bluuebunny/crossref_metadata_2025_split huggingface dataset:
Synergistic effect between CD40 and class II signals overcome the requirement for class II dimerization in superantigen‐induced cytokine gene expression
Authors: Mehindate Khalil , Al‐Daccak Reem , Damdoumi Farida , Mourad Walid 
Published: March 2007

AbstractAlthough staphylococcal enterotoxin A (SEA), B (SEB), and toxic shock syndrome toxin 1 (TSST‐1) bind to major histocompatibility complex (MHC) class II molecules, they differ in their mode of binding. Signaling induced by these toxins via MHC class II molecules seems to be largely mediated by their mode of interaction. In the present study, we have demonstrated that contrary to SEA, stimulation of the human monocytic cell line THP‐1 with SEB or TSST‐1 failed to induce interleukin‐1β or tumor necrosis factor‐α gene expression. Treatment of THP‐1 cells with interferon‐γ increased the level of MHC class II expression but did not enhance the SEB and TSST‐1 response. However, cross‐linking of SEB or TSST‐1 bound to MHC class II molecules with specific antibodies leads to cytokine gene expression, indicating that dimerization of class II molecules is a requirement for this superantigen‐induced response. The presence of anti‐CD40 antibodies in the course of SEB or TSST‐1 stimulation overcomes this requirement, indicating that certain signal(s) induced via CD40 molecules can replace those induced by dimerization of class II molecules. Pretreatment with anti‐lymphocyte functional antigen‐1 (LFA‐1) antibodies completely inhibited SEA‐induced response as well as that induced by SEB or TSST‐1 in the presence of CD40 antibodies, supporting the involvement of LFA‐1 intercellular adhesion molecule system in these responses. The entirety of these results demonstrate clearly that dimerization of class II molecules is a prerequisite for superantigen‐induced T cell‐independent cytokine gene expression which can be replaced by signaling via CD40 in an LFA‐1‐dependent system.
Marked depletion at the late pro‐B cell stage in the bone marrow of lpr mice correlates with the development of lymphadenopathy but not autoimmunity
Authors: Dautigny Nicole , Chabre Henri , Garcia Corinne , Ezine Sophie 
Published: March 2007

AbstractWe have found that old lpr mice exhibit a loss of mature B cells in the bone marrow. The deleted population is HSAlo B220hi and is generated from the peripheral pool. Abnormalities in the microenvironment could explain the absence of mature B cells. Thus, old lpr bones were grafted under the skin of normal adult Ly5.1 hosts and examined 3 weeks later for the presence of Ly5.1+ B220hi cells. Our data show that the lpr medullary compartment was efficiently restored by host B cells. These results suggest that the bone marrow microenvironment of old lpr mice is able to sustain mature B cells. However, transfer of T cell‐depleted bone marrow cells from old lpr mice to Rag‐2−/− mice leads to incomplete and inefficient repopulation of the host medullary compartment. Thus, a defect at an early stage of B cell differentiation was detected: using four‐color flow cytometry, we found a profound depletion of the late pro‐B B220+ CD43+ HSA+ BP‐1+ cell population in aging lpr mice. This depletion was not observed in old autoimmune‐prone MRL‐+/+ mice which develop only autoantibodies but was present in B6‐lpr mice which develop a lymphadenopathy and an indolent autoimmune syndrome. Altogether, our results demonstrate an age‐linked defect in the progression of B cell differentiation in lpr mice independent of the presence of autoantibodies and targeted to the late pro‐B cell subset.
Differential expression of interleukin‐5 mRNA+ cells and eosinophils in Nippostrongylus brasiliensis infection in resistant and susceptible strains of mice
Authors: Zhou Yafen , Bao Shisan , Rothwell Terence L. W. , Husband Alan J. 
Published: March 2007

