bluuebunny/crossref_metadata_2025_split huggingface dataset:
An amphibian CD3 homologue of the mammalian CD3 γ and δ genes
Authors: Dzialo Robin C. , Cooper Max D. 
Published: March 2007

AbstractT cell receptor (TCR) genes have been identified in representatives of both cartilaginous and bony vertebrates. The CD3 chains that serve as signal transducing elements of the TCR complex in mammals have been defined to a limited extent in birds. In these studies a CD3 homologue was identified in an amphibian representative, Xenopus laevis, using degenerate oligomer primers designed from conserved regions of avian and mammalian CD3γ/δ subunits. The reverse transcriptase polymerase chain reaction amplified product of Xenopus splenocyte RNA was then used to isolate full‐length cDNA clones from a splenic library. When employed as probes, the cDNA clones hybridized with a 1‐kb mRNA transcript in Xenopus T cells, but not in other cell types. Comparison of the deduced amino acid sequence indicated a similar degree of homology with mammalian and avian CD3 γ and δ chains. Genomic analysis indicated that the Xenopus CD3 molecule is encoded by five exons, a structure resembling the mammalian CD3δ gene rather than the seven exon CD3γ gene. Southern blot analysis and sequencing of the 5′ flanking region failed to yield evidence of a related Xenopus gene. This amphibian CD3 gene thus appears to represent an ancestral form of the mammalian CD3 γ and δ genes.
Antigen‐specific T cell receptor antagonism by antigen‐presenting cells treated with the hemolysin of Listeria monocytogenes: a novel type of immune escape
Authors: Darji Ayub , Stockinger Brigitta , Wehland Jürgen , Chakraborty Trinad , Weiss Siegfried 
Published: March 2007

AbstractWe have examined the influence of listeriolysin O (LLO), the hemolysin secreted by the pathogenic bacterium Listeria monocytogenes, on major histocompatibility complex class II‐dependent T cell activation. Stimulation of T cells by native antigens but not by peptides is inhibited upon pretreatment of antigen‐presenting cells (APC) with LLO. Experiments presented here reveal that this inhibition is not due to a lack in processing of antigen by APC but is the result of an irreversible inactivation of T cells that recognize antigen on LLO‐treated APC. Incubation of mixtures of two different T cells where only one antigen was presented on LLO‐treated APC suggested that T cell inactivation is antigen specific. The inactivation was dominant and could be observed even in the presence of amounts of synthetic peptides that normally lead to T cell responses. This condition is reminiscent of the T cell inhibition observed when antagonistic and stimulatory peptides are added to APC at the same time. Our results thus reveal a novel type of interference by pathogens with antigen presentation and T cell stimulation that could give the pathogen a decisive advantage in dissemination and disease.
Cross‐reactive memory T cells for Epstein‐Barr virus augment the alloresponse to common human leukocyte antigens: degenerate recognition of major histocompatibility complex‐bound peptide by T cells and its role in alloreactivity
Authors: Burrows Scott R. , Silins Sharon L. , Khanna Rajiv , Burrows Jacqueline M. , Rischmueller Maureen , McCluskey James , Moss Denis J. 
Published: March 2007

AbstractIn the present report, cytotoxic T lymphocyte (CTL) clones are described that display dual specificity for one of two common human leukocyte antigens (HLA B14 or B35) as alloantigens, and an immunodominant epitope (FLRGRAYGL) from Epstein‐Barr virus (EBV) that binds to HLA B8. These T cell clonotypes were isolated from several unrelated HLA B8+, EBV‐exposed individuals, and each distinct cross‐reactivity pattern was associated with a common, public T cell receptor (TCR). In some individuals, CTL cross‐reactive with these alloantigens completely dominated the memory response to this EBV epitope. Moreover, these memory T cells to EBV could be reactivated as a significant component of the repertoire of CTL responding to allogeneic stimulator cells expressing either HLA B14 or B35. These data illustrate how a history of infection with an immunogenic virus such as EBV can augment responsiveness to particular alloantigens; such influences may underlie the observed clinical association between herpesvirus infection and both allograft rejection and graft‐versus‐host disease. We have also explored the molecular basis for T cell cross‐reactivity with alloantigens using the HLA B35 allo‐reactive CTL clonotype. To elucidate the structural features of peptides that may be cross‐recognized by these T cells, mono‐substituted analogs of the viral epitope were screened for recognition, revealing broad specificity for major histocompatibility complex (MHC)‐bound peptide. Based on the particular amino acid changes tolerated by the CTL at each peptide position, the human protein sequence database was searched for possible sequences that were recognized in association with HLA B35. Four peptides were identified (MPEATVYGL, IPIAPVYGM, KPSPPYFGL, and KPIVVLHGY) that were powerful activating ligands for the CTL when presented on HLA B35 but not B8. Thus, equivalent epitopes, capable of fully activating a single TCR, were formed by peptides with minimal obvious sequence homology bound to either HLA B8 or B35. These data indicate that degenerate peptide recognition by TCR may play an important role in the vigorous response of self‐MHC‐restricted T cells to alloantigens.
Maternal immunoglobulins have no effect on the rate of maturation of the B cell compartment of the offspring
Authors: Delassus Sylvie , Darche Sylvie , Kourilsky Philippe , Cumano Ana 
Published: March 2007

