bluuebunny/crossref_metadata_2025_split huggingface dataset:
Germinal center B cells rescued from apoptosis by CD40 ligation or attachment to follicular dendritic cells, but not by engagement of surface immunoglobulin or adhesion receptors, become resistant to CD95‐induced apoptosis
Authors: Koopman Gerrit , Keehnen Robert M. J. , Lindhout Ernst , Zhou David F. H. , De Groot Cornelis , Pals Steven T. 
Published: March 2007

AbstractGerminal centers (GC) constitute a specialized microenvironment essential for the formation of memory B cells, B cell affinity maturation and isotype switching. Within the GC, the B cells closely interact with follicular dendritic cells (FDC) and T cells, which both provide stimuli to the B cells that prevent their entry into apoptosis and promote their differentiation into memory cells or plasma cells. Cross‐linking of B cell immunoglobulin (Ig) receptors by antigen, stimulation of the integrin adhesion molecules LFA‐1 and VLA‐4 on the B cell through interaction with their counter receptors ICAM‐1 and VCAM‐1 on the FDC and cross‐linking of CD40 on the B cells through interaction with the CD40 ligand (CD40L) on T cells have been shown to prevent entry into apoptosis of GC B cells. Triggering of CD95, on the other hand, has been shown to induce apoptosis. We therefore investigated the interaction between adhesion‐mediated signals, Ig, CD40, and CD95. The spontaneous apoptosis of GC B cells was not further increased by adding anti‐CD95. However. CD95 stimulation did result in apoptosis of GC B cells in the presence of anti‐Ig or adhesion‐mediated rescue signals, which indicates that CD95 expressed on GC B cells is functionally active. In contrast, anti‐CD95 was unable to induce apoptosis in cells rescued via CD40 stimulation, suggesting an important role for CD40L expressed on GC T cells in apoptosis regulation. We also studied apoptosis of B cells adhering to FDC, and found that B cells that interact with FDC were also rescued from CD95‐induced apoptosis. A human CD40.Fcu fusion protein that blocks CD40 ligation failed to inhibit this effect. Our studies therefore indicate that neither CD40, Ig receptors, nor adhesion receptors mediate rescue from apoptosis by FDC.
Functional relevance during lymphocyte migration and cellular localization of activated β1 integrins
Authors: Gómez Manuel , Luque Alfonso , Del Pozo Miguel A. , Hogg Nancy , Sánchez‐Madrid Francisco , Cabañas Carlos 
Published: March 2007

AbstractThe state of integrin activation can be assessed by monoclonal antibodies (mAb) that selectively recognize integrins in their active form. We demonstrate herein that the expression of the epitope recognized by mAb HUTS‐21 is induced on T lymphoblasts upon binding of soluble vascular cell adhesion molecule (VCAM)‐1 and an 80‐kDa tryptic fragment of fibronectin (FN80) to the β1 integrins very late activation antigen (VLA)‐4 and VLA‐5, and that this effect is dependent on ligand concentration and is specific for β1 integrins. On T lymphoblasts adhering to immobilized fibronectin, the HUTS‐21 epitope localized exclusively to sites of integrin binding to fibronectin. These results indicate that mAb HUTS‐21 recognizes a ligand‐induced binding site (LIBS) on the common β1 subunit of VLA proteins. Engagement of β1 integrins through this LIBS epitope inhibited T lym‐phoblast movement on fibronectin, as determined by quantitative time‐lapse video microscopy studies. Furthermore, the HUTS‐21 mAb also prevented T lymphoblast‐directed migration through gradients of substratum‐immobilized β1 integrin ligands such as fibronectin or VCAM‐1, whereas it did not affect migration on intercellular adhesion molecule (ICAM)‐1. This anti‐LIBS mAb stimulated cell adhesion through postreceptor events, without affecting receptor affinity for ligand, and appears to interfere with cell migration by a mechanism distinct from that of other anti‐β1 activating antibodies.
Expression of pro‐inflammatory cytokines by TCRαβ+ T and TCRγδ+ T cells in an experimental model of colitis
Authors: Simpson Stephen J. , Holländer Georg A. , Mizoguchi Emiko , Allen Deborah , Bhan Atul K. , Wang Baoping , Terhorst Cox 
Published: March 2007

