h of culture and stained for the following cytokines: interleukin(IL)‐1α, IL‐1β, IL‐1ra, IL‐6, IL‐8, IL‐2, tumor necrosis factor interferon(IFN)‐γ and TNF‐α and TNF‐β and granulocyte macrophage‐colony‐stimulating factor. Stimulation with SPE‐A lead to extensive lymphokine and monokine production. With the addition of IVIg prior to stimulation there was a strong reduction of blast transformation and an almost complete inhibition of lymphokine production, in particular in the synthesis of IFN‐γ and TNF‐β while the synthesis of IL‐1 and IL‐8 was either unaffected or increased. Adding IVIg 24 h after SPE‐A stimulation also resulted in reduced blast transformation and decreased synthesis of IFN‐γ and TNF‐β. These results indicate an immunomodulatory potential by IVIg on streptococcally induced T cell activation and lymphokine production.
gld/gld mice are unable to express a functional ligand for Fas
Authors: Ramsdell Fred , Seaman Michael S. , Miller Robert E. , Tough Teresa W. , Alderson Mark R. , Lynch David H. 
Published: March 2007

AbstractMice homozygous for either the lpr or gld genes develop phenotypically identical autoimmune disorders. The gene responsible for the pathology in lpr/lpr mice encodes the Fas antigen, a protein associated with the induction of programmed cell death. To determine if the defect associated with gld represents a mutation in the ligand for Fas, we have assessed the ability of lymphoid cells from homozygous gld/gld mice to lyse target cells in a Fas‐dependent manner. Using an antagonistic antibody to Fas, we demonstrate that activated T cells from normal and lpr mice are capable of inducing Fas‐mediated lysis of tumor target cells. In contrast, activated T cells from gld/gld mice fail to induce lysis of tumor targets, although cells from gld mice are able to lyse specific allogeneic targets following mixed lymphocyte culture. In addition, activated T cells from gld/gld homozygous animals are not capable of binding to a Fas.Fc fusion protein at high levels, whereas activated T cells from normal and lpr/lpr animals bind Fas.Fc efficiently. These data indicate that mice homozygous for gld are unable to express a functional ligand for Fas.
T cell receptor antagonist peptides are highly effective inhibitors of experimental allergic encephalomyelitis
Authors: Franco Alessandra , Southwood Scott , Arrhenius Thomas , Kuchroo Vijay K. , Grey Howard M. , Sette Alessandro , Ishioka Glenn Y. 
Published: March 2007

AbstractThe feasibility of using T cell receptor (TcR) antagonist peptides to inhibit autoimmune disease has been examined. First, the fine antigenic structure of the I‐As‐restricted encephalitogenic determinant proteolipid protein (PLP) 139–151 has been analyzed. It was found that residues 145 and 148 were I‐As anchor residues, and residue 144 appeared to be especially critical in T cell activation. Residues 142, 143, 146, and 147 were found to be crucial for activation of some, but not all, of the T cells studied. Next, good I‐As‐binding nonantigenic analogs were tested for TcR antagonism. Accordingly, several single substitution analogs were identified which could act as TcR antagonists. Moreover, when two such analogs were combined, the resulting TcR antagonist pool inhibited most of the PLP 139–151‐specific T cell clones in vitro. When the efficacy of this TcR antagonist pool in inhibiting EAE induction in vivo was examined, it was found that the analog pool was a remarkably potent inhibitor of disease induction. The TcR antagonist pool was approximately 10‐fold more potent than our best major histocompatibility complex blocker and was still capable of significant inhibition when injected in equimolar amounts with the encephalitogenic PLP 139–151 determinant.
Distinct roles for CD4 and CD8 as co‐receptors in T cell receptor signalling
Authors: Maroun Christiane R. , Julius Michael 
Published: March 2007

