bluuebunny/crossref_metadata_2025_split huggingface dataset:
Altered T lymphocyte signaling in rheumatoid arthritis
Authors: Allen Maggie E. , Young Stephen P. , Michell Robert H. , Bacon Paul A. 
Published: March 2007

AbstractSynovial and peripheral blood T cells from patients with rheumatoid arthritis are functionally deficient. This may be secondary to their reduced cytokine (e.g. interleukin‐2) synthesis. We have investigated the possibility of an alteration in pathways common to interleukin‐2 production and proliferation in peripheral blood T cells from patients with active rheumatoid arthritis. Intracellular calcium levels ([Ca2+]i) were analyzed by flow cytometric methods in Indo 1‐loaded T cells. These were purified by negative selection from patients or age/sex‐matched controls, and stimulated with phytohemagglutinin‐P or anti‐CD3. Rheumatoid [Ca2+]i responses to both stimuli were reduced (p < 0.005). Patient cell samples included a larger proportion of non‐responding cells, but even in the responsive population the magnitude of the response in rheumatoid cells was impaired compared with those in normal cell samples (p < 0.0001) for both stimuli. Proliferation responses were also impaired (p < 0.005), and there was a positive correlation between the paired [Ca2+]i elevation and proliferative responses for both stimuli. CD2 and CD3 expression were normal, and the proportions of CD4, CD8 and CD45RO and CD45RA subsets were also unaffected by disease. Thus a signaling defect downstream of CD2 or CD3 surface molecules may contribute to functional deficiencies in rheumatoid T lymphocytes. This effect is not due to non‐steroidal anti‐inflammatory drugs which some patients were taking. We have demonstrated similar alterations in [Ca2+]i responses and proliferation in a smaller study of patients with inflammatory bowel disease, indicating that such changes might be present in other chronic inflammatory states.
Co‐expression of CD8α in CD4+ T cell receptor αβ+ T cells migrating into the murine small intestine epithelial layer
Authors: Reimann Jörg , Rudolphi Angelika 
Published: March 2007

AbstractWe investigated the surface phenotype of CD3+CD4+ T cell receptor (TCR) αβ+ T cells repopulating the intestinal lymphoid tissues of C.B‐17 scidlscid (severe‐combined immunodeficient; scid) (H‐2d, Ld+) mice. CD4+ CD8− T cells were cell sorter‐purified from various secondary and tertiary lymphoid organs of congenic C.B‐17 +/+ (H‐2d, Ld+) or semi‐syngeneic dm2 (H‐2d, Ld−) immunocompetent donor mice. After transfer of 105 cells into young scid mice, a mucosa‐homing, memory CD44hi CD45RBlo CD4+ T cell population was selectively engrafted. Large numbers of single‐positive (SP) CD3+ CD2+ CD28+ CD4+ CD8− T cells that expressed the α4 integrin chain CD49d were found in the spleen, the mesenteric lymph nodes, the peritoneal cavity and the gut lamina propria of transplanted scid mice. Unexpectedly, large populations of donor‐type doublepositive (DP) CD4+ CD8α+ CD8β− T cells with high expression of the CD3/TCR complex appeared in the epithelial layer of the small intestine of transplanted scid mice. In contrast to SP CD4+ T cells, the intraepithelial DP T cells showed low expression of the CD2 and the CD28 co‐stimulator molecules, and of the α4 integrin chain CD49d, but expressed high levels of the αIEL integrin chain CD103. The TCR‐Vβ repertoire of DP but not SP intraepithelial CD4+ T cells was biased towards usage of the Vβ6 and Vβ8 viable domains. Highly purified populations of SP and DP CD4+ T cell populations from the small intestine epithelial layer of transplanted scid mice had different abilities to repopulate secondary scid recipient mice: SP CD4+ T cells repopulated various lymphoid tissues of the immunodeficient host, while intraepithelial DP CD4+ T cells did not. Hence, a subset of CD3+ CD4+ TCRαβ+ T cells apparently undergoes striking phenotypic changes when it enters the microenvironment of the small intestine epithelial layer.
Leishmania infantum‐specific T cell lines derived from asymptomatic dogs that lyse infected macrophages in a major histocompatibility complex‐restricted manner
Authors: Pinelli Elena , Gonzalo Rosa M. , Boog Claire J. P. , Rutten Victor P. M. G. , Gebhard Douglas , Del Real Gustavo , Ruitenberg E. Joost 
Published: March 2007

