bluuebunny/crossref_metadata_2025_split huggingface dataset:
Homotypic interaction of the heat‐stable antigen is not responsible for its co‐stimulatory activity for T cell clonal expansion
Authors: Zhou Qunmin , Wu Yan , Nielsen Peter J. , Liu Yang 
Published: March 2007

AbstractThe heat‐stable antigen (HSA) is an important co‐stimulatory molecule on antigen‐presenting cells (APC). However, the receptor on T cells that receives the co‐stimulatory signal from HSA has not been identified. Because the HSA is transiently expressed on T cells after the T cell receptor/CD3 complex is engaged, and because it can bind to itself in a homotypic fashion, it has been proposed that homotypic interaction of HSA is responsible for its co‐stimulatory activity. Here we test this hypothesis using mice that have a targeted mutation of the HSA gene, as well as novel transgenic mice that constitutively express HSA on T cells. We show that HSA‐deficient T cells remain responsive to co‐stimulation by HSA. Furthermore, constitutive expression of HSA does not enhance T cell response to co‐stimulatory by HSA. Taken together, our results demonstrate that homotypic interaction of HSA is not responsible for co‐stimulation mediated by HSA expressed on APC.
The mast cell function‐associated antigen exhibits saccharide binding capacity
Authors: Binsack Ralf , Pecht Israel 
Published: March 2007

AbstractThe mast cell function‐associated antigen (MAFA) is a membrane glycoprotein first identified on rat mucosal type mast cells (line RBL‐2H3) and known to inhibit the FcεRI‐mediated secretory response. In its extracellular domain, an amino acid stretch homologous to the carbohydrate binding domain of calcium‐dependent animal lectins has been found. To investigate its carbohydrate binding capacity, the MAFA has been expressed in the Spodoptera frugiperda insect cell line (Sf9) using the baculovirus expression system. Analysis by flow cytometry and surface labeling with 125I showed that the recombinant MAFA (rMAFA) was expressed as a monomeric and disulfide‐linked homodimeric glycoprotein in the membrane of the insect cells, and both forms exhibited the same epitopes as the protein isolated from RBL‐2H3 cells. Immunoaffinity‐purified rMAFA was then employed for studies of its saccharide binding capacity by using different neoglycans and glycoproteins. The rMAFA was found to bind specifically terminal mannose residues in a Ca2+‐dependent manner. These results support the notion that the extracellular domain of the MAFA is indeed able to bind ligands, which may be modulatory for the mast cell response.
MUC1 peptide epitopes associated with five different H‐2 class I molecules
Authors: Apostolopoulos Vasso , Haurum John S. , McKenzie Ian F. C. 
Published: March 2007

AbstractWe have previously described the induction of murine CD8+ major histocompatibility complex (MHC) class I‐restricted cytotoxic T cells (CTL) recognizing the 20‐amino acid repeat region of the human mucin 1 (MUC1) variable number of tandem repeats region (VNTR), a mucin greatly increased in expression in breast cancer and proposed as a target for immunotherapy. In that study, CTL could detect MUC1 peptides associated with the MHC of all nine strains examined, and we now report the different epitopes presented by five different MHC class I molecules. The epitopes were defined in CTL assays using peptide‐pulsed phytohemagglutinin blasts or MHC class I‐transfected L cells as targets; in addition, peptide binding assays and T cell proliferation studies were performed. Within the 20‐amino acid VNTR, nine potential epitopes could be defined. The epitopes for the four MHC class I molecules [Kb (three epitopes), Dd, Ld and Kk] were closely related, all containing the amino acids PDTRPAP. For Db, three epitopes were identified, all containing APGSTAP. Most of the epitopes did not contain a consensus motif for the particular MHC class I allele, and bound with low ‘affinity’, compared with known high‐affinity peptides. CD8+ T cell proliferation also occurred to the same MHC class I‐presented epitopes. Finally, when conventional anchor residues were introduced into the peptides, peptide binding increased, whereas CTL recognition was either retained (Kb) or lost (Db) depending on the epitope.
Down‐regulation of the major circulating precursors of proteins deposited in secondary amyloidosis by a recombinant mouse interleukin‐1 receptor antagonist
Authors: Grehan Sharon , Herbert Jeff , Whitehead Alexander S. 
Published: March 2007