AbstractTo elucidate a general role of maternal immunoglobulins (Ig) on the kinetics of B cell development of the offspring, we studied non‐genetic influences of maternal Ig on the developing immune system of B cell‐competent mice. These animals were the offsprings of either B cell‐deprived μMT or of normal C57BL/6 females. In these mice, we have compared the kinetics of Ig production, the numbers of B cell progenitors, the expression of surface markers specific of the B lineage and the progression of Ig variable gene expression. We show that the absence of maternal Ig has no detectable effect on the kinetics of IgM and IgG production by the offspring's immune system. The number of B cell precursors, the kinetics of generation of B cells and their pattern of surface markers expression is identical in both types of mice. The acquisition of diversity in the B cell repertoire and the changes in the ratios of variable gene family expression are also indistinguishable. We conclude that maternally derived Ig has no influence on the rate of development and maturation of the B cell compartment of the offspring.
Predominant pathogenic role of tumor necrosis factor in experimental colitis in mice
Authors: Neurath Markus F. , Fuss Ivan , Pasparakis Manolis , Alexopoulou Lena , Haralambous Sylva , Meyer zum Büschenfelde Karl‐Hermann , Strober Warren , Kollias George 
Published: March 2007

AbstractAntibodies to tumor necrosis factor (TNF)‐α have been recently proposed as effective treatment for patients with Crohn's disease. Here, we analyze the functional role of TNF‐α in a mouse model of chronic intestinal inflammation induced by the hapten reagent 2,4,6,‐trinitrobenzene sulfonic acid (TNBS) that mimics some characteristics of Crohn's disease in humans. Macrophage‐enriched lamina propria (LP) mononuclear cells from mice with TNBS‐induced colitis produced 10–30‐fold higher levels of TNF‐α mRNA and protein than cells from control mice. When mice with chronic colitis were treated by intraperitoneal injection of antibodies to TNF‐α, an improvement of both the clinical and histopathologic signs of disease was found. Isolated macrophage‐enriched LP cells from anti‐TNF‐α‐treated mice produced strikingly less pro‐inflammatory cytokines such as interleukin (IL)‐1 and IL‐6 in cell culture. The predominant role of TNF‐α in the mouse TNBS‐induced colitis model was further underlined by the finding that striking colonic inflammation and lethal pancolitis was induced in TNF‐α‐transgenic mice upon TNBS treatment. Conversely, no significant TNBS‐induced colitis could be induced in mice in which the TNF‐α gene had been inactivated by homologous recombination. Complementation of TNF‐α function in TNF−/− mice by the expression of a mouse TNF‐α transgene was sufficient to reverse this effect. Taken together, the data provide direct evidence for a predominant role of TNF‐α in a mouse model of chronic intestinal inflammation and encourage further clinical trials with antibodies to TNF‐α for the treatment of patients with Crohn's disease.
CD5− CD8αβ intestinal intraepithelial lymphocytes (IEL) are induced to express CD5 upon antigen‐specific activation: CD5− and CD5+ CD8αβ IEL do not represent separate T cell lineages
Authors: Müller Stefan , Jungo Myriam , Aichele Peter , Mueller Christoph 
Published: March 2007

