bluuebunny/crossref_metadata_2025_split huggingface dataset:
Induction of protective cytotoxic T cells with viral proteins
Authors: Bachmann Martin F. , Kündig Thomas M. , Freer Giulia , Li Yan , Kang Chil Yong , Bishop David H. , Hengartner Hans , Zinkernagel Rolf M. 
Published: March 2007

AbstractInduction of CD8+, class I‐restricted T cells by non‐infectious, exogenous antigens has been documented for model protein antigens such as ovalbumin and for major histocompatibility complex restricted short peptides in viral and tumor systems. However, the protective capacity of cytotoxic T cells induced by conventional proteins has not been tested in vivo so far. We, therefore, evaluated the induction of protective cytotoxic T cells against three different full‐length recombinant viral proteins derived from a baculovirus expression system, i.e. the glycoprotein and nucleoprotein of lymphocytic choriomeningitis virus (LCMV) and the nucleoprotein of vesicular stomatitis virus (VSV). These viral proteins induced cytotoxic T cells in a T helper cell‐independent fashion which lysed infected target cells in vitro and protected mice from viral replication, immunopathological disease and growth of a tumor expressing the same antigen as a tumor antigen. These results are surprising, since it had been shown earlier for completely inactivated nonreplicating viral vaccines and again here for β‐propiolactone‐inactivated VSV or UV‐light inactivated LCMV that nonreplicating viral vaccines were incapable of inducing protective cytotoxic T cells. Our data show that immunization of mice with as little as 10 μg of non‐infectious viral proteins triggered long‐lasting CD8+ T cell‐mediated antiviral immunity. It was found that the protein alone was only weakly able to induce cytotoxic T cells, and that association with cellular debris functioned as an adjuvant. These findings may be relevant for our understanding of the phenomenon of cross‐priming and have obvious implications for vaccine strategies.
Inhibition of nitric oxide synthesis by interleukin‐4 may involve inhibiting the activation of protein kinase C epsilon
Authors: Sands William A. , Bulut Vedat , Severn Alison , Xu Damo , Liew Foo Y. 
Published: March 2007

AbstractThe murine macrophage cell line, J774, when activated with interferon‐γ (IFN‐γ), expressed high level of inducible nitric oxide synthase (iNOS) and bound significantly more [3H]‐phorbol‐dibutyrate (PBu2) compared to non‐activated cells. The increased PBu2 binding to the particulate fraction of the cells is a measure of activation and translocation of protein kinase C (PKC). Both the expression of iNOS and the enhanced PBu2 binding in the activated J774 cells were significantly inhibited by the pretreatment of the cells with murine recombinant interleukin‐4 (IL‐4). Stimulation of J774 cells by IFN‐γ and lipopolysaccharide results in the translocation predominantly of the epsilon isoform of PKC (PKC‐ϵ), and this is inhibited by IL‐4. The inhibition of PKC activation was also evident by measuring the PKC activity in the cytosolic fraction of the IL‐4‐treated cells. Activated J774 cells pretreated with IL‐4 or a PKC‐specific inhibitor (RO31‐8220) failed to express mRNA of iNOS analyzed by PCR. These results, therefore, suggest that the inhibition of nitric oxide synthesis in activated murine macrophages by IL‐4 is at the transcriptional level and may involve the inhibition of the activation of PKC‐ϵ.
T lymphocytes derived from skin lesions of patients with psoriasis vulgaris express a novel cytokine pattern that is distinct from that of T helper type 1 and T helper type 2 cells
Authors: Vollmer Sigrid , Menssen Antje , Trommler Paul , Schendel Dolores , Prinz Jörg Christoph 
Published: March 2007