AbstractAn inflammatory response was induced in C57BL/6 mice using silver nitrate. Co‐administration of a recombinant mouse interleukin‐1 receptor antagonist (rmIL‐1ra) significantly reduced the magnitude of hepatic induction of the mRNA specifying the serum amyloid A (A‐SAA) isoforms A‐SAA1 and A‐SAA2 for up to 24 h. In relative terms, the amount by which the induction of serum A‐SAA protein levels could be countered by the antagonist was less, probably reflecting extrahepatic A‐SAA synthesis that is regulated independently of IL‐1. Induction of hepatic serum amyloid P component (SAP) mRNA and other acute‐phase reactant (APR) mRNA were all partially blocked by rmIL‐1ra for up to 24 h, indicating that induction of these APR mRNA involves both IL‐1 and additional factors acting independently of IL‐1. Hepatic mRNA levels of the negative APR apolipoprotein A‐I (apo A‐I) and serum albumin were down‐regulated by silver nitrate treatment; rmIL‐1ra partially restored serum albumin mRNA levels but not those of apo A‐I. The IL‐1ra‐mediated reduction in inflammation‐induced hepatic mRNA and serum protein concentrations of A‐SAA and SAP (the precursors of the main protein components of amyloid deposits in secondary amyloidosis) was, however, not sufficient to prevent or delay early amyloid deposition in the silver nitrate/amyloid enhancing factor model of accelerated amyloidosis. The rmIL‐1ra may be a useful component in future therapies to control inflammation and secondary amyloidosis; in addition, it will be a useful tool for the detailed analysis of the IL‐1‐driven aspects of inflammation per se.
Human recombinant interferon‐β influences T helper subset differentiation by regulating cytokine secretion pattern and expression of homing receptors
Authors: McRae Bradford L. , Picker Louis J. , van Seventer Gijs A. 
Published: March 2007

AbstractType I interferons (IFN) are important regulators of both innate and acquired immunity. We have used an in vitro system of human CD4+ T cell differentiation to determine how IFN‐β influences development of T helper (Th) subsets and homing receptor expression. IFN‐β promoted differentiation of CD4+ T cells that produce low levels of both IFN‐γ and lymphotoxin compared to interleukin (IL)‐12‐derived Th1 CD4+ T cells. IFN‐β inhibited production of Th2 cytokines (IL‐5 and IL‐13) and augmented IL‐12‐mediated IL‐10 secretion. In addition, IFN‐β significantly enhanced L‐selectin expression on CD4+ T cells and synergized with IL‐12 to induce expression of cutaneous lymphocyte‐associated antigen (CLA). This Th1 L‐selectin+, CLA+ phenotype is characteristic of T cells found in normal human skin and suggests a role for type I IFN in the regulation of Th subset differentiation and tissue‐specific homing receptors.
Interleukin‐12 up‐regulates the induction of an antigen‐specific antibody response in cultures of human lymphocytes
Authors: Luzzati Alma L. , Giordani Luciana , Giacomini Elena 
Published: March 2007

AbstractThe influence of interleukin‐12 (IL‐12) on the induction of a specific antibody response to the T‐dependent antigen sheep erythrocytes (SRBC) in cultures of human blood lymphocytes was investigated. The response, evaluated as number of antigen‐induced antibody‐producing cells, was greatly increased in the presence of IL‐12. When a two‐stage limiting dilution culture system was used, the plot of the number of seeded cells versus the logarithm of the fraction of negative cultures deviated from linearity in antigen‐ and IL‐12‐stimulated cultures. However, linearity was reached when IL‐2 was added in the second stage. Under these latter conditions, since single‐hit criteria were fulfilled, it was possible to estimate the frequency of SRBC‐specific B cell precursors able to respond to the antigen and to show that such frequency was increased upon addition of IL‐12. Thus, the enhancing effect of IL‐12 may be based on an increased frequency of responding precursor cells. The results here presented demonstrate, to our knowledge for the first time, a definite role of IL‐12 in the induction of a specific antibody response in human cells. Further, they stress the importance for such studies of appropriate in vitro systems. Finally, they show that the induction of primary immune responses in cultures of human peripheral blood lymphocytes mostly depends on the proper cytokine balance at different time points.
Genetically modified bone marrow‐derived dendritic cells expressing tumor‐associated viral or “self” antigens induce antitumor immunity in vivo
Authors: Tüting Thomas , Deleo Albert B. , Lotze Michael T. , Storkus Walter J. 
Published: March 2007