AbstractProtective immunity to leishmaniasis has been demonstrated in murine models to be mediated by T cells and the cytokines they produce. We have previously shown that resistance to experimental Leishmania infantum infection in the dog, a natural host and reservoir of the parasite, is associated with the proliferation of peripheral blood mononuclear cells (PBMC) to parasite antigen and to the production of interleukin‐2 and tumour necrosis factor. In this study we show that PBMC from asymptomatic experimentally infected dogs produce interferon‐γ upon parasite antigen‐specific stimulation, whereas lymphocytes from symptomatic dogs do not. In addition, we report for the first time the lysis of L. infantum‐infected macrophages by PBMC from asymptomatic dogs and by parasite‐specific T cell lines derived from these animals. These T cell lines were generated by restimulation in vitro with parasite soluble antigen and irradiated autologous PBMC as antigen‐presenting cells. We show that lysis of infected macrophages by T cell lines is major histocompatibility complex restricted. Characterization of parasite‐specific cytotoxic T cell lines revealed that the responding cells are CD8+. However, for some animals, CD4+ T cells that lyse infected macrophages were also found. In contrast to asymptomatic dogs, lymphocytes from symptomatic dogs failed to proliferate and produce interferon‐γ after Leishmania antigen stimulation in vitro and were not capable of lysing infected macrophages. These results suggest that both the production of interferon‐γ and the destruction of the parasitized host cells by Leishmania‐specific T cells play an important role in resistance to visceral leishmaniasis.
Expression of two T cell receptor α chains on the surface of normal murine T cells
Authors: Heath William R. , Carbone Francis R. , Bertolino Patrick , Kelly Jannice , Cose Steve , Miller Jacques F. A. P. 
Published: March 2007

AbstractWe have previously reported that a subset of T cells in T cell receptor (TCR)‐transgenic mice may express two different α chains on their surface. The expression of two functional α chains has also been demonstrated for human peripheral blood T cells. In this report, we show that a proportion of normal murine lymph node T cells express two functional α chains on their surface. The extrapolated frequency of these cells present in the normal repertoire ranges from 7–21%, with an average of 15%. Our analysis of a small number of antigen‐specific T cell clones suggests that the frequency of antigen‐responsive cells expressing two surface α chains is relatively low. This raises the possibility that dual α chain T cells may have a selective disadvantage in responding to specific antigen.
Mapping T cell recognition: the identification of a T cell receptor residue critical to the specific interaction with an influenza hemagglutinin peptide
Authors: Wedderburn Lucy R. , Searle Stephen J. M. , Rees Anthony R. , Lamb Jonathan R. , Owen Michael J. 
Published: March 2007

AbstractThe fine specificity of T cell receptor (TCR) interaction with the influenza hemagglutinin peptide HA 307–319 in the context of the DR1 (DRA, DRB1*0101) and DR4 (DRA, DRB1*0404) was studied in two human T cell clones (HA1.7 and Cl‐1) derived from different individuals. Sequencing of amplified TCR transcripts revealed that these two clones express highly related TCRα chains, with a conserved junctional motif, but very different TCRβ chains. Modeling studies led to the prediction that the conserved glutamic acid residue in the TCRα chain could interact with the lysine at position 316 in the peptide, a known TCR contact residue. HA1.7 TCR‐CD3ζ, chimeric constructs were expressed in the rat basophil line (RBL) and shown to confer specific antigen recognition. In two TCRα chain mutants, with the conserved glutamic acid residue altered to alanine and lysine, respectively, peptide recognition was lost. Specific recognition was not rescued by altered peptide ligands. Furthermore, Jurkat derivatives expressing the related Jurkat TCRα chain paired with the HA 1.7 TCRβ chain did not recognize the HA 307–319 /DR1 complex. These data provide evidence for the critical interaction of a TCR residue with antigenic peptide.
Vitamin A deficiency results in a priming environment conducive for Th1 cell development
Authors: Cantorna Margherita T. , Nashold Faye E. , Hayes Colleen E. 
Published: March 2007