AbstractIn various immunological disorders the pathomechanisms of tissue damage are causally associated with specific patterns of locally produced cytokines. To study the molecular and cellular mechanisms involved in the manifestation of psoriasis vulgaris we have assessed the cytokine mRNA profile expressed in lesional psoriatic skin and in T cell clones (TCC) that were established from skin lesions of patients with psoriasis. As demonstrated by use of the polymerase chain reaction (PCR), psoriasis lesions consistently exhibit transcription of a complex pattern of cytokines. It includes mediators selectively produced by T lymphocytes [interferon (IFN)‐γ, tumor necrosis factor (TNF)‐β, interleukin (IL)‐2, IL‐3 and IL‐5] as well as cytokines secreted by various cell types [transforming growth factor (TGF)‐α/‐β, TNF‐α, IL‐6/‐8 and granulocyte‐macrophage‐colony stimulating factor], while IL‐4 is missing. With the exception of TGF‐α, this cytokine profile was also observed in lesional psoriatic T cell clones yielding supernatants mitogenic for keratinocytes in vitro (MTCC), but not in T cell clones yielding supernatants that inhibited keratinocyte proliferation (STCC).The congruent cytokine expression of psoriatic skin lesions and MTCC emphasizes that inflammation in psoriasis is driven by a sofar unrecognized regulatory T cell subset that may serve to control epidermal regeneration and convey immunosurveillance over epithelial surfaces. It is characterized by the combined expression of IFN‐γ, TGF‐β, IL‐2 and IL‐5 in the absence of IL‐4 and by its selective capacity to enhance keratinocyte proliferation. This newly defined combination of regulatory properties of a distinct T cell population cannot be reconciled with an immune response of the T helper cells (TH)0, TH1 or TH2 type.
Regulation of IgG antibody titers by the amount persisting of immune‐complexed antigen
Authors: Bachmann Martin F. , Kündig Thomas M. , Hengartner Hans , Zinkernagel Rolf M. 
Published: March 2007

AbstractAntigens normally induce an immunoglobulin (Ig)G response which stays at an elevated level for several weeks or months, constituting an important part of the immunological memory. This study investigated factors influencing the level of neutralizing IgG titers against a virus and shows that within the range tested it was independent of the number of initially available and potentially responding T helper and B cells, but was regulated by the amount of specific IgG‐immune complexes forming depots of persisting antigen. These findings support the notion that the efficiency of vaccines in inducing long‐lasting protective IgG is regulated predominantly by the amount of persisting (and presumably follicular dendritic cell‐associated) antigen‐antibody complexes.
Cross‐reactivity between an HLA‐B27‐derived peptide and a retinal autoantigen peptide: a clue to major histocompatibility complex association with autoimmune disease
Authors: Wildner Gerhild , Thurau Stephan R. 
Published: March 2007

AbstractStatistical correlations between the expression of various HLA antigens and certain autoimmune diseases have been observed for both HLA class I and II antigens. Autoimmune diseases like spondyloarthropathies and anterior uveitis are associated with HLA‐B27, but uveitis in Behçet's disease with HLA‐B51. We describe a peptide from disease‐associated HLA class I antigens sharing sequence homologies with a highly uveitogenic epitope from the retinal autoantigen S‐antigen. S‐antigen induces autoimmune uveitis in the animal model and is a major autoantigen in human disease. The HLA peptide induced uveitis in the Lewis rat and, moreover, suppressed S‐antigen‐induced disease when administered orally. Patients' PBL cross‐reacted with the HLA‐ and corresponding retinal peptide, explaining the organ specificity of the disease.
Regulation of ICAM‐3 (CD50) membrane expression on human neutrophils through a proteolytic shedding mechanism
Authors: del Pozo Miguel A. , Pulido Rafael , Muñoz Cecilia , Alvarez Vicente , Humbría Alicia , Campanero Miguel R. , Sánchez‐Madrid Francisco 
Published: March 2007

AbstractThe regulation of the cell surface expression of ICAM‐3 (CD50) was investigated in human neutrophils. Immunofluorescence flow cytometry analysis revealed a remarkable and very rapid down‐regulation of the ICAM‐3 cell surface expression upon neutrophil activation with stimulating agents such as phorbol myristate acetate (PMA) or calcium ionophore. A similar low expression of ICAM‐3 was observed on neutrophils from patients undergoing hemodialysis with cell‐activating cellulosic membranes. Internalization assays with 125I‐labeled anti‐ICAM‐3 monoclonal antibody (mAb) suggested that ICAM‐3‐down‐regulation was due to antigen release from the cell surface towards the outer milieu, rather than to antigen internalization. Immunoprecipitation studies confirmed this down‐regulatory effect, and revealed the presence of ICAM‐3 in cell‐free supernatants from activated neutrophils. Furthermore, the presence of a soluble form of ICAM‐3 with a range of concentrations of 0–296 ng/ml in the plasma from healthy human volunteers was detected by using a two‐site mAb radioimmunoassay. A proteolytic mechanism likely accounts for this process since protease inhibitors virtually abrogated the PMA‐induced down‐regulation of ICAM‐3. Functional studies showed that anti‐ICAM‐3 mAb were able to trigger homotypic neutrophil aggregation both before and after ICAM‐3 down‐regulation, indicating that the fraction of ICAM‐3 molecules remaining on the neutrophil surface upon activation are still capable of sustaining cell adhesion. In contrast, the loss of L‐selectin (CD62L) on activated neutrophils was almost complete, thus leading to an impairment of L‐selectin‐mediated neutrophil‐endothelial cell adhesion. These results indicate that ICAM‐3 is released to the medium upon neutrophil stimulation and that both ICAM‐3 and L‐selectin have a role in the neutrophil adhesive phenomena.
Macrophage – T cell interaction in experimental mycobacterial infection. Selective regulation of co‐stimulatory molecules on Mycobacterium‐ infected macrophages and its implication in the suppression of cell‐mediated immune response
Authors: Saha Bhaskar , Das Gobardhan , Vohra Harpreet , Ganguly Nirmal K. , Mishra Gyan C. 
Published: March 2007