AbstractThe clinical application of synthetic tumor peptide‐based vaccines is currently limited to patients with specified major histocompatibility complex (MHC) class I alleles. Such logistic limitations may be overcome using tumor gene‐based approaches. Here we describe the effective generation of dendritic cells (DC) expressing tumor peptide‐MHC complexes as a result of particle‐mediated transfer of genes encoding tumor‐associated antigens (TAA). Bone marrow‐derived DC were transfected with plasmid DNA encoding the tumor‐associated viral antigen E7 derived from human papilloma virus (HPV) 16. When applied as a vaccine, these genetically modified DC induced antigen‐specific CD8+ cyto‐toxic T lymphocytes (CTL) in vivo and promoted the rejection of a subsequent, normally lethal challenge with an HPV 16‐transformed tumor cell line. Of greatest interest, immunization of mice with syngeneic DC genetically modified to enhance their presentation of a constitutive “self” epitope derived from the tumor‐suppressor gene product p53 caused a significant reduction in the in vivo growth of a chemically induced p53‐positive sarcoma. These results suggest that cancer vaccines consisting of DC genetically modified to express TAA of viral or “self” origin effectively induce antitumor immunity in vivo.
Granulocyte‐macrophage colony‐stimulating factor induces a unique set of STAT factors in murine dendritic cells
Authors: Welte Thomas , Koch Franz , Schuler Gerold , Lechner Judith , Doppler Wolfgang , Heufler Christine 
Published: March 2007

AbstractCytokine‐mediated signaling pathways were studied in mouse dendritic cells (DC) by analysis of the activation pattern of STAT factors. Electrophoretic mobility shift assays were performed to detect STAT isoform‐specific complexes. Granulocyte‐macrophage colony‐stimulating factor (GM‐CSF) simultaneously induced complexes containing STAT1, STAT3, STAT5A, STAT5B and STAT6. In non‐DC, a similar broad activation pattern of STAT factors by GM‐CSF or other cytokines has not been observed so far. By comparison, in peritoneal macrophages, GM‐CSF induced a complex with the properties of a truncated form of STAT5. Other cytokines tested on DC either failed to induce STAT factors [interleukin (IL)‐1β, IL‐2, IL‐15], or activated the same STAT factors as observed in peritoneal macrophages (IL‐4, IFN‐γ). Our results implicate a specific effect of GM‐CSF on STAT signaling in DC which might account for the cell type‐specific effect of this cytokine on development and function.
In vitro cell death of activated lymphocytes in Omenn's syndrome
Authors: Brugnoni Duilio , Airò Paolo , Facchetti Fabio , Blanzuoli Laura , Ugazio Alberto G. , Cattaneo Roberto , Notarangelo Luigi D. 
Published: March 2007

AbstractOmenn's syndrome (OS) is characterized by erythrodermia, hepatosplenomegaly, lymphadenopathy, hypereosinophilia and elevated IgE levels associated with increased susceptibility to severe infections. Peripheral blood T cells, though usually present in normal number, show an activated phenotype (including an increased expression of CD95/Fas), a Th2 pattern of cytokine secretion and defective proliferative response to mitogens. In this report, we demonstrate that T cells from patients with OS undergo an excessive cell death in vitro resulting from two mechanisms. First, a substantial number of peripheral blood lymphocytes from OS patients die in unstimulated cultures (p = 0.009 vs. healthy controls). This spontaneous apoptosis is associated with reduced expression of bcl‐2 gene product (p < 0.05) and can be prevented by addition of interleukin (IL)‐2 (which also prevents down‐modulation of bcl‐2), while is independent from CD95 signaling. Second, lymphocytes from OS patients are highly susceptible to activation‐induced cell death (AICD) induced with mitogens. This mechanism is largely independent from IL‐2, while it can be significantly inhibited blocking CD95 with an IgG2b monoclonal antibody (mAb). The dependence of AICD from signals transduced via CD95 was confirmed showing that cross‐linking CD95 with an IgM mAb induces a higher cell death in purified CD4+ CD45RO+ cells from OS patients than in controls (comparable for CD95 expression). Both mechanisms of cell death observed in this study result from lymphocyte hyperactivation occurring in vivo in these patients and may contribute to functional T cell defects of OS.
Control of self‐reactive cytotoxic T lymphocytes expressing γδ T cell receptors by natural killer inhibitory receptors
Authors: Halary Franck , Peyrat Marie‐Alix , Champagne Eric , Lopez‐Botet Miguel , Moretta Alessandro , Moretta Lorenzo , Vié Henri , Fournié Jean‐Jacques , Bonneville Marc 
Published: March 2007