AbstractCertain infections, like that with the human immunodeficiency virus‐1, deplete vitamin A, and when vitamin A levels are low, immune dysfunctions establish susceptibility to further infection. Our research has focused on the immune dysfunctions that are a consequence of vitamin A deficiency and that predispose to further infection. We previously studied a helminth infection in mice, and showed that when vitamin A levels are low, the immune response develops a strong regulatory T cell imbalance with excessive T helper type‐1 cell interferon (IFN)‐γ synthesis and insufficient T helper type‐2 cell development and function. Here, we studied the T cell priming environment in vitamin A‐deficient mice to learn how that priming environment might produce a regulatory T cell imbalance and consequently distort the ability of the immune system to respond to an infection. Our results show that during vitamin A deficiency, the priming environment included constitutive interleukin (IL)‐12 and IFN‐γ transcripts, but it was devoid of constitutive IL‐4 and IL‐10 transcripts. Dietary all‐trans‐retinoic acid supplementation down‐regulated the level of constitutive IL‐12 and IFN‐γ transcripts. Furthermore, when T cells from naive vitamin A‐deficient animals were stimulated through the T cell receptor, they produced excess IFN‐γ protein compared to T cells from control animals. In contrast, T cell stimulation failed to induce IL‐4 or IL‐10 secretion. The inducible IFN‐γ was largely from CD8+ T cells and all‐trans‐retinoic acid addition in vitro inhibited IFN‐γ production at the transcript level. Retinoic acid addition in vitro also decreased natural killer cell IFN‐γ synthesis at the transcript level. Taken together, the distorted constitutive and inducible cytokine gene expression patterns that occurred when vitamin A levels were low would be expected strongly to favor T helper type‐1 development and limit T helper type‐2 cell growth and differentiation, thereby limiting the animal's humoral immune response capability.
Expression in vivo of CD45RA, CD45RB and CD44 on T cell receptor‐transgenic CD8+ T cells following immunization
Authors: Pihlgren Maria , Lightstone Liz , Mamalaki Clio , Rimon Galia , Kioussis Dimitris , Marvel Jacqueline 
Published: March 2007

AbstractWe used mice transgenic for a major histocompatibility complex class I‐restricted T cell receptor to study the changes of phenotype in vivo which follow priming by antigen of CD8 T cells. We show that following priming with peptide, CD44 on CD8 T cells is up‐regulated. The change of phenotype was relatively stable, as primed CD8 cells isolated from thymectomized mice 6 weeks after priming still expressed increased levels of CD44. CD8 T cells in these mice are still responsive to peptide and could represent long‐lived primed cells. No downregulation in vivo of the CD45RA or CD45RB isoforms was found, indicating that there is a differential regulation of the expression of CD44 and CD45RB by activated CD8 transgenic T cells. These results contradict earlier studies in vitro which showed that CD8 T cells which have been primed earlier belong to the CD45RA− or CD45RB− subset.
Primary proliferative T cell response to wild‐type p53 protein in patients with breast cancer
Authors: Tilkin Anne‐Françoise , Lubin Richard , Soussi Thierry , Lazar Vladimir , Janin Nicolas , Mathieu Marie‐Christine , Lefrère Isabelle , Carlu Christiane , Roy Marguerite , Kayibanda Michèle , Bellet Dominique , Guillet Jean‐Gérard , Paillerets Brigitte Bressac‐De 
Published: March 2007

AbstractMutations in the p53 tumor suppressor gene are the most frequent genetic alterations found in human tumors. These are mainly point mutations that lead to single amino acid substitutions. The mutated proteins have a longer half‐life than wild‐type p53 and accumulate in the nucleus of tumor cells. Anti‐p53 antibodies have been found in sera of patients with several types of cancers including breast cancer. This report describes a T cell immune response in three patients with breast tumors who had mutated p53 gene and accumulated p53 protein. All showed a humoral response to p53 protein and the T cells of these patients recognized the wild‐type p53 protein and proliferated in response to it. The data reported here are relevant to the immune processes leading to autoimmunity and have a bearing on anti‐p53 vaccine development in tumor immunology.
Induction of peptide‐specific primary cytotoxic T lymphocyte responses from human peripheral blood
Authors: Plebanski Magdalena , Allsopp Catherine E. M. , Aidoo Michael , Reyburn Hugh , Hill Adrian V. S. 
Published: March 2007