AbstractInterleukin (IL)‐5 is produced by both T cells and eosinophils and has been implicated in lymphocyte and eosinophil differentiation and maturation. The extent to which differences in IL‐5 expression contribute to genetic variability in parasite immunity was investigated by comparing eosinophilia, IgE production, mastocytosis and IL‐5 mRNA+ cells following Nippostrongylus brasiliensis infection of resistant (BALB/c) and susceptible (C57BL/6) mice. In uninfected mice, IL‐5 mRNA+ cells detected by in situ hybridization were distributed throughout the lamina propria and crypt regions of the small intestine in both strains, but were 1.5‐fold higher in BALB/c than in C57BL/6 mice. Following N. brasiliensis infection, the numbers of IL‐5 mRNA+ cells in BALB/c mice continued to increase until day 11 post‐infection at which time they were more than 4‐fold more numerous than in uninfected control mice of the same strain. In C57BL/6 mice, IL‐5 mRNA+ cells reached peak numbers on day 7 post‐infection, only 1.5‐fold higher than uninfected controls, but the numbers began to decline thereafter. At all time points after day 5, the numbers of IL‐5 mRNA+ cells in the gut of C57BL/6 mice were significantly lower than BALB/c mice. The differences in numbers of IL‐5 mRNA+ cells induced by infection in each strain of mice correlated with changes in blood and intestinal eosinophilia, mastocytosis and IgE production and was reflected in differences in worm expulsion and egg counts. Although numbers of intestinal IgA‐containing cells increased in both strains after infection, there was no difference between strains except at day 11 when there were significantly higher numbers in BALB/c mice than in C57BL/6 mice. These results suggest that IL‐5 is an important regulatory factor determining host immunity to parasite infection and that differential regulation of IL‐5 expression explains in part the observed strain differences with respect to parasite resistance.
Bcl‐2 delays macrophage engulfment of human B cells induced to undergo apoptosis
Authors: Flora Pauline K. , Devitt Andrew , Johnson Gerald D. , Milner Anne E. , Gregory Christopher D. 
Published: March 2007

AbstractThe capacity to be recognized and engulfed by phagocytes is an important characteristic of cells dying by apoptosis. Phagocytosis of apoptotic cells occurs rapidly in vivo, probably prior to plasma membrane breakdown. While the molecular mechanisms mediating phagocytosis of apoptotic cells are beginning to be defined, little is yet known of the relationship between the cell‐death program itself and the surface changes on the dying cells that signal for engulfment. Here, we investigate to what extent the apoptosis repressor Bcl‐2 can modulate the recognition and phagocytosis of human B cells exposed to triggers of apoptosis. Burkitt lymphoma (BL)‐derived, Bcl‐2− B cells were induced into apoptosis either by the Ca2+‐ionophore ionomycin or by the inhibitor of protein synthesis cycloheximide. Apoptotic BL cells, but not viable BL cells, were recognized and phagocytosed by monocyte‐derived macrophages. bcl‐2‐transfected BL populations showed a reduced capacity both to undergo apoptosis in response to these inducing agents and to interact with macrophages. Like their Bcl‐2− counterparts, Bcl‐2+ BL cells interacted with macrophages only after activation of their apoptotic program as assessed by changes in nuclear morphology. These results demonstrate not only that continued protein synthesis in B cells undergoing apoptosis is not essential for their recognition by macrophages, but also that macrophage recognition of apoptotic B cells cannot be uncoupled from the cell‐death program that is controlled by Bcl‐2. In this respect, the behavior of B cells contrasts markedly with that of neutrophils in which Bcl‐2 has been reported to inhibit apoptosis without affecting phagocytic clearance (Lagasse and Weissman, J. Exp. Med. 1994. 179: 1047).
Major histocompatibility complex class I‐dependent skewing of the natural killer cell Ly49 receptor reportoire
Authors: Held Werner , Dorfman Jeffrey R. , Wu Ming‐Fan , Raulet David H. 
Published: March 2007

AbstractSubsets of mouse natural killer (NK) cells express receptors encoded by the Ly49 gene family that recognize allelic determinants on major histocompatibility complex (MHC) class I molecules. Recognition of self class I molecules typically inhibits NK cell lytic function. The presence of NK cell subsets expressing receptors which are able to discriminate class I alleles raises the possibility that there exist mechanisms to coordinate the NK cell receptor repertoire with the class I molecules of the host. In the present study, we determined the effects of class I gene expression on the frequencies of NK cells expressing three different Ly49 receptors defined by monoclonal antibodies. We show here an MHC‐dependent skewing of NK cell subsets expressing multiple Ly49 receptors with specificity for self MHC. The results provide the first evidence that the frequencies of NK cells expressing different Ly49 receptors are determined by the host's MHC molecules. The results also extend previous findings that MHC class I expression influences the cell surface levels of each Ly49 receptor, suggesting an additional mechanism by which MHC molecules may influence the effective specificity of NK cells. Models to account for self tolerance and MHC‐controlled repertoire differences are discussed.
T cell receptor and CD8‐dependent tyrosine phosphorylation events in cytotoxic T lymphocytes: activation of p56lck by CD8 binding to class I protein
Authors: Anel Alberto , O'Rourke Anne M. , Kleinfeld Alan M. , Mescher Matthew F. 
Published: March 2007