AbstractThe majority of peripheral blood γδ T cells in human adults expresses T cell receptors (TCR) with identical V regions (Vγ9 and Vδ2). These Vγ9Vδ2 T cells recognize the major histocompatibility complex (MHC) class I‐deficient B cell line Daudi and broadly distributed nonpeptidic antigens present in bacteria and parasites. Here we show that unlike αβ or Vγ9− γδ T cells, the majority of Vγ9Vδ2T cells harbor natural killer inhibitory receptors (KIR) (mainly CD94/NKG2A heterodimers), which are known to deliver inhibitory signals upon interaction with MHC class I molecules. Within Vγ9δ2 T cells, KIR were mainly expressed by clones exhibiting a strong lytic activity against Daudi cells. In stark contrast, almost all Vγ9Vδ2 T cell clones devoid of killing activity were KIR−, thus suggesting a coordinate acquisition of KIR and cytotoxic activity within Vγ9Vδ2 T cells. In functional terms, KIR inhibited lysis of MHC class I‐positive tumor B cell lines by Vγ9Vδ2 cytotoxic T lymphocytes (CTL) and raised their threshold of activation by microbial antigens presented by MHC class I‐positive cells. Furthermore, masking KIR or MHC class I molecules revealed a TCR‐dependent recognition by Vγ9Vδ2 CTL of ligands expressed by activated T lymphocytes, including the effector cells themselves. Taken together, these results suggest a general implication of Vγ9Vδ2 T cells in immune response regulation and a central role of KIR in the control of self‐reactive γδ CTL.
Cloning of NKG2‐F, a new member of the NKG2 family of human natural killer cell receptor genes
Authors: Plougastel Béatrice , Trowsdale John 
Published: March 2007

AbstractThe NKG2 family of genes encodes at least four different type II transmembrane molecules (NKG2‐A, NKG2‐B, NKG2‐C and NKG2‐E) which contain a C‐lectin domain. These proteins have been shown to be covalently associated with CD94, another C‐type lectin member. The heterodimers are involved in natural killer cell‐mediated recognition of different HLA‐allotypes. Here we describe the cloning of a new NKG2‐related gene, termed NKG2‐F, localized 25 kb from NKG2‐A as well as its relationship with the previously described NKG2‐D cDNA. Despite the similarities with the other NKG2 genes, NKG2‐F encodes a putative protein which does not contain any lectin domain. However, a conserved 24‐amino acid sequence, present in all members of the NKG2 family, suggests that NKG2‐F is also able to form heterodimers with CD94.
Influence of complement on the allospecific antibody response to a primary vascularized organ graft
Authors: Pratt Julian R. , Harmer Andrea W. , Levin James , Sacks Steven H. 
Published: March 2007

AbstractThe induction of antibody responses against T cell‐dependent antigens has been reported to be influenced by complement. We therefore asked if the primary induction of alloantibodies against transplantation antigens, an important determinant of transplant outcome, is complement sensitive and whether this has functional implications. We transplanted rat kidney allografts into fully major histocompatibility complex‐mismatched recipients, in which complement activation was inhibited by daily injection of soluble recombinant human complement receptor type 1 (sCR1). Control allograft recipients were injected with saline. Animals in the control group showed a marked antibody response against donor‐specific antigens and an increase in the proportion of activated B and T splenocytes by day 5 after transplantation. Complement‐inhibited rats showed a reduced level of antibody binding on target cells sharing the same histocompatibility antigens as the donor strain (p< 0.001), and a reduced level of activated splenic B (p< 0.01) and T (p< 0.01) cells. In a functional assay, the plasma of complement‐inhibited rats showed reduced cytotoxic activity against donor‐specific cells, and their grafts contained less bound antibody than controls. Analysis beyond 6 days was obscured due to the development of antibodies against sCR1. We conclude that complement activation facilitates the induction of the alloantibody response. Sparing of vascular injury and prolongation of graft survival, previously reported in complement‐inhibited rats (Pratt J. R. et al.,Am. J. Path.1996,149: 2055), could therefore be due to down‐regulation of the B cell response as well as reduced complement‐dependent cytotoxicity. Inhibition of complement may provide an ancillary approach to the prevention of allospecific antibody formation and the prolongation of allograft survival in primary kidney grafting.
T helper cell priming of mice to Borrelia burgdorferi Osp A leads to induction of protective antibodies following experimental but not tickborne infection
Authors: Zhong Weimin , Gern Lise , Kramer Michael , Wallich Reinhard , Simon Markus M. 
Published: March 2007