AbstractAn inflammatory bowel disease (IBD) comparable to human ulcerative colitis is induced upon transfer of T cell‐depleted wild‐type (F1) bone marrow into syngeneic T cell‐deficient (tgε26) mice (F1 → tgε26). Previously we have shown that activated CD4+ T cells predominate in transplanted tgε26 mice, and adoptive transfer experiments verified the potential of these cells to cause disease in immunodeficient recipient mice. Using flow cytometry for the detection of intracellular cytokine expression, we demonstrate in the present study that large numbers of CD4+ and CD8+ TCRαβ+ T cells from the intraepithelial region and lamina propria of the colon of diseased, but not from disease‐free mice, produced interferon‐γ (IFN‐γ) and tumor necrosis factor‐α (TNF‐α). Large numbers of T cells from peripheral lymphoid tissues of these animals also expressed IFN‐α and TNF‐α, but few expressed interleukin‐4, demonstrating g strong bias towards Th1‐type T cell responses in these animals. TCRγδ+ T cells, typically minor constituents of the inflammatory infiltrate of the colon in F1 → tgε26 mice, also expressed IFN‐γ at a high frequency upon CD3 stimulation. In light of these findings we examined the potential involvement of TCRγδ+ T cells by testing their ability to induce colitis in tgε26 mice. We report here that tgε26 mice transplanted with T cell‐depleted bone marrow from TCRαnull and TCRβnull animals developed IBD. Furthermore, disease in these mice correlated with the development of peripheral and colonic TCRαδ+ T cells capable of IFN‐γ production. These results suggest that IFN‐γ may be a common mediator of IBD utilized by pathogenic T cells of distinct phenotype.
The influence of granulocyte/macrophage colony‐stimulating factor on dendritic cell levels in mouse lymphoid organs
Authors: Vremec David , Lieschke Graham J. , Dunn Ashley R. , Robb Lorraine , Metcalf Donald , Shortman Ken 
Published: March 2007

AbstractTo ascertain whether the development of dendritic cells (DC) in mouse lymphoid organs is dependent on granulocyte/macrophage colony‐stimulating factor (GM‐CSF), we determined the number of DC in the thymus, spleen and lymph nodes of normal mice, of mice with the genes coding for GM‐CSF or its receptor inactivated, and of transgenic mice with excessive levels of GM‐CSF. DC were extracted from the tissues and enriched prior to flow cytometric analysis. The total DC level and the incidence of DC expressing lymphoid‐related markers (CD8hiCD11blo) and myeloid‐related markers (CD8loCD11bhi) were monitored. Both in GM‐CSF null mice, and GM‐CSF receptor null mice, DC of all surface phenotypes were present in all lymphoid organs; only small decreases in DC levels were recorded, except for the lymph nodes of GM‐CSF receptor null mice which showed a more pronounced (threefold) decrease in DC numbers. Since the GM‐CSF receptor null mice lacked the β chain common to the GM‐CSF, interleukin (IL)‐3 and IL‐5 receptors, the development of DC in the absence of GM‐CSF was not due to common β chain mediated developmental signals elicited by IL‐3 or IL‐5. In GM‐CSF transgenic mice, there was only a 50 % increase in DC numbers in thymus and spleen, paralleling an increase in overall cellularity, but a more pronounced (threefold) increase in DC numbers in lymph nodes. There was no evidence that GM‐CSF had a selective effect on any particular DC subpopulation defined by CD8 or CD11b expression. We conclude that the development of most lymphoid tissue DC can proceed in the absence of GM‐CSF, although this cytokine can produce some elevation of DC levels. It is not clear whether the enhancing effect of GM‐CSF is direct or an indirect effect mediated by other cytokines.
Co‐receptor‐independent signal transduction in a mismatched CD8+ major histocompatibility complex class II‐specific allogeneic cytotoxic T lymphocyte
Authors: Eshima Koji , Tachibana Makoto , Suzuki Harumi , Yamazaki Sunao , Shinohara Nobukata 
Published: March 2007