AbstractTyrosine phosphorylation of proteins plays a central role in T cell activation. Mitogens or anti‐receptor antibodies have been employed to study these signaling events, but the extent to which these mimic receptor interactions with native ligands is unclear. Cytotoxic T lymphocytes can be activated for functional responses using purified, native class I ligands presented on a surface. Previous work showed that stimulation with fluid‐phase anti‐T cell receptor (TCR) monoclonal antibody (mAb) activates CD8 to mediate adhesion to class I proteins and that activated CD8 generates a co‐stimulatory signal upon binding to class I. Changes in tyrosine phosphorylation of substrates and activity of the p56lck kinase have now been examined in this two‐step process. The observed changes are small in comparison to those found using more potent nonphysiological stimuli, but may more accurately reflect the events required for activation of functional responses. Fluid‐phase anti‐TCR mAb caused increased tyrosine phosphorylation of a discrete subset of cellular substrates. Increased phosphorylation of additional substrates occurred upon CD8 binding to class I, resulting in a phosphorylation pattern comparable to that found in cells stimulated with class I alloantigen. Anti‐TCR mAb alone caused increased tyrosine phosphorylation of p56lck. When CD8 bound to class I, phosphorylation of p56lck decreased to below the basal level found in unstimulated cells, accompanied by a substantial increase in kinase activity. These results are consistent with the two‐step model for TCR activation of CD8/class I interactions and directly demonstrate that CD8 binding to class I leads to up‐regulation of p56lck activity.
CD40 is functionally expressed on human keratinocytes
Authors: Denfeld Ralf W. , Hollenbaugh Diane , Fehrenbach Alexandra , Weiss Johannes M. , von Leoprechting Achim , Mai Brigit , Voith Ursula , Schöpf Erwin , Aruffo Alejandro , Simon Jan C. 
Published: March 2007

AbstractThe CD40/gp39 pathway is known to be an important feature of B/T cell collaboration leading to T cell‐dependent activation, proliferation or differentiation of B cells. Additionally, CD40 is involved in the regulation of B cell survival and apoptosis. Recently, CD40 has been shown to be expressed functionally on non‐hematopoietic cells, i.e. endothelial cells. Here, we demonstrate that human keratinocytes (KC) cultured in vitro express CD40 constitutively. The surface expression of CD40 is markedly up‐regulated following stimulation with interferon (IFN)‐γ, but not with tumor necrosis factor‐α or interleukin (IL)‐1β. This process is regulated at the CD40 mRNA level as demonstrated by Northern blot analysis. Furthermore, ligation of CD40 via soluble gp39, the CD40 ligand, enhances intercellular adhesion molecule (ICAM)‐1 and Bcl‐x up‐regulation on IFN‐γ‐stimulated KC, but not lymphocyte function‐associated antigen (LFA)‐3, B7‐2, HLA‐DR, or Fas expression. The release of IL‐8 is also induced following CD40 ligation on KC. In psoriasis, a T cell‐mediated inflammatory skin disease, KC have a markedly enhanced expression of CD40. This expression co‐localizes with the expression of ICAM‐1, Bcl‐x, and an influx of CD3+ T cells. These findings suggest a functional role of CD40 on KC in inflammatory skin disorders such as psoriasis and could make a therapeutic intervention by disrupting the CD40/gp39 pathway an approach to consider in these inflammatory skin diseases.
Attenuation of collagen‐induced arthritis in mice by treatment with vector cells engineered to secrete interleukin‐13
Authors: Bessis Natacha , Boissier Marie‐Christophe , Ferrara Pascual , Blankenstein Thomas , Fradelizi Didier , Fournier Catherine 
Published: March 2007