AbstractThe most important immunopathological consequence of experimental mycobacterial infection is the suppression of T cell‐mediated immune response to both mitogens and mycobacterial antigens. We registered that there was decreased concanavalin A‐induced spleen cell proliferation in infected susceptible BALB/c mice as compared to normal mice. In resistant (C3H/HeJ) mice, infection with the bacteria did not induce any suppression in the mitogen‐induced lymphoproliferation. Likewise, delayed‐type hypersensitivity (DTH) responses, to keyhole limpet hemocyanin and mycobacterial crude soluble antigen were suppressed in infected BALB/c mice but not in C3H/HeJ mice. This depressed T helper cell function may either be due to defective T cell‐receptor occupancy by antigen‐Ia complex or altered co‐stimulatory signals provided by antigen‐presenting cells. In the present study, we have investigated the status of certain co‐stimulatory molecules on the infected macrophages from both susceptible and resistant mice. Our results demonstrate that upon mycobacterial infection, the macrophages are rendered incapable of delivering the co‐stimulatory signals to T helper cells, possibly due to the involvement of prostaglandin, as inhibition of its biosynthesis by indomethacin reversed the defect. Furthermore, the selective regulation was bacteria‐induced as killing of the bacteria by rifampicin abrogated the derangements in the expression of co‐stimulatory molecules on the Mycobacterium‐infected macrophages. Our observations revealed that upon infection with Mycobacterium tuberculosis, B7 was down‐regulated while ICAM‐1 was increased only in BALB/c but not in C3H/HeJ mice. Expression of VCAM‐1 did not change during the infection in either strain of mice. We found that these changes in ICAM‐1 and B7 expression on the surface of infected macrophages resulted in inhibition of DTH‐mediating functions of T helper cells from BALB/c mice. The results obtained in this study describe not only a novel immune evasion strategy adopted by Mycobacterium, but also open up the possibility of immunotherapy of mycobacterial infection by selective manipulation of co‐stimulatory molecules.
Soluble complement receptor type 1 (CD35) is released from leukocytes by surface cleavage
Authors: Danielsson Carina , Pascual Manuel , French Lars , Steiger Gertraud , Schifferli Jürg‐Alfred 
Published: March 2007

AbstractThe soluble form of complement receptor type 1 in human plasma (sCR1) might correspond to the shedding of the receptor by proteolytic cleavage at the cell surface. A new enzyme‐linked immunosorbent assay (ELISA) was established to specifically measure membrane‐bound CR1 using a rabbit polyclonal antibody against a 19‐amino acid peptide corresponding to the C‐terminal sequence of the intracellular domain of CR1 (mCR1‐ELISA). This ELISA measured CR1 from solubilized erythrocyte membranes, polymorphonucelar leukocytes (PMN), a B lymphocyte cell line and renal podocyte‐derived urinary vesicles in a dose‐dependent manner. In contrast, and similarly to recombinant soluble CR1 which lacks the intracellular domain of CR1, plasmatic sCR1 was not recognized, suggesting that sCR1 corresponds to an extracellular fragment of whole CR1. In vitro, PMN were shown to release a soluble form of CR1 which was also not recognized in the mCR1‐ELISA, and whose size was smaller (5 kDa) than the CR1 of PMN cell membranes. The release of soluble CR1 was highest for PMN and HL60 cells, followed by U937 cells and three different B lymphocyte cell lines, whereas T lymphocyte cell lines did not release soluble CR1. The levels of CR1 gene expression were also higher in PMN compared to remaining blood leukocytes and the different cell lines tested above. Incubation of PMN with formyl‐methionyl‐leucyl‐phenylalanine, tumor necrosis factor‐α or lipopolysaccharide accelerated the release of soluble CR1, and incubation with granulocyte/macrophage colony‐stimulating factor resulted in sustained CR1 gene expression and higher total soluble CR1 release. Our results suggest that soluble CR1 is produced by cleavage of cell surface CR1, and that a large fraction of human plasma sCR1 is cleaved from PMN. The release of sCR1 by leukocytes may play a role in the control of complement activation at sites of inflammation.
Gut‐homing CD4+ T cell receptor αβ+ T cells in the pathogenesis of murine inflammatory bowel disease
Authors: Rudolphi Angelika , Boll Guido , Poulsen Steen S. , Claesson Mogens H. , Reimann Jörg 
Published: March 2007