AbstractVarious protocols were developed and compared for eliciting specific cytotoxic T lymphocyte (CTL) cell lines from the unselected human peripheral blood mononuclear cells of naive donors. Interleukin‐7 and CD4+ T cells primed in vitro by keyhole limpet hemocyanin were shown to act together in the generation of these responses. Primary responses were consistently induced with a variety of different HLA class I‐binding malarial peptides. Primary CTL responses could be induced from unselected CD8+ and from CD45RA+CD8+ T cells. The CTL lines derived from these naive donors were CD8+ and demonstrated a high level of HLA class I‐restricted killing for > 3 months after priming in vitro. They were also able to recognize and kill targets infected with a recombinant vaccinia virus containing the full‐length antigen. In addition, this same protocol enhanced up to fourfold the levels of secondary CTL responses induced. The optimal method presented for naive cytotoxic T cell stimulation is simple, rapid and generally applicable and should provide a useful tool for both basic research and human therapy.
CD40 ligand‐independent B cell activation revealed by CD40 ligand‐deficient T cell clones: evidence for distinct activation requirements for antibody formation and B cell proliferation
Authors: Lane Peter , Burdet Corinne , McConnell Fiona , Lanzavecchia Antonio , Padovan Elisabetta 
Published: March 2007

AbstractWe report the capacity of CD40 ligand (CD40L)‐negative T cell clones to activate human B cells. CD40L‐negative T cells induce a level of B cell proliferation 10–20% of that seen with normal T cells. The signal provided by the negative clones is synergistic with that derived from a CD40L transfectant, and restores B cell proliferation to normal levels, showing that CD40L‐negative T cell clones are not inherently inhibitory for B cells. Although their capacity to induce proliferation was much reduced, CD40L‐negative T cell clones were still strong inducers of B cell differentiation to plasma cells. This differentiation to plasma cells was inhibited by a CD40L transfectant. The data are discussed with regard to the normal in vivo mechanism for maintaining B cell memory and memory antibody responses to T‐dependent antigens.
The self antigen heme evades immune recognition by sequestration in some hemoproteins
Authors: Sutherland Robyn M. , Brassell Stephen , Liu Qiang , Paterson Yvonne 
Published: March 2007

AbstractHeme is a non‐protein autoantigen which is ubiquitous in vivo, primarily complexed in various hemoproteins or bound to specialized carrier molecules. Nevertheless, heme is able to stimulate a high frequency of CD4+, class II‐restricted T cells, freshly explanted from unprimed mice, to proliferate in vitro. In this study, we show that heme incorporated into various species of mammalian cytochrome c (cyt c), including murine cyt c, represents a facultative cryptic determinant, able to be recalled only at high doses of native cyt c. By contrast, avian cyt c is of comparable antigenicity to free heme. Artificially denatured carboxymethylated (CM) mammalian cyt c exhibited greatly increased antigenicity, comparable to that of heme and avian cyt c, indicating that the crypticity of heme in native mammalian cyt c is due to the resistance of the native conformation of this molecule to antigen processing within murine antigen‐presenting cells. Thus, tolerance to the heme group of at least some hemoproteins, may be maintained by the crypticity of the heme, rather than by deletion of hemereactive T cells. Given the high frequency of heme‐reactive T cells in unprimed mice, these findings suggest that heme may become an important modulator during an inflammatory response.
Destructive proteolysis by cysteine proteases in antigen presentation of ovalbumin
Authors: Rodriguez G. Marcela , Dimen Stephanie 
Published: March 2007

AbstractMost native antigens require digestion by acidic proteases in order to be recognized in the context of major histocompatibility complex class II by T helper cells (Th). We have studied the roles of three different acidic proteases, cathepsin D, cathepsin B and cathepsin L, in the processing of ovalbumin (OVA) for presentation in the context of I‐Ad. We report that digestion of OVA in vitro with the aspartyl protease cathepsin D generates the epitope OVA322–336, which is recognized by I‐Ad‐restricted OVA‐specific Th in the presence of paraformaldehyde‐fixed antigen‐presenting cells (APC). In contrast, digestion of OVA with the cysteine proteases cathepsin B and L not only failed to generate an epitope, but also destroyed OVA322–336. In the presence of fixed APC expressing I‐Ad, OVA322–336 was protected from destructive proteolysis by cathepsin L. These results illustrate the dependence of epitope selection on the intracellular proteolytic environment in APC, and suggest that mechanisms must exist for protection of epitopes from destructive proteolysis in the processing compartments.
Phosphatidylinositol 4,5‐bisphosphate hydrolysis accompanies T cell receptor‐induced apoptosis of murine thymocytes within the thymus
Authors: Conroy Louise A. , Jenkinson Eric J. , Owen John J. T. , Michell Robert H. 
Published: March 2007