AbstractWe demonstrate that CD4 and CD8 modify signals induced through the T cell receptor for antigen (TCRαβ) in distinct fashions. Pretreatment of CD4+ lymph node T cells with CD4‐specific monoclonal antibody results in a tenfold inhibition of DNA synthesis induced by anti‐TCRαβ. In contrast, pretreatment of CD8+ T cells with CD8‐specific mAb has no effect on DNA synthesis subsequently induced through TCRαβ. While inhibiting late activation signals, pretreatment with anti‐CD4 does not detectably alter the pattern of anti‐TCRαβ‐induced tyrosine phosphorylation of cellular proteins, nor subsequent Ca2+ mobilization. The distinct biological consequences of anti‐CD4 and anti‐CD8 pretreatment correlate with the differential association of their respective ligands with the cellular protein tyrosine kinase, p56lck. While both T cell lineages contain similar levels of cellular p56lck, tenfold more is associated with CD4 than with CD8. This difference is associated with the differential effects of pretreatment with anti‐CD4 and anti‐CD8 on the distribution and activity of p56lck. Further, antibody‐mediated aggregation of TCRαβ on CD4+ T cells induces the appearance of a p56lck species with decreased mobility in sodium dodecylsulfate‐polyacrylamide gel electrophoresis. This effect is observed in CD4+ T cells exclusively and involves the fraction of p56lck which is not associated with CD4. The results presented here demonstrate that the signalling elements which couple the antigen receptor to second messenger‐generating systems are under distinct physical and/or functional constraints in the two T cell lineages.
Anti‐LFA‐1 (CD11a) monoclonal antibody interferes with neonatal induction of tolerance to alloantigens
Authors: Schurmans Stephane , Gonzalez Antonio , Revilla Conchi , Ramos Angeles , Lambert Paul Henri , Merino Jesus 
Published: March 2007

AbstractThe injection of (C57BL/6 × BALB/c)F1 spleen cells into newborn BALB/c mice results in the induction of a specific cytotoxic T lymphocyte (CTL) tolerance to the alloantigens. On the contrary, alloreactive CD4+ T cells persist in the host and are still able to activate autoreactive F1 B cells to produce autoantibodies. This state of “split tolerance” is closely associated with the development of a lupus‐like autoimmune syndrome. The LFA‐1 integrin plays a relevant role in homing, intercellular adhesion and tranduction of co‐stimulatory signals in leukocytes. Because of the beneficial effects of anti‐LFA‐1 monoclonal antibodies (mAb) treatment in various models of organ transplantation and autoimmune disease, we have investigated if such a treatment could interfere with the induction of neonatal tolerance or the development of the autoimmune syndrome in F1 cell‐injected newborn mice. For this purpose, BALB/c mice neonatally injected with F1 cells were treated from day 1 up to day 15 with a non‐cytotoxic anti‐LFA‐1 (CD11a) mAb. Anti‐LFA‐1 mAb treatment interfered with the persistence of a stable chimerism and with the establishment of CTL tolerance, as shown by rejection of allogeneic skin grafts and F1 B cells, and by a normal in vitro CTL activity against the corresponding alloantigens. As a consequence, these mice did not develop the characteristic autoimmune features seen in close association with an effective induction of CTL tolerance to alloantigens. These results stress the importance of the interactions between LFA‐1 and its ligands during the neonatal induction of tolerance to alloantigens.
Interleukin‐10 inhibits B7 and intercellular adhesion molecule‐1 expression on human monocytes
Authors: Willems Fabienne , Marchant Arnaud , Delville Jean‐Pierre , Gérard Catherine , Delvaux Anne , Velu Thierry , De Boer Mark , Goldman Michel 
Published: March 2007

AbstractThere is evidence that interleukin −10(IL‐10) interferes with the costimulatory properties of antigen‐presenting cells and, thereby, inhibits their ability to induce T cell activation. To determine whether this effect might involve modulation of the expression of accessory molecules, we analyzed by flow cytometry the influence of human IL‐10 on the basal expression of intercellular adhesion molecule 1 (ICAM‐1) as well as on the interferon γ(IFN‐γ)‐induced up‐regulation of ICAM‐1 and B7 at the surface of human monocytes. IL‐10 inhibited both the basal expression and the IFN‐γ‐induced ICAM‐1 up‐regulation. IL‐10 also reduced B7 up‐regulation on IFN‐γ‐stimulated monocytes. The inhibitory effect of IL‐10 both on ICAM‐1 and B7 expression was shown to be dose dependent. We conclude that the ability of IL‐10 to decrease both ICAM‐1 and B7 expression on monocytes might contribute to its immunosuppressive properties.
T cells of staphylococcal enterotoxin B‐tolerized autoimmune MRL‐lpr/lpr mice require co‐stimulation through the B7‐CD28/CTLA‐4 pathway for activation and can be reanergized in vivo by stimulation of the T cell receptor in the absence of this co‐stimulatory signal
Authors: Zhou Tong , Weaver Casey , Linsley Peter S. , Mountz John D. 
Published: March 2007