AbstractWe followed αβ T cell receptor (TCR) usage in subsets of gut intraepithelial lymphocytes (IEL) in major histocompatibility complex class I‐restricted αβ TCR‐transgenic (tg) mice. The proportion of tg αβ TCR+ CD8αβ IEL is reduced compared with CD8+ splenocytes of the same animal, particularly under conventional conditions of maintenance. Further fractionation of CD8αβ IEL according to the expression level of surface CD5 revealed that in conventionally housed animals tg TCR+ CD5− CD8αβ IEL are as frequent as in specific pathogen‐free (SPF) mice, whereas tg TCR+ CD5int or, even more pronounced, tg TCR+ CD5hi CD8αβ IEL are greatly diminished when compared with mice kept under SPF conditions. Upon antigen‐specific stimulation of CD5− CD8αβ IEL in vitro, CD5 surface expression is up‐regulated on a large fraction of cells within 48 h. Up‐regulation of CD5 surface expression is further enhanced by the presence of the anti‐αIEL monoclonal antibody 2E7. This clearly demonstrates that CD5−, and CD5+ CD8αβ IEL cannot be considered as separate T cell lineages.
Impaired induction of cytotoxic T lymphocytes by antagonism of a weak agonist borne by a variant hepatitis C virus epitope
Authors: Kaneko Takashi , Moriyama Takashi , Udaka Keiko , Hiroishi Kazumasa , Kita Hiroto , Okamoto Hiroaki , Yagita Hideo , Okumura Ko , Imawari Michio 
Published: March 2007

AbstractAn epitope that acted as a weak agonist in the cytotoxicity assay was identified as part of the capsid protein of a hepatitis C virus (HCV) variant. In a low concentration, the variant epitope also had a weak antagonistic effect. When a minute amount of this variant epitope was added to the culture for induction, it selectively attenuated the expansion of major cytotoxic T cell populations and drastically reduced the cytotoxic responses against the wild‐type epitope. Thus, antagonism to induction suppressed immune responses against both the wild type and the variant, thereby helping the persistence of not only variant itself but also the wild‐type HCV. Because this variant was a weak agonist, most cytotoxic T cells induced with the wild‐type epitope were cross‐reactive with the variant and susceptible to the antagonism to induction. Only the T cells which were not cross‐reactive with the variant and not susceptible to the antagonism survived the antagonism in induction. This implied that the specificity of the remaining immune response, if any, was directed exclusively to the wild‐type epitope after the emergence of the variant. For viruses like HCV, being heterogeneous itself may contribute significantly toward persistent infection through antagonism to induction.
Organ‐selective regulation of vascular adhesion protein‐1 expression in man
Authors: Arvilommi Anna‐Maija , Salmi Marko , Jalkanen Sirpa 
Published: March 2007

AbstractVascular adhesion protein‐1 (VAP‐1) is an endothelial molecule which mediates lymphocyte binding to endothelium in peripheral lymph nodes and at certain sites of inflammation. The expression of VAP‐1 in vivo is strongly up‐regulated in inflamed tissues, such as gut and skin. The purpose of this work was to examine the factors responsible for this induction of VAP‐1. Since the expression of VAP‐1 could not be induced in cultured endothelial cells with a large panel of mediators, we used an organ culture technique for the investigation of the regulation of VAP‐1 expression in a more physiological micromilieu. Indeed, we found that the expression of endothelial VAP‐1 could be up‐regulated in human tonsillar tissue with interleukin (IL)‐1, IL‐4, tumor necrosis factor (TNF‐α), interferon (IFN)‐γ and lipopolysaccharide, whereas histamine, thrombin, dibutyryl cAMP, N‐formyl‐Met‐Leu‐Phe (fMLP) and phorbol 12‐myristate 13‐acetate (PMA) had no effect. The induced VAP‐1 protein was similar in molecular weight to the non‐induced VAP‐1, suggesting that VAP‐1 synthesized de novo carries appropriate carbohydrate moieties. In contrast to tonsil organ culture, similar inductions performed with human appendix showed no up‐regulation of VAP‐1 expression, indicating that the regulation of VAP‐1 expression exhibits organ‐selective characteristics. Furthermore, in these tissues the smooth muscle cells, which constitutively express VAP‐1, could not be stimulated to alter their level of expression of this molecule. In conclusion, the expression of VAP‐1 can be markedly up‐regulated with several mediators in tonsil but not in appendix organ culture, whereas cultured endothelial cells cannot be induced to express VAP‐1. These results indicate that the expression of VAP‐1 is regulated in a tissue‐ and cell type‐selective manner, and a correct micromilieu is required for the up‐regulation to occur.
G1 arrest and high expression of cyclin kinase and apoptosis inhibitors in accumulated activated/memory phenotype CD4+ cells of older lupus mice
Authors: Sabzevari Helen , Propp Stephanie , Kono Dwight H. , Theofilopoulos Argyrios N. 
Published: March 2007