AbstractThe contribution of co‐receptors in signal transduction upon T cell receptor (TCR)‐mediated recognition of major histocompatibility complex (MHC) class II antigen by mature T lymphocytes expressing TCR derived from the apparently co‐receptor‐independent, I‐Ak‐specific allogeneic CD8+ CTL clone QM11 has been examined. Mature double‐negative, CD8+ and CD4+ bulk T cell lines and clones expressing TCRQM11 were developed from TCRQM11 transgenic mice. All these T cells, irrespective of co‐receptor expression, showed specific lytic activity on cells expressing I‐Ak. Furthermore, co‐receptorless mutants were obtained from a CD4+ and CD8+ clone. The responses of these co‐receptorless mutants upon specific recognition of the alloantigen, as judged by cytolytic activity, granule exocytosis, lymphokine production, proliferation, and tyrosine phos‐phorylation of the ξ chain, were comparable to those of the original clones. Thus, the results proved the co‐receptor independence of the recognition of I‐Ak by TCRQM11 and further indicated there is no indispensable unique signal transduced by co‐receptors. However, when the amount of the available antigen was limited by anti‐I‐Ak antibody, the CD4+ T cell clone showed a remarkable resistance to the inhibition whereas the mismatched CD8+ clone was readily inhibitable. The anti‐I‐Ak‐resistant component of the CD4+ clone showed dependency on the CD4 molecule. Taken collectively, the results indicate that the role played by a co‐receptor molecule in mature T cells is purely quantitative amplification of the signal through the formation of a TCR/MHC/co‐receptor ternary complex, and also indicate that the role of co‐receptor molecules as TCR‐independent adhesion molecules is at best minimal.
Vα domain modulates the multiple topologies of mouse T cell receptor Vβ20/staphylococcal enterotoxins A and E complexes
Authors: De Alba Yolanda Bravo , Marche Patrice N. , Cazenave Pierre‐André , Cloutier Isabelle , Sekaly Rafick‐Pierre , Thibodeau Jacques 
Published: March 2007

AbstractThe superantigens staphylococcal enterotoxin A and E (SEA and SEE) both contact major histocompatibility complex (MHC) class II molecules on two sites located on the α and β chains. We have investigated the role of the T cell receptor (TCR) α chain in the modulation of the various topologies of TCR/SEA (or SEE)/class II complexes. For this purpose, we have used three mouse Vβ20 T cell lines expressing different Vα domains and two T cell hybridomas expressing mouse Vβ1 or Vβ11 segments. The response of these T cells to SEA and SEE was studied in the context of presentation by wild‐type human MHC class II molecules; or by mutants on MHC, in each of the two superantigen binding sites (position α39K and β81H) to which the superantigens can still bind but with an altered conformation. Although Vβ20 T cell lines are efficiently stimulated using SEA and SEE presented by wild‐type HLA‐DR1 molecules, our results show that the nature of the TCR Vα domain can affect differently the recognition of the toxins bound to mutant class II molecules. This suggests that various functional topologies exist for both SEA and SEE/class II complexes and that the T cell response to each of these complexes can be modulated by the Vα domain of the TCR. Interestingly, the recognition of SEA and SEE is achieved in different fashions by a given Vβ20 T cell line.
A γδ T cell specific surface receptor (WC1) signaling G0/G1 cell cycle arrest
Authors: Takamatsu Haru‐Hisa , Kirkham Paul A. , Parkhouse R. Michael E. 
Published: March 2007