AbstractThe anti‐inflammatory effects of the recently identified cytokine interleukin (IL)‐13 on collagen‐induced arthritis (CIA) was explored and compared to those of IL‐4 using systemic administration of these cytokines via two injections of xenogeneic vector cells transfected with a plasmid construct. CIA was induced in DBA/1 mice by immunization with native bovine type II collagen (CII). Chinese hamster ovary (CHO) fibroblasts transfected with the mouse IL‐13 or IL‐4 genes were inoculated subcutaneously on days 10 and 25 post‐priming with CII and mice were monitored for signs of arthritis by observers unaware of the status of the animals. Incidence and severity of CIA were significantly reduced in the groups of mice treated with IL‐13 and IL‐4 gene‐transfected CHO cells compared to control groups receiving nontransfected cells. Expression of various cytokines in spleen cells from individual mice was assessed by quantitative reverse transcriptase‐polymerase chain reaction at different times after immunization. Our data show that IL‐13‐induced suppression of CIA coincided with a decreased TNF‐α mRNA expression in the spleen of treated animals. This may explain at least partially the anti‐inflammatory effects of IL‐13 in CIA. Thus, our results may have important implications for the clinical use of T helper (Th)1/Th2 modulatory cytokines as therapeutic agents in the treatment of autoimmune diseases.
Antigenicity of HIV‐derived T helper determinants in the context of carrier recombinant proteins: effect on T helper cell repertoire selection
Authors: Manca Fabrizio , De Berardinis Piergiuseppe , Fenoglio Daniela , Ombra Maria Neve , Li Pira Giuseppina , Saverino Daniele , Autiero Monica , Lozzi Luisa , Bracci Luisa , Guardiola John 
Published: March 2007

AbstractT helper (Th) epitopes can be included in a recombinant protein with B and CTL epitopes to create more effective immunogens. To determine whether the antigenicity of HIV Th epitopes is preserved in this altered molecular context, human Th clones specific for peptides of HIV gp120 and reverse transcriptase p66 were challenged with recombinant proteins carrying the antigenic epitopes in different sites. We found that a given epitope was recognized by a specific T cell clone only when it was inserted in a particular position of the carrier. However, the permissive position was not the same for all epitopes. Enzymatic excision from a nonpermissive context or insertion of a polyserine spacer between the epitope and the carrier restored antigenicity. Nevertheless, antigenicity was not abolished in a synthetic peptide encompassing the epitope and the neighboring residues from the nonpermissive location. These data suggest that, in this case, the primary sequence of the chimeric protein flanking the HIV peptide is not responsible for loss of antigenicity. Furthermore, constructs carrying the epitope in a given position were recognized by peptide‐specific Th clones raised from some individuals, but not from others. We show that this is due neither to individual modes of processing nor to the use of distinct major histocompatibility complex MHC class II restriction elements, but rather that it is related to the fine specificity of the clones. To study the effect of epitope context on selection of T cell repertoire in a naive individual, T cell lines were generated in vitro by stimulation with different peptide constructs. This resulted in the induction of diverse clonotypes defined by the pattern of recognition of different constructs, by T cell receptor Vβ gene usage and by fine epitope mapping.
Exogenous and endogenous antigens are differentially presented by mast cells to CD4+ T lymphocytes
Authors: Frandji Pierre , Tkaczyk Christine , Oskeritzian Carole , David Bernard , Desaymard Catherine , Mécheri Salaheddine 
Published: March 2007

AbstractIn the present work, we explored the cytokine‐dependent regulation of bone marrow‐derived mast cell (BMMC) antigen‐presenting cell (APC) function, and co‐stimulation requirements, and analyzed the nature of antigens presented to T cells. We observed an up‐regulation of the APC function of mast cells induced by granulocyte/macrophage‐colony‐stimulating factor (GM‐CSF) and a complete abrogation by interferon (IFN)‐γ. Expression of co‐stimulatory molecules CD80 and CD86 was suggested by the ability of mast cells to activate purified lymph node‐derived T cells. Indeed, addition of the fusion protein mCTLA4‐Ig strongly inhibited antigen presentation by mast cells to normal T cells and to the T cell hybridoma 3DO‐54.8. The regulatory mechanisms of APC function by GM‐CSF and IFN‐γ were investigated by measuring CD80 and CD86 transcripts in mast cells. GM‐CSF‐treated mast cells showed a strong increase in the expression of both CD80 and CD86 transcripts, whereas in IFN‐γ‐treated mast cells, this expression was completely abrogated. Thus, up‐ and down‐regulation of CD80 and CD86 expression by GM‐CSF and IFN‐γ is directly correlated to the APC function. In addition, we analyzed antigen presentation by mast cells of endogenous self‐antigens. Mast cells failed to activate anti‐I‐A or anti‐I‐E‐specific T cell hybridomas and alloreactive T cells in primary mixed lymphocyte reactions (MLR). Furthermore, mast cells did not present the mouse β2‐microglobulin (mβ2‐m) peptide 25–40, constitutively expressed on B cells. However, mast cells, especially those treated with GM‐CSF, activated an anti‐mβ2‐m‐specific T cell hybridoma in the presence of exogenous peptide. The minor lymphocyte‐stimulating antigen‐1 Mls‐1a is a viral superantigen (vSAG) encoded by the the mouse mammary tumor provirus‐7 (MMTV‐7). Mast cells, despite a reasonable amount of major histocompatibility complex class II on the cell surface and the presence of MMTV transcripts predicted to encode the vSAG, cannot stimulate in vivo or in vitro Vβ6+ T cells specific for Mls‐1a. In contrast, mast cells could present the exogenous bacterial SAG, staphylococcal enterotoxin B (SEB), to specific Vβ8+ T cells. The selective ability of mast cells to present exogenous antigens may have physiological relevance in that mast cells could participate in immune response regulatory mechanisms by discriminating self from nonself.
Differential nuclear localization of p50, p52, and RelB proteins in human accessory cells of the immune response in situ
Authors: Feuillard Jean , Körner Marie , Israel Alain , Vassy Jeanny , Raphael Martine 
Published: March 2007