AbstractThe CD28/CTLA‐4 receptors on T cells interact with the B7 molecule on antigen‐presenting cells (APC) to produce a co‐stimulatory signal that determines the outcome of activation. The role of this co‐stimulatory signal in T cell activation and loss of tolerance in autoimmune MRL‐lpr/lpr mice has not been investigated previously. The present study examines the contribution of the CD28/CTLA‐4 co‐stimulatory pathway to the loss of T cell tolerance in Vβ8 transgenic MRL‐lpr/lpr and ‐+/+ mice in which neonatal tolerance has been induced by the superantigen staphylococcal enterotoxin B (SEB). An artificial APC transfected with the murine B7 gene, and a CTLA‐4‐Ig fusion protein were used to analyze the significance of the CD28/CTLA‐4 pathway in vitro. The CTLA‐4‐Ig fusion protein was also used to inhibit the pathway in vivo. Our results demonstrate that CD28 and CTLA‐4 mRNA was overexpressed in the lymph nodes of lpr/lpr mice (MRL, C57BL/6, C3H and AKR), but not in +/+ mice of the same background strain. Lymph node T cells and thymocytes from SEB neonatally tolerized MRL‐lpr/lpr mice that had undergone tolerance loss, proliferated when cultured with SEB and B7+ fibroblasts in vitro, but did not proliferate when the SEB was presented in the context of B7− fibroblasts. This in vitro tolerance loss could be prevented by blocking of B7 signaling by CTLA‐4‐Ig. This loss of tolerance did not occur in lymph node T cells from thymectomized MRL‐lpr/lpr mice. SEB challenge of tolerized MRL‐lpr/lpr mice in vivo led to weight loss, increased serum cytokine levels and depletion of Vβ8+ T cells. These effects were blocked by blocking of the co‐stimulatory pathway by treatment with the CTLA‐4‐Ig fusion protein prior to and during challenge with SEB. T cells from thymus and lymph nodes of these mice did not proliferate later in response to stimulation in vitro with SEB even in the presence of B7+ APC. Nonresponsiveness was not due to deletion of Vβ8+ CD28+ T cells, as the number of these cells was increased after treatment with SEB and the CTLA‐4‐Ig fusion protein. These results suggest that the response of autoreactive T cells in the thymus and lymph nodes depends on signaling by B7 in vivo and in vitro and that SEB‐reactive T cells can be reanergized in vivo by stimulation of the T cell receptor in the absence of signaling through the CD28/CTLA‐4 co‐stimulatory pathway.
Mutagenesis of the human interleukin‐6 fourth predicted α‐helix: Involvement of the Arg168 in the binding site
Authors: Fontaine Véronique , Ooms Josette , Content Jean 
Published: March 2007

AbstractRandom substitutions of amino acid 161–184 of human interleukin‐6 (hIL‐6) have been generated at the cDNA level using oligonucleotide‐directed mutagenesis. Among the majority of the mutant proteins showing a reduced biological activity on murine hybridoma cells, only those having a substitution of Met161, Arg168, Arg179 or Met184, retained a tertiary structure similar to the IL‐6 folding. These residues are thus probably involved in the interaction with the IL‐6 receptor. However, the contacts established by Arg168 and Arg179 seem far more important for the biological activity. According to Bazan's model of cytokine folding and the receptor binding site on the fourth α‐helix, based on growth hormone similarity, we propose that Arg168 and Arg179 are located on the exposed surface of this presumed helix.