AbstractThree monoclonal antibodies (mAb; SC‐6, SC‐12, and SC‐29) reactive with the γδ T cell‐restricted antigen WC1 were obtained immunizing mice with an ovine interleukin (IL)‐2‐dependent γδ T cell line. These mAb strongly inhibited DNA synthesis in IL‐2‐dependent γδ T cell lines with cell cycle arrest in G0/G1 phase, but did not induce apoptosis. The mAb‐induced growth arrest was reversible, either by removing the mAb or by co‐culture with mitogen or anti‐CD3 in the presence of IL‐2. In contrast, addition of phorbol ester, ionomycin and IL‐2 had no effect on the mAb‐induced growth arrest. The observations define a biologically important role for the cell surface molecule WC1 in the regulation of γδ T cell proliferation and also provide a suitable system to study the relevant signal transduction events.
Thymic stromal organization is regulated by the specificity of T cell receptor/major histocompatibility complex interactions
Authors: Brabb Thea , Huseby Eric S. , Morgan Todd M. , Sant'Angelo Derek B. , Kirchner Jacqueline , Farr Andrew G. , Goverman Joan 
Published: March 2007

AbstractThe thymic architecture is normally compartmentalized into a central medulla surrounded by a peripheral cortical region. We investigated how compartmentalization of the thymic stroma is regulated using T cell receptor (TCR)‐transgenic mouse models. Our studies show that the signals generated by TCR/peptide/major histocompatibility complex interactions regulate thymic stromal cell compartmentalization. In TCR‐transgenic mice, normal stromal cell compartmentalization occurs when the transgenic TCR is expressed on a background that does not result in skewing toward either positive or negative selection. In models representing strong positive selection, the thymic stromal elements do not fully organize into a central medulla. Instead, small medullary foci are dispersed throughout the thymus with some regions residing directly under the capsule. The highest degree of disorganization in medullary epithelial regions is observed in TCR‐transgenic mice that exhibit negative selection. Although the medullary foci lack central organization, the expression in these regions of CD80, CD86 and CD40, as well as the clustering of dendritic cells, is similar to that observed in medullae of wild‐type mice. Thus, the organization of the medulla appears to occur in two stages: (1) small medullary epithelial regions that are dispersed in fetal thymi expand and associate with antigen‐presenting cells, and (2) the expanded medullary foci organize into a central medullary compartment. Our data suggest a model in which this second stage of stromal cell organization is increasingly inhibited as the normal balance of TCR‐mediated signals is skewed by higher‐avidity interactions between thymocytes and antigen‐presenting cells.
Human Th1 cells preferentially induce interleukin (IL)‐1β while Th2 cells induce IL‐1 receptor antagonist production upon cell/cell contact with monocytes
Authors: Chizzolini Carlo , Chicheportiche Rachel , Burger Danielle , Dayer Jean‐Michel 
Published: March 2007

AbstractThe role of human T cells in the induction and regulation, upon cell/cell contact, of inflammatory responses by monocytic cells was investigated. The production of interleukin (IL)‐1β and IL‐1 receptor antagonist (IL‐1Ra) by the monocytic THP‐1 cell line was measured upon contact with either Th1 or Th2 cell clones. CD4+ T cell clones specific for purified protein derivative of Mycobacterium tuberculosis, predominantly Th1 [high interferon (IFN)‐γ and low IL‐4 producers], or tetanus toxoid, predominantly Th2 (low IFN‐γ and high IL‐4 producers), were generated. Cell membranes from antigen‐stimulated, but not from resting T cell clones induced dose‐dependent cytokine production by THP‐1 cells. Th1 clones induced higher levels of IL‐1β production (484–806 pg/ml) than did Th2 clones (21–114 pg/ml). In contrast, Th1 clones induced lower levels of IL‐1Ra (0.9–7.8 ng/ml) than did Th2 clones (7.0–49.6 ng/ml). Similar results were obtained when T cell clones were activated by cross‐linked CD3 and CD28. IL‐1β production by THP‐1 cells correlated with IFN‐γ production by T cell clones but was unaffected by IFN‐γ neutralization. IL‐1Ra production by THP‐1 cells correlated with IL‐4 production by T cells and was partially inhibited by IL‐4 neutralization. These data indicate that activated Th1 and Th2 cells express different molecules on the cell surface able to induce distinct pro‐inflammatory (IL‐1β) or anti‐inflammatory (IL‐1Ra) responses in monocytes. This differential induction of molecules with opposite effects on inflammation stresses the functional heterogeneity in CD4+ T cells.
Bacille Calmette Guérin and interleukin‐12 down‐modulate interleukin‐4‐producing CD4+ NK1+ T lymphocytes
Authors: Emoto Masashi , Emoto Yoshiko , Kaufmann Stefan H. E. 
Published: March 2007