AbstractA general characteristic of lupus‐prone mice (and humans) is the expedited accumulation of large numbers of presumably self‐reactive activated/memory phenotype T cells. The mechanism by which these cells escape apoptosis has not been defined. We used activated/memory phenotype CD4+ cells from male BXSB mice with early‐life severe lupus‐like disease to investigate cell cycle status and apoptosis susceptibility, and to determine the role of corresponding genes in survival of these cells. In vitro acridine orange staining indicated that most of the rapidly accumulating memory phenotype CD4+ T cells of 4‐month‐old male BXSB mice are G1 arrested. Long‐term bromodeoxyuridine in vivo labeling also showed that with advanced age, there was a shift of the CD4+ CD44hi male cells from predominantly cycling to predominantly noncycling. Moreover, the CD4+ CD44hi cells of older males were refractory to anti‐CD3‐induced proliferation and apoptosis. Using a multiprobe RNase protection assay encompassing riboprobe panels for cell cycle and apoptosis‐related genes, we found that these cells exhibited high expression of certain members of the Ink4 (p18Ink4C) and Cip/Kip (p21Cip1) families of cyclin kinase inhibitors as well as of the apoptosis‐inhibiting Bcl‐xL gene. Western blot analysis confirmed increased levels of Bcl‐xL and p21Cip1, and also identified increases in another cyclin kinase inhibitor, p27Kip1. We propose that in autoimmunity, self‐reactive CD4+ cells are subjected to successive rounds of activation/division that eventually lead to a build‐up in cyclin‐dependent kinase inhibitors. Once high levels of such inhibitors are reached, they cause refractoriness to further activation, impaired cell cycle entry and resistance to apoptosis, a situation akin to replicative senescence.
Affinity of the interaction between Fcgamma receptor type III (FcγRIII) and monomeric human IgG subclasses. Role of FcγRIII glycosylation
Authors: Galon Jérǒme , Robertson Michael W. , Galinha Annie , Maziéres Noëlle , Spagnoli Roberto , Fridman Wolf‐Herman , Sautès Catherine 
Published: March 2007

AbstractBinding of the Fc region of IgG antibodies to low affinity Fcγ receptors (FcγR) triggers important effector functions in the immune system. The type IIIb FcγR (FcγRIIIb or CD16) is a heavily glycosylated protein anchored to the membrane of neutrophils by a glycosylphosphatidylinositol link. This receptor contributes to cell activation by IgG immune complexes. To better understand the nature of the ligand‐receptor association, we have studied the affinity and kinetics of the interaction between human IgG subclasses and two soluble forms of FcγRIIIb (sFcγRIIIb or sCD16) corresponding to the 188 N‐terminal amino acids of the extracellular region of the receptor, a glycosylated one made in eucaryotic cells (euc.sCD16) and a non‐glycosylated one (proc.sCD16) made in Escherichia coli. Experiments using a BIAcoreTM instrument, to measure protein binding in real time, showed that monomeric human IgG1 and IgG3, but not IgG2, IgG4, IgA and divalent antigen‐binding fragments (F(ab′)2) of IgG1, bound to immobilized euc.sCD16 with an affinity constant (KA) of 1.3 ± 0.6 × 106 M−1 and 2.6 ± 0.4 × 105 M−1, respectively. The affinity constant of proc.sCD16 for human IgG1 was in the same range (1.1 ± 0.2 × 106 M−1), whereas that for human IgG3 was twofold higher (4.2 ± 0.4 × 105 M−1). The specificity of the non‐glycosylated receptor for human IgG subclasses bound to Sepharose was IgG1 > IgG3 ≫ IgG4 ⋙ IgG2. Thus, the extracellular polypeptide of FcγRIIIb dictates the interaction of the receptor with IgG subclasses although glycosylation plays an inhibitory role in the interaction with human IgG3.
Tumor necrosis factor blockade in actively induced experimental autoimmune encephalomyelitis prevents clinical disease despite activated T cell infiltration to the central nervous system
Authors: Körner Heinrich , Lemckert Frances A. , Chaudhri Geeta , Etteldorf Susanne , Sedgwick Jonathon D. 
Published: March 2007