AbstractWe studied which T cell subsets from the gut‐associated lymphoid tissue (GALT) can migrate out of the gut mucosa and repopulate GALT compartments of an immunodeficient (semi)syngeneic host. Many distinct lymphocyte subsets were found in GALT of immunocompetent H‐2d (BALB/c, BALB/cdm2, C. B‐17+/+) mice. No antigen receptor‐expressing lymphoid cells were found in GALT of congenic C. B‐17 scid/scid (scid) mice. The heterotopic transplantation of a full‐thickness gut wall graft from the ileum or colon of immunocompetent (C. B‐17+/+, BALB/cdm2) donor mice onto immunodeficient scid mice selectively reconstituted a CD3+ T cell receptor αβ+ CD4+ T cell subset. CD4+ cells of this subset expressed the surface phenotype of mucosa‐seeking, memory T cells. In the immunodeficient scid host, this gut‐derived CD4+ T cell subset was found in spleen, peritoneal cavity, mesenteric lymph nodes (LN), epithelial layer and lamina propria of the small and large intestine, but not in peripheral LN. Scid mice heterotopically transplanted with gut from a congenic, immunocompetent donor developed clinical and histological signs of inflammatory bowel disease (IBD). Hence, the selective repopulation of GALT compartments with CD4+ T cells from normal GALT plays an essential role in the pathogenesis of IBD in an immunodeficient host.
Involvement of the tumor necrosis factor receptor p75 in mediating cytotoxicity and gene regulating activities
Authors: Medvedev Andrei E. , Sundan Anders , Espevik Terje 
Published: March 2007

AbstractUsing agonistic antibodies (Ab) we have examined whether the 75‐kDa chain of the tumor necrosis factor receptor (p75 TNFR) is capable of mediating cytotoxic response and gene regulation alone or in cooperation with p55 TNFR. Addition of an anti‐p75 TNFR polyclonal antiserum or anti‐p75 monoclonal antibody (mAb) plus anti‐immunoglobulin (Ig) led to cytotoxic response of human KYM‐1 rhabdomyosarcoma cells. Anti‐p75 mAb alone had no effect pointing out the importance of strong receptor stimulation for signal transduction into the cell. Simultaneous triggering of both the p55 and p75 TNFR by agonistic Ab resulted in additive cytotoxic action on KYM‐1 cells. The anti‐p75 mAb 3H5, directed to a non‐TNF binding site on the human p75 TNFR, was used to confirm further the ability of the p75 TNFR to potentiate p55 TNFR‐mediated cell death. While exhibiting no cytotoxicity by its own, 3H5 significantly augmented the cytotoxic effect of the anti‐p55 mAb htr9 towards KYM‐1 cells. Neither the anti‐p75 TNFR antiserum nor anti‐p75 mAb were cytotoxic for human U937 cells suggesting that the cytolysis resulting from p75 TNFR cross‐linking is cell specific. Noteworthy, stimulation of the p75 TNFR with mAb plus anti‐Ig or polyclonal antiserum led to a marked enhancement of the p55 TNFR‐induced U937 cell death, indicating collaboration between the two TNFR in induction of cytotoxicity also in this cell line. However, 3H5 mAb did not affect the ability of anti‐p55 mAb to lyse U937 cells. Altogether, these data demonstrate the difference between KYM‐1 and U937 cell lines with respect to the role for the p75 TNFR in mediating cytotoxicity. Both TNFR were found to mediate cytomegalovirus (CMV) promoter activation in human SW480T‐βGal cells and nuclear transcription factor χB (NF‐χB) induction in this cell line as well as in KYM‐1 cells. It was demonstrated for the first time that independent stimulation of both TNFR resulted in an additive effect on the CMV promoter activation and induction of the NF‐χB. Taken together, these results indicate that the p75 TNFR induces cytotoxicity in a cell‐specific manner and potentiates p55 TNFR‐mediated cytotoxic response and gene regulation.
An inhibitor of cytotoxic functions produced by CD8+CD57+ T lymphocytes from patients suffering from AIDS and immunosuppressed bone marrow recipients
Authors: Sadat‐Sowti Behazine , Debré Patrice , Mollet Lucile , Quint Laurent , Hadida Fabienne , Leblond Véronique , Bismuth Georges , Autran Brigitte 
Published: March 2007