AbstractEarly production of interleukin‐12 (IL‐12) by macrophages and of IL‐4 from CD4+ NK1+ T cells influence development of the acquired immune response against infectious agents, namely differentiation of interferon‐γ‐secreting T helper 1 (Th1) cells against intracellular pathogens and of IL‐4‐producing Th2 cells against helminths. Evidence has been presented for transient convertibility of Th1 and Th2 cells in the presence of the polarizing cytokines IL‐4 or IL‐12, respectively. Moreover, it is likely that IL‐4 dominates over IL‐12, suggesting that Th2 cell development is preferred in the presence of both cytokines. Mycobacterium bovis Bacille Calmette Guérin (BCG) and IL‐12 are potent inducers of Th1 responses. Here we show that BCG and IL‐12 down‐modulate IL‐4‐producing CD4+ NK1+ TCRα/βintermediate liver lymphocytes. Our data provide further insights into the mechanisms by which BCG and IL‐12 may promote unrestricted development of Th1 responses in vivo: BCG and IL‐12 not only provide the positive stimuli for Th1 cell differentiation, but also interfere with antagonizing signals.
γδ cells involved in contact sensitivity preferentially rearrange the Vγ3 region and require interleukin‐7
Authors: Dieli Francesco , Asherson Geoffrey L. , Sireci Guido , Dominici Roberto , Gervasi Francesco , Vendetti Silvia , Colizzi Vittorio , Salerno Alfredo 
Published: March 2007

AbstractPtak and Askenase showed that both αβ and γδ cells are required for transfer of contact sensitivity (CS). This study confirms that day 4 immune cells depleted of γδ cells fail to transfer CS to trinitrochlorobenzene (TNP‐Cl) systemically and demonstrates that administration of anti‐γδ monoclonal antibodies (mAb) in vivo abolishes the CS reaction. Moreover, γδ cells accumulate at the antigen challenge site: these cells have the unusual phenotype CD8α+, CD8β‐, IL‐4 R+ which we suggest is due to their state of activation. Following immunization with contact sensitizer on the skin, the absolute number of γδ cells increases in the regional lymph nodes with a peak at 4 days. Of the γδ cells, 80%, both in the lymph nodes of TNP‐Cl‐immune mice and accumulating at the antigen challenge site are Vγ3+. The γδ cells expressing Vγ3, which is characteristic of dendritic epithelial T cells (DETC), obtained 4 days after sensitization, proliferate in response to interleukin (IL)‐7, but only poorly to IL‐2 and IL‐4. They also respond to concanavalin A and immobilized anti‐γδ mAb, but not to haptens or heat‐shocked syngeneic spleen cells. Furthermore, injection of mice with mAb to IL‐7 inhibits accumulation of Vγ3+ cells both in the lymph nodes after skin sensitization and at the antigen‐challenge site. Altogether, these results strongly support the view that DETC are related to, or the original source of, the γδ cells found in the lymph node after skin sensitization and at the site of challenge, and that IL‐7 is implicated in these phenomena.
Overexpression of mitogen‐activated protein kinase kinase kinase reversed cAMP inhibiton of NF‐χB in T cells
Authors: Ho Huang‐Yao , Lee Hsiu‐Hsiang , Lai Ming‐Zong 
Published: March 2007