AbstractRecently, we demonstrated that experimental autoimmune encephalomyelitis (EAE) in the rat, passively transferred using myelin basic protein (MBP)‐reactive encephalitogenic CD4+ T cells, was preventable by administration of a p55‐tumor necrosis factor‐IgG fusion protein (TNFR‐IgG). This was despite quantitatively and qualitatively normal movement of these MBP‐specific T cells to the central nervous system (CNS). To extend these findings, the effect of TNFR‐IgG on EAE actively induced by injection of MBP in complete Freund's adjuvant was examined. This form of EAE in the rat typically involves an acute, self‐limiting neurological deficit, substantial CNS inflammation, but minimal demyelination. Here we show that administration of TNFR‐IgG prior to onset of disease signs completely prevented the neurological deficit or markedly reduced its severity. This blockade of clinical disease was dissociated from weight loss which occurred at the same tempo and magnitude as in control rats exhibiting neurological signs of disease such as paralysis. The timing of TNF blockade was critical as established clinical disease was relatively refractory to TNFR‐IgG treatment. Activated CD4+ T cells expressing normal or elevated levels of VLA4, major histocompatibility complex class II, MRC OX40 and CD25 were isolated from or immunohistochemically localized in the CNS of clinically healthy rats treated before disease onset. There was a reduction of the amount of other inflammatory leukocytes in the CNS of these treated animals but, more importantly, the activation state of inflammatory leukocytes, as well as that of microglia isolated from treated animals, was reduced. Thus, TNFR‐IgG, when administered before disease onset, appears to act by inhibiting an effector function of activated T cells and possibly other inflammatory leukocytes necessary to bring about the neurological deficit. However, while TNF is a critically important cytokine for the early events leading to initiation of EAE, it is not a necessary factor in the acute neurological deficit characteristic of this form of EAE, once disease onset has occurred.
The fate of activated T cells migrating through the body: rescue from apoptosis in the tissue of origin
Authors: Bode Ulrike , Wonigeit Kurt , Pabst Reinhard , Westermann Jürgen 
Published: March 2007

AbstractAfter activation within a lymphoid tissue, T lymphocytes enter the blood, where they circulate and then re‐enter many organs. However, they predominantly end up in the tissue of origin, a phenomenon so far thought to be caused by organ‐specific homing. We analyzed the fate of T cells from different sources stimulated via the T cell receptor and CD28 and then injected intravenously into rats. Our results showed that preferential proliferation and reduced apoptosis, rather than preferential immigration, were responsible for the accumulation of activated T cells in the tissue of origin, explaining how immune responses can spread from site to site but still be restricted to certain regions. Manipulating the life span of such cells might be a promising approach to influencing immune responses.
Qa‐1 interaction and T cell recognition of the Qa‐1 determinant modifier peptide
Authors: Cotterill Lisa A. , Stauss Hans J. , Millrain Margaret M. , Pappin Darryl J. C. , Rahman Dinah , Canas Benito , Chandler Phillip , Stackpoole Arthur , Simpson Elizabeth , Robinson Peter J. , Dyson P. Julian 
Published: March 2007

AbstractThe peptide‐binding properties of the nonclassical major histocompatibility complex (MHC) class 1b molecule Qa‐1 were investigated using a transfected hybrid molecule composed of the α1 and α2 domains of Qa‐1b and the α3 domain of H‐2Db. This allowed the use of a monoclonal antibody directed against H‐2Db whilst retaining the peptide‐binding groove of Qa‐1b. By comparison with classical MHC class I molecules, intracellular maturation of the chimeric molecule was inefficient with weak intracellular association with β2‐microglobulin. However, at the cell surface the hybrid molecules were stably associated with β2‐microglobulin and were recognized by cytotoxic T lymphocyte (CTL) clones specific for the Qa‐1b ‐presented peptide Qdm (AMAPRTLLL). A whole‐cell binding assay was used to determine which residues of Qdm were important for binding to Qa‐1b and CTL clones served to identify residues important for T cell recognition. Substitutions at position 1 and 5 did not reduce the efficiency of binding and had little effect on CTL recognition. In contrast, substitutions at position 9 resulted in loss of MHC class I binding. Mass spectrometric analysis of peptides eluted from immunopurified Qa‐1b/Db molecules indicated that Qdm was the dominant peptide. The closely related peptide, AMVPRTLLL, which is derived from the signal sequence of H‐2Dk, was also present, although it was considerably less abundant. The mass profile suggested the presence of additional peptides the majority of which consisted of eight to ten amino acid residues. Finally, the finding that a peptide derived from Klebsiella pneumoniae can bind raises the possibility that this non‐classical MHC class I molecule may play a role in the presentation of peptides of microorganisms.