AbstractAntibodies to the outer surface lipoprotein A (Osp A) of Borrelia burgdorferi confer protection to SCID mice against subsequent tick‐borne or experimental infection. However, Osp A‐specific antibodies are hardly detectable in naturally infected humans, dogs, hamsters and mice. This is most probably due to limited expression of Osp A on spirochetes transmitted from the vector to the host. Here we have tested whether T cell priming of mice would lead to the induction of protective Osp A‐specific antibodies upon infection. It is shown that AKR/N mice, previously immunized with either a single T helper cell peptide of Osp A, or a mixture of 27 peptides spanning the entire molecule, develop Osp A‐specific IgM or IgG antibodies, including those to a prominent protective B cell epitope of Osp A, LA‐2, within 7 days of infection with low doses (103) of culture‐derived spirochetes. In marked contrast, the same groups of pre‐sensitized mice failed to generate any detectable Osp A‐specific antibodies after tick‐borne infection for more than 40 days after infection. All mice, irrespective of their state of T cell immunity to OspA or the mode of infection, produced similar levels of Osp C‐specific IgM and IgG antibodies as early as day 14 after infection. None of the mice previously immunized with Osp A peptides were protected against experimental infection, in spite of the appearance of protective antibodies. It is clear from these data that, in contrast to culture‐derived spirochetes, the naturally transmitted pathogen fails to express Osp A within the mammalian host at levels sufficient for induction of B cell responses, even in the presence of pre‐activated T helper cells. Together with the fact that Osp A‐specific antibodies are mainly operative by eliminating spirochetes from the vector during infestation, the data suggest that Osp A‐vaccination for T helper cell immunity alone is not sufficient to prevent Lyme disease.
Separately expressed T cell receptor α and β chain transgenes exert opposite effects on T cell differentiation and neoplastic transformation
Authors: Brabb Thea , Rubicz Rohina , Mannikko Valerie , Goverman Joan 
Published: March 2007

AbstractTwo aspects of T cell differentiation in T cell receptor (TCR)‐transgenic mice, the generation of an unusual population of CD4−CD8−TCR+ thymocytes and the absence of γδ cells, have been the focus of extensive investigation. To examine the basis for these phenomena, we investigated the effects of separate expression of a transgenic TCR α chain and a transgenic TCR β chain on thymocyte differentiation. Our data indicate that expression of a transgenic TCR α chain causes thymocytes to differentiate into a CD4−CD8−TCR+ lineage at an early developmental stage, depleting the number of thymocytes that differentiate into the αβ lineage. Surprisingly, expression of the TCR α chain transgene is also associated with the development of T cell lymphosarcoma. In contrast, expression of the transgenic TCR β chain causes immature T cells to accelerate differentiation into the αβ lineage and thus inhibits the generation of γδ cells. Our observations provide a model for understanding T cell differentiation in TCR‐transgenic mice.
A T cell receptor (TCR) antagonist competitively inhibits serial TCR triggering by low‐affinity ligands, but does not affect triggering by high‐affinity anti‐CD3 antibodies
Authors: Viola Antonella , Linkert Susanne , Lanzavecchia Antonio 
Published: March 2007

AbstractIt has been demonstrated that modified peptides which fail to induce detectable T cell responses can act as T cell receptor (TCR) antagonists when presented together with agonist by the same antigen‐presenting cell (APC). We report that a TCR antagonist competitively inhibits TCR triggering induced by low‐affinity ligands such as agonistic peptides or bacterial superantigens. However, the same antagonist cannot inhibit TCR triggering and T cell activation induced by high‐affinity anti‐CD3 antibodies that engage most TCR at once. These results indicate that TCR antagonists inhibit T cell responses by interfering with the ongoing process of serial triggering, rather than by delivering an inhibitory signal to T cells.