AbstractcAMP inhibits T cell activation by acting as an antagonist for selective kinases and transcriptional factors. We have recently demonstrated that cAMP inhibited c‐Jun N‐terminal kinase (JNK) but left the mitogen‐activated protein (MAP) kinase cascade almost unaffected in T lymphocytes. In accordance with recent reports, we also observed a selective suppression of nuclear factor NF‐χB activation by cAMP. The possible link between the JNK cascade and NF‐χB activation was demonstrated by the fact that the active form of MAP kinase kinase kinase (ΔMEKK), a constitutive activator of JNK, induced NF‐χB but not AP‐1, Oct, and NF‐AT in T cells. In contrast, the induction of MAP kinase kinase (MEK)‐MAP kinase did not stimulate NF‐χB activity. The specific activation of NF‐χB by a single MEKK‐JNK cascade was thus unusual, given that the activation of other transcriptional elements in T cells requires at least two signal pathways. This was further confirmed by the fact that cAMP inhibition of NF‐χB activation was reversed by overexpression of ΔMEKK.
The propensity to apoptosis of centrocytes and centroblasts correlates with elevated levels of intracellular myc protein
Authors: Cutrona Giovanna , Dono Mariella , Pastorino Sandra , Ulivi Massimo , Burgio Vito L. , Zupo Simona , Roncella Silvio , Ferrarini Manlio 
Published: March 2007

AbstractIn this study, we investigated the c‐myc expression by tonsillar germinal center (GC) B cells using reverse transcriptase‐polymerase chain reaction, flow cytometry, Western blot and in situ immunohistochemical methods. The results obtained demonstrate elevated levels of c‐myc mRNA and of Myc protein in GC B cells compared to those of the other resting or activated tonsillar B cells. Separation of GC B cells into centroblasts and centrocytes revealed that, while differing in their cell cycle status, surface marker expression and morphology, the two cell types had the same propensity to apoptosis and elevated Myc protein expression, thus reinforcing the notion of a close correlation between these two events. Based upon these observations and other considerations it is proposed that elevation of Myc proteins confers to GC B cells a particular propensity to apoptosis, while the subsequent decision between progression into the cell cycle or programmed cell death is dictated by other signals that are delivered in the GC and perhaps operate at the level of other proto‐oncogenes.
CD73 mediates lymphocyte binding to vascular endothelium in inflamed human skin
Authors: Arvilommi Anna‐Maija , Salmi Marko , Airas Laura , Kalimo Kirsti , Jalkanen Sirpa 
Published: March 2007

AbstractInflammatory diseases of the skin are characterized by abundant lymphocytic infiltrates at the site of inflammation, which are critical for the perpetuation of chronic disease. Lymphocytes gain entry to the site of inflammation by the use of adhesion molecules, which recognize their counterparts on vascular endothelial cells. CD73 is a lymphocyte differentiation antigen, which has recently been shown to mediate lymphocyte binding to cultured endothelial cells. Here, we have examined its expression and function in inflammatory situations using inflammatory skin diseases as a model. In several idiopathic and allergic disorders of the skin, a vast majority of the skin‐infiltrating lymphocytes were found to express CD73. However, on the circulating lymphocytes of these patients the expression of CD73 does not differ from that of healthy individuals. Of the peripheral blood lymphocytes (PEL) of patients, 13% are CD73+; of these, 9% express the cutaneous lymphocyte antigen (CLA), 32% express CD45RO, and 86% are L‐selectin+. Only 1% of PEL express both CLA and CD73. In contrast, most skin‐infiltrating lymphocytes express both molecules, which led us to investigate the role of CD73 in the skin‐homing behavior of these cells. In the frozen‐section adhesion assay, when PBL were treated with the anti‐CD73 monoclonal antibody 4G4, their binding to the vascular endothelium in inflamed skin was inhibited by 70%. Taken together, our results demonstrate that CD73+ lymphocytes preferentially accumulate into inflamed skin and, most importantly, that CD73 is involved in lymphocyte binding to vessels in inflamed skin. In the future, these findings may offer new means to treat inflammatory disorders of the skin.