AbstractRegulation of the development of thymocytes into mature T cells within the thymus is now known to involve antigen‐induced deletion, by apoptosis, of potentially autoreactive thymocytes, and it can be mimicked either by stimulating the T cell receptor (TcR) complex by monoclonal antibody (mAb) or by ionophore‐induced elevation of cytosolic [Ca2+]. To identify signaling pathways employed by the TcR complex of immature thymocytes, we examined the effects of anti‐CD3 and anti‐TcRß constant (c) region mAb, staphylococcal enterotoxin B (SEB) and pharmacological agents on the generation of inositol phosphates through hydrolysis of phosphatidylinositol 4,5‐bisphosphate [PtdIns(4,5)P2] both in cultured fetal mouse thymic lobes and in the CD4+CD8+ immature thymocyte cell line, TM10G. Stimulation of the TcR complex with anti‐CD3 mAb provoked an accumulation of inositol phosphates diagnostic of the occurrence of receptor‐stimulated phosphoinositidase C (PLC) activation. Anti‐TcRCß mAb and SEB provoked smaller but similar responses. The PLC activation evoked by anti‐CD3 mAb was suppressed by inhibitors of receptor tyrosine kinases and was unmodified by protein kinase C activation or elevation of cytosolic [Ca2+]. It thus appears that apoptosis triggered by TcR stimulation is associated with PLC activation by a receptor‐regulated tyrosine kinase. Treatment of thymic lobes or TM10G cells with fluoroaluminate provoked apoptosis of a wider range of thymocyte subtypes and such stimulation also provoked an accumulation of inositol phosphates. The responses to fluoroaluminate were not prevented by inhibitors of tyrosine kinases, suggesting that unidentified GTP‐binding proteins which couple to PLC activation may also be capable of initiating apoptosis by a route independent of the TcR. These results, when considered alongside previous studies of mature T cells, indicate that stimulation of immature thymocytes or of mature T cells through their TcR complex activates the PLC‐catalyzed PtdIns(4,5)P2 hydrolysis signaling pathway, and thus that this signaling pathway may be implicated both in provoking apoptosis in immature T cells and in initiating proliferation in mature T cells.
Germinal‐center cell proliferation in response to T‐independent antigens: A stathmokinetic, morphometric and immunohistochemical study in vivo
Authors: Goodlad John R. , Macartney James C. 
Published: March 2007

AbstractAlthough the nature of the germinal center reaction during responses to T‐dependent antigens has been well documented, much less is known regarding the relationship between germinal centers and T‐independent antigens. In this study, germinal‐center cell proliferation was determined at specific time points in spleens of C3H/HeN mice following immunization with either the type‐1, T‐independent antigen dinitrophenol‐lipopolysaccharide (DNP‐LPS), or the type‐2, T‐independent antigen DNP‐Ficoll. A stathmokinetic technique was employed to assess proliferation in terms of germinal center cell birth rate and morphometry was used to measure actual growth and regression of the germinal center cell population. An estimate of the absolute rate of germinal‐center (GC) cell proliferation was derived from these two values. In addition, immunohisto‐chemistry was performed to correlate changes in GC cell proliferation with the presence or absence of antigen within GC. Following immunization with both antigens, there was an initial reduction of proliferation within pre‐existing germinal centers which manifested as either GC dissociation (DNP‐LPS) or a suppression of birth rates (DNP‐Ficoll). This was followed by a period of increased GC cell proliferation in animals immunized with DNP‐LPS, but not in those exposed to DNP‐Ficoll. GC cell proliferation was then measured in mice treated with cyclosporin A from 1 day before to 2 days after immunization with DNP‐LPS. In these animals, the expected increase in GC cell birth rates did not take place. Immunohistochemistry showed that DNP‐Ficoll and DNP‐LPS were present in GC from 1 day after immunization until the end of the experiment on day 7. Treatment with cyclosporin A did not affect the deposition of DNP‐LPS in GC. These results show that only some T‐independent antigens are able to stimulate GC cell proliferation, and we propose that this is related to their ability to recruit precursors of GC B cells into the GC reaction. In addition, the results indicate that GC proliferation seen in response to a so‐called T‐independent antigen is at least partly driven by T cell‐derived cytokines.