AbstractThe Rel/NF‐ϰB proteins, p50, p52, p65, c‐Rel, and RelB, constitute a family of transcription factors involved in the positive regulation of a variety of genes during the immune response. Recently, it has been shown that RelB knockout mice have no dendritic cells (DC). An overexpression of p50 has been described in follicular dendritic cells (FDC). A constitutive NF‐ϰB activity has been reported in mature macrophages. This led to the hypothesis that some of the Rel/NF‐ϰB proteins were key nuclear factors in functions of accessory cells of the immune response. Therefore, we investigated in situ the nuclear localization of Rel/NF‐ϰB proteins in accessory cells of the immune system by immunohistochemistry and double labeling by immunofluorescence from five normal human tonsils and five lymph nodes with follicular hyperplasia. Nuclear p65 and c‐Rel proteins were found in all cell types including lymphocytes. In germinal centers GC, p50, p52, and RelB were found in the nuclei of FDC only and were not detected in the nuclei of CD68+ cells. In T cell areas, p50, p52, and RelB were found in the nuclei of HLA‐DR+ cells with an antigen‐presenting cell (APC) morphology. p52 and RelB were detected in the nuclei in both CDla+ and CD68+ cells from the T cell area, whereas p50 was found only in CD68− and CDla− cells. Cells with nuclear p50 were negative for the CD38, CD20 and CD2 markers. These results show that, physiologically, high levels of nuclear of p50, p52 and RelB are restricted to accessory cells of the immune system, which include FDC in GC, and DC and macrophages in the T cell zone, that specialized scavenger macrophages from GC do not have detectable levels of p52 and RelB, whereas macrophages from the T cell area, known to present the antigen to T cells, do have both nuclear p52 and RelB, and that in the T cell zone, p52 and RelB are located in nuclei of both CDla+, CD68+ or both, cells APC, whereas p50 is restricted to CDla− and CD68− APC. The different patterns of p50, p52 and RelB protein nuclear localization may provide insight into their different roles during the immune response in vivo.
Partial correction of the TH2/TH1 imbalance in neonatal murine responses to vaccine antigens through selective adjuvant effects
Authors: Barrios Christy , Brandt Christian , Berney Monika , Lambert Paul‐Henri , Siegrist Claire‐Anne 
Published: March 2007

AbstractWe have recently shown that neonatal responses to a pannel of vaccine antigens and presentation systems differed qualitatively from adult responses by a bias towards a TH2 pattern. Here we report that a selected adjuvant comprising block copolymers in a water‐in‐oil emulsion can induce balanced TH1/TH2 responses in BALB/c mice primed at 1 week of age with an immunodominant tetanus peptide vaccine. However, using this specific TH1‐driving adjuvant only at time of boosting was not sufficient to fully circumvent the persisting influence of TH2‐biased neonatal responses. Unexpectedly also, a significant local toxicity was observed in newborn and young mice, whereas only mild reactions occurred in adults. Thus, although the induction of strong TH1 responses in the neonatal period can be achieved using specific adjuvants, through modulation of the immunological environment present at time of priming, whether such immunization strategies would be safe in the neonatal period remains to be demonstrated. These observations should be taken into consideration in the development of novel vaccines that will have to be already effective early in life.