bluuebunny/crossref_metadata_2025_split huggingface dataset:
Activation of mitogen‐activated protein kinases via CD40 is distinct from that stimulated by surface IgM on B cells
Authors: Kashiwada Masaki , Kaneko Yoriaki , Yagita Hideo , Okumura Ko , Takemori Toshitada 
Published: March 2007

AbstractCD40 plays critical roles in B cell proliferation and differentiation in response to T cell‐dependent antigenic stimulation. It has been suggested that CD40‐mediated biological activities are transduced by a CD40 receptor‐associated factor, CRAF1 and probably by protein tyrosine kinase Lyn and its substrates, phospholipase Cγ (PLCγ) and phosphatidylinositol‐3 kinase (PI‐3 kinase). Here, we describe the novel finding that a mitogen‐activated protein kinase (MAPK)/extracellular signal‐regulated protein kinase (ERK) cascade is involved in CD40 signaling in mouse B cells. Analysis of ERK activities in the B cell lymphoma cell line WEHI 231, which shows an increase in DNA synthesis or arrest of the cell cycle by cross‐linking of CD40 or surface IgM (sIgM) cross‐linking, respectively, indicated that one of the ERK isoforms, ERK2, was preferentially and rapidly activated after CD40 cross‐linking. The CD40‐mediated ERK2 activation was comparable to that after sIgM stimulation, although the activity was reduced toward the basal level within several minutes after stimulation. In contrast, ERK1 and ERK2 were activated to a similar extent by sIgM cross‐linking, and the activities remained stable for at least 10 min. Furthermore, similar features of differential activation of ERK isoforms were observed in normal resting B cells in CD40 and sIgM signaling. These results suggest divergent regulatory pathways for ERK1 and ERK2 activation, and they support the notion that CD40 signaling may utilize a limited set of elements in the ERK cascade. Co‐stimulation of WEHI 231 cells with anti‐CD40 mAb rescues the cells from anti‐IgM‐mediated apoptosis, whereas this co‐stimulation resulted in activation of ERK isoforms comparable to that in sIgM stimulation, without a synergistic effect. This result indicates the dominance of ERK activation in sIgM signaling over that of CD40, and it suggests that ERK activation may not be linked to the biological effect that CD40 stimulation in this cell line.
Mechanisms of peripheral T cell deletion: anergized T cells are Fas resistant but undergo proliferation‐associated apoptosis
Authors: Miethke Thomas , Vabulas Ramunas , Bittlingmaier Renate , Heeg Klaus , Wagner Hermann 
Published: March 2007

AbstractThe complementary receptor pair Fas ligand: Fas controls apoptosis during activation‐induced cell death (AICD) of peripheral T cells sensitized for the Fas signal pathway by interleukin‐2 (IL‐2). In the present study, we used the bacterial superantigen staphylococcal enterotoxin B (SEB) to anergize ligand‐reactive peripheral T cells in wild‐type and Fas‐defective lpr mice. In a second step, we investigated whether apoptosis in anergized and thus operationally IL‐2‐defective peripheral T cells is triggered via the Fas signal pathway. We report here that SEB‐driven anergy induction and deletion of anergized peripheral Vβ8+ T cells is similar in wild‐type and healthy C3H/lpr mice. In monitoring SEB‐driven Vβ8+ T cell apoptosis in situ, we observe in both wild‐type and lpr mice an intimate association between proliferation and apoptosis of anergized Vβ8+ T cells. We further show that Vβ8+ T cells activated in vitro from wild‐type mice express a Fas‐sensitive phenotype determined by Fas cross‐linking which causes apoptosis. In contrast, Vβ8+ T cells anergized in vivo from wild‐type mice are Fas resistant. As expected, T cells from lpr mice activated in vitro or anergized in vivo are Fas resistant. Taken together, these data indicate that both in wild‐type and Fas‐defective C3H/lpr mice, anergized T cells become deleted via a Fas‐independent, proliferation‐associated apoptosis signal pathway.
Relationship between Th1/Th2 cytokine patterns and the arthritogenic response in collagen‐induced arthritis
Authors: Mauri Claudia , Williams Richard O. , Walmsley Marita , Feldmann Marc 
Published: March 2007