AbstractAn inhibitor of the cytotoxic functions (ICF) mediated by human immunodeficiency virus (HIV)‐ or HLA‐specific cytotoxic T lymphocytes, natural killer and lymphokine‐activated killer (LAK) cells is secreted by CD8+CD57− T lymphocytes, a subset expanded during infection with HIV and after bone marrow transplantation. We previously showed an apparent molecular mass of 20–30 kDa for this soluble glycosylated concanavalin A‐binding inhibitor which is distinct from known cytokines. Here, we report a characterization of the mechanism of action of this CD8+CD57+ ICF. We show that the ICF‐induced inhibition of LAK cell cytolytic activity is transient, with a spontaneous recovery of cytolytic potential after 18 h. When testing interactions of ICF with a large set of cytokines we found that the ICF‐mediated inhibition of cytotoxic functions is antagonized by two cytokines: recombinant interleukin (rIL)‐4 and recombinant interferon (rIFN)‐γ. Finally, we show that ICF acts at the level of cytolytic effector cells, where it induces a significant increase of cyclic AMP (cAMP) level. In contrast, no modification of either cell surface antigen expression or of target/effector cell conjugate formation could be evidenced. Addition of rIL‐4 and rIFN‐γ reverses such an increase of cAMP levels and in parallel restores the cytolytic activity. Altogether, these data demonstrate that the glycoprotein ICF produced by CD8+CD57+ cells (1) inhibits cell‐mediated cytotoxicity by sensitizing cytolytic effector cells to the cAMP pathway, and (2) is part of a cytokine network controlling cell‐mediated cytotoxic functions.
Age‐related decrease in the proportion of germinal center B cells from mouse Peyer's patches is accompanied by an accumulation of somatic mutations in their immunoglobulin genes
Authors: González‐Fernández Africa , Gilmore David , Milstein César 
Published: March 2007

AbstractSomatic hypermutation of immunoglobulin genes and the generation of memory B cells seems to take place in germinal centers, which are chronically present in Peyer's patches. Age‐associated changes in the germinal center B cell compartment of Peyer's patches and in the mutations of a χ light chain transgene were analyzed in unimmunized mice. Somatic mutations accumulate in germinal center B cells slowly and continuously to reach an apparent plateau when the animals are around 5 months old. In contrast, the proportion of germinal center B cells reaches a maximum in very young mice (about 2 months old) and decreases progressively thereafter. These results suggest that the highly mutated B cells in older mice arise by the successive accumulation of mutations in memory cells. The data also show that the optimum time for the analysis of hypermutation of transgenes in Peyer's patches is when the mice are about 5 months old.
Dysregulation of interleukin‐7 receptor may generate loss of cytotoxic T cell response in human immunodeficiency virus type 1 infection
Authors: Carini Claudio , McLane Mary Fran , Mayer Kenneth H. , Essex Max 
Published: March 2007

AbstractVirus‐specific cytotoxic T lymphocytes (CTL) play a crucial role in modulating an immune response against human immunodeficiency type 1 (HIV‐1) infection. The generation of effector cytotoxic cells from CTL precursors involves intricate interactions with antigen via T cell receptors (TcR) and soluble cytokines. Interleukin (IL)‐7 can affect T cell maturation and differentiation. Here we report on a group of five HIV‐1‐positive individuals who tested negative for env‐and gag‐specific CTL activity. When exogenous recombinant human IL‐7 was added as a stimulus to the cultures, none (0/5) of the CTL‐negative individuals exhibited a CTL response. Individuals that were negative for HIV‐1‐specific CTL activity were found to lack IL‐7 receptor (IL‐7R) on CD8+ cells with a comparable reduction on CD4+ cells. Increased shedding of IL‐7R in the culture supernatant was observed. A significant reduction in receptor number was detected by binding of 125I‐labeled IL‐7 and Scatchard analysis. The lack of IL‐7R is probably not due to endogenous IL‐7, since it was not detectable in the culture supernatants of the patients studied. HIV‐1 proteins may cause down‐modulation of IL‐7R expression, either by producing an insufficient number of molecules or by rapid decay of IL‐7R on T cells. These changes may alter the cells' capability to respond to the IL‐7 growth signal, resulting in CTL failure and subsequent mishandling of the virus.