AbstractIt is hypothesized that the balance of cytokines produced by Th1/Th2 subsets of T helper cells plays an important role in the development of autoimmune diseases. Murine collagen‐induced arthritis (CIA) is an example of an autoimmune disease in which immunization with cartilage‐derived type II collagen induces, firstly, a T cell response to type II collagen and, secondly, the manifestation of a destructive inflammatory response in affected joints. We have investigated the role of Th1/Th2 responses in the development of CIA by monitoring levels of interferon (IFN)‐γ (a Th1 cytokine) and interleukin (IL)‐4 and IL‐10 (Th2 cytokines), and IL‐1β and tumor necrosis factor (TNF) (pro‐inflammatory cytokines) produced by cultured draining lymph node cells (LNC) from collagen‐immunized DBA/1 mice during the induction phase of arthritis and throughout the time of clinical manifestation and subsequent remission of the disease. Although a transient increase in IL‐10 was detected 3 days after immunization, Th2 cytokine production was found to be almost completely suppressed 6 days after immunization. In contrast, IFN‐γ was detected in LNC cultures as early as 6 days after immunization and the addition of type II collagen to the culture medium resulted in an approximately 10‐fold increase in IFN‐γ production, indicating that a predominantly Th1 response had become established by this time. IFN‐γ production by LNC was found to be further increased at the time of clinical manifestation of arthritis and could be up‐regulated by co‐culture with type II collagen. IL‐10 was not detected in LNC cultures at the onset of arthritis and IL‐4, although present, was found to be markedly suppressed in LNC cultures containing type II collagen. These findings indicate that Th1 responses are predominant at the time of onset of arthritis and that the activation of collagen‐specific Th1 cells may result in suppression of Th2 activity. IFN‐γ production declined progressively during the progression and subsequent remission of arthritis whereas levels of IL‐10 increased and low, though persistent, levels of IL‐4 were detected throughout this period. High levels of IL‐1β and TNF‐α production were detected at the onset of the disease. The role of Th1 responses in the development of CIA was further emphasized by the observation that immunization of mice with type II collagen in incomplete Freund's adjuvant, which normally fails to induce arthritis, resulted in a predominantly Th2 cytokine profile.
Accessory signaling by CD40 for T cell activation: induction of Th1 and Th2 cytokines and synergy with interleukin‐12 for interferon‐γ production
Authors: Peng Xiaohui , Kasran Ahmad , Warmerdam Petra A. M. , De Boer Mark , Ceuppens Jan L. 
Published: March 2007

AbstractThe interaction of CD40 ligand (CD40L) on activated T cells with CD40 on B cells, monocytes and dendritic cells is essential for humoral immunity and for up‐regulation of antigen‐presenting cell (APC) functions, as a result of signaling through CD40. There are also some indications that after interaction with CD40, CD40L can directly signal T cells. In this study we demonstrate that upon stimulation of human peripheral blood T cells through the T cell receptor (TCR)/CD3 complex, CD40/CD40L interaction strongly enhances the production of Th1 cytokines such as interleukin (IL)‐2 and interferon (IFN)‐γ and Th2 cytokines such as IL‐4, IL‐5 and IL‐10 by a direct effect on T cells. Furthermore, CD40/CD40L interaction synergizes with IL‐12 in selectively enhancing IFN‐γ production by purified anti‐CD3‐stimulated T cells. These effects were observed at both the protein and the mRNA level. Both CD4+ and CD8+ T cells were able to produce IFN‐γ in the presence of helper signals from IL‐12 and CD40, although CD8+ T cells were less active. Since CD40/CD40L interaction also up‐regulates IL‐12 production and B7 expression by APC, our results suggest that CD40/CD40L interaction is bidirectional, and promotes activation of both APC and T cells.
Cell type‐specific processing of the I‐Ed‐restricted hen egg lysozyme determinant 107–116
Authors: Robadey Chantal , Wallny Hans‐Joachim , Demotz Stéphane 
Published: March 2007

AbstractClass II major histocompatibility complex heterodimers present to T cells determinants as sets of antigen fragments with ragged N and C termini. It is not yet elucidated whether different types of antigen‐presenting cells generate identical sets of peptides containing the same determinant. Taking advantage of recombinant I‐Ed molecules produced by insect cells as empty heterodimers, a sensitive T cell stimulation assay was developed to analyze naturally processed hen egg lysozyme (HEL) peptides. I‐Ed preparations were isolated from antigen‐presenting cells cultured with HEL. Following acid treatment, peptides eluted from I‐Ed were chromatographed and the fractions incubated at acidic pH with purified recombinant I‐Ed molecules, conditions which favor peptide binding. The stimulatory capacity of the reconstituted peptide‐I‐Ed complexes adsorbed on the well surface of cell culture plates was then evaluated by measuring interleukin‐2 secreted by an HEL 107–116‐specific, I‐Ed‐restricted T cell hybridoma. We found that the B lymphoma A20 and an I‐Ed‐transfected fibroblast cell line generated distinct sets of peptides containing the HEL sequence 107–116. Our results suggest the possibility that presentation of one determinant by different types of antigen‐presenting cells stimulates populations of T cells with distinct fine antigen specificities.
Induction of class II major histocompatibility complex blockade as well as T cell tolerance by peptides administered in soluble form
Authors: Nihira Shin‐Ichi , Falcioni Fiorenza , Juretic Antonio , Bolin David , Nagy Zoltan A. 
Published: March 2007

AbstractPeptides binding to a particular class II major histocompatibility complex (MHC) molecule can inhibit the activation of T cells by other peptides binding to the same molecule, a phenomenon termed class II MHC blockade. All class II‐binding peptides exert MHC blockade in vivo in depot form with adjuvant, and some also retain their blocking properties in soluble form. We demonstrate here that soluble peptides, when used at doses causing short‐term MHC blockade, can also induce long‐term antigen‐specific T cell tolerance to themselves. The tolerogenicity of soluble peptides correlates with their antigenicity in adjuvant, but it is not necessarily related to their capacity to act as class II blockers in vivo. The tolerant state is manifested in a decreased production of both T helper cell 1 (Th1)‐type and Th2‐type lymphokines, and it cannot be reversed by interleukin‐2. Once T cells are primed with a peptide in complete Freund's adjuvant, they are resistant to tolerization with the same peptide applied in soluble form. Tolerance induction is partially impaired in B cell‐deficient μMT−/− mice, suggesting a role for B cell antigen presentation in this process. The results suggest that the potential immunogenicity of class II MHC blockers could be circumvented by choosing a tolerogenic mode of application.
A point mutation in the human transporter associated with antigen processing (TAP2) alters the peptide transport specificity
Authors: Armandola Elena A. , Momburg Frank , Nijenhuis Marga , Bulbuc Nadja , Früh Klaus , Hämmerling Günter J. 
Published: March 2007

AbstractThe heterodimeric transporter associated with antigen processing (TAP1/TAP2) translocates peptides from the cytosol into the endoplasmic reticulum where loading of major histocompatibility complex class I molecules takes place. TAP transporters from different species are known to exhibit distinct transport specificities with regard to the C‐terminal amino acid (aa) of peptides. Thus, human TAP (hTAP), and rat TAP (rTAP) containing the rTAP2a allele are rather promiscuous, whereas mouse TAP (mTAP), and rTAP containing the rTAP2u allele are restrictive and select against peptides with C‐terminal small polar/hydrophobic or positively charged aa. The structural basis for this selectivity is not clear. To assess the relative contribution of the TAP1 and TAP2 subunits to transport specificity, we have constructed and analyzed interspecies TAP hybrids and point mutants of hTAP2 expressed in Sf9 insect cells and in TAP‐deficient T2 cells. Transport assays with 20 C‐terminal variants of the peptide RYWA‐NATRSX showed that: first, transport specificity with regard to C‐terminal aa is mainly influenced by TAP2, but TAP1 can also contribute. Second, the selective transport of peptides with C‐terminal positively charged aa is critically controlled by the amino‐terminal region (1–361) on the TAP2 chain, while transport of peptides with C‐terminal small polar/hydrophobic aa is determined by residues located within as well as outside the region 1–361. Third, a single point mutation in hTAP2 (374A → D) resulted in a drastic alteration of the transport pattern. These results indicate that both TAP1 and TAP2 contribute to efficient peptide transport and that single point mutations in hTAP2 are able to alter the peptide transport specificity. This opens the possibility that naturally occurring mutations in one of the hTAP subunits may alter epitope selection in vivo.
Redirecting the complete T cell receptor/CD3 signaling machinery towards native antigen via modified T cell receptor
Authors: Brocker Thomas , Riedinger Mireille , Karjalainen Klaus 
Published: March 2007

AbstractWe show that a chimeric T cell receptor (TCR) β chain consisting of a single‐chain Fv portion derived from a monoclonal antibody and the full TCR β chain is able to assemble functionally with endogenous TCR/CD3 components and transfer the antibody specificity as well as the TCR specificity into TCRβ− as well as into TCRβ+ T cells. This allows the incorporation new non‐major histocompatibility complex‐restricted ligand specificities into the intact TCR/CD3 complex which can exploit the full range of biological activities of the endogenous TCR signaling machinery. This approach can provide wider opportunities to redirect T cells to virus or tumor antigen‐bearing cells.
Evidence for intact CD28 signaling in T cell hyporesponsiveness induced by the HIV‐1 nef gene
Authors: Collette Yves , Mawas Claude , Olive Daniel 
Published: March 2007

AbstractInfection by human immunodeficiency virus (HIV)‐1 is associated with quantitative and qualitative T cell alterations that severely impair the host's immune defense system. The molecular basis for this immunosuppression remains unclear. Peripheral blood mononuclear cells (PBMC) isolated from patients show markedly decreased interleukin (IL)‐2 secretion but unaffected or even increased T helper (Th)2 cytokine production. T cell functional defects were recently reported to correlate more with T cell receptor (TcR) signaling, whereas signals provided by ligation of co‐receptors CD27 and CD28 appeared to be preserved. Among the various mechanisms proposed to be involved in HIV‐1‐induced T cell dysfunction, we and others have reported that the nef gene product exhibited significant immunosuppressive activity. By using an inducible stably integrated nef gene, we demonstrated that Nef specifically down‐regulated IL‐2 and interferon (IFN)‐γ produced upon TcR triggering. Here, using the same experimental system, we extended our initial observations to additional mitogenic signals, and investigated the co‐stimulatory function of CD28. Nef down‐regulated IL‐2, but not IL‐4 produced upon induction by combinations of mitogens that mimicked TcR signals together with CD28 mAb or CD28's natural ligand (CD80 and CD86). However, the co‐signals provided by CD28 to up‐regulate IL‐2 induction were unaffected by Nef, since IL‐2 produced by nef‐transfected cells was proportionally enhanced to the same extent as that of control cells, either upon stimulation by the CD28 mAb or CD80 and CD86. In addition, phosphatidylinositol‐3 kinase recruitement induced upon CD28 triggering was also found to be unaltered by nef expression. Together with the observation that similar levels of the Nef protein were detected in nef‐transfected cells and upon infection of PBMC, these data suggest a selective immunosuppression induced by nef in human T cells by altering TcR signaling without detectable impact on CD28 co‐receptor function. These data agree with the T cell defects observed in PBMC isolated from HIV‐infected individuals.
Molecular Ig gene analysis reveals that monocytoid B cell lymphoma is a malignancy of mature B cells carrying somatically mutated V region genes and suggests that rearrangement of the kappa‐deleting element (resulting in deletion of the Ig kappa enhancers) abolishes somatic hypermutation in the human
Authors: Küppers Ralf , Hajadi Mande , Plank Lukas , Rajewsky Klaus , Hansmann Martin‐Leo 
Published: March 2007

AbstractFive cases of monocytoid B cell lymphoma (MBCL) were analyzed for somatic mutations in the rearranged V region genes. Somatic mutations were found in four of the five cases, whereas one unusual CD5+ lymphoma harbored unmutated V region genes. Since somatic mutations are introduced into V regiongenes of antigen‐activated B cells in the course of T cell‐dependent immune responses, these results suggest a derivation of the tumor B cells in MBCL from antigen‐experienced mature B cells. An analysis of the ϰ‐deleting element in two of the cases in which mutated VH but unmutated and nonfunctional Vϰ gene rearrangements were found suggests that somatic hypermutation does not take place in human rearranged Vϰ region genes when the Cϰ gene and the ϰ enhancers have been deleted in cis by rearrangement of the ϰ‐deleting element.
Sequential antigen‐specific growth of T cells in the T zones and follicles in response to pigeon cytochrome c
Authors: Gulbranson‐Judge Adam , Maclennan Ian 
Published: March 2007

AbstractThe sites of accumulation and growth of antigen‐specific T cells was assessed during the Vα11/Vβ3 T cell receptor‐restricted response of IEk+ mice to pigeon cytochrome c. In the T zone, the response was early but transient; Vα11/Vβ3+ T cell numbers fell to background levels as germinal centers developed. The follicles were a major site of specific T cell growth, but Vα11/Vβ3+ T cells were not obvious in foci of extrafollicular B cell growth in the red pulp. As germinal centers waned, Vα11/Vβ3+ T cells in the T zones again rose above background levels and some persisted in the follicles. After the initial stage of T cell priming, specific T cell growth seems to occur where specific interaction can occur with B cells that are presenting processed antigen.
Chemically induced sarcomas from nude mice are more immunogenic than similar sarcomas from congenic normal mice
Authors: Svane Inge Marie , Engel Anne‐Marie , Nielsen Mai‐Britt , Ljunggren Hans‐Gustaf , Rygaard Jørgen , Werdelin Ole 
Published: March 2007

AbstractTo detect possible differences in immunogenicity between tumors induced in T cell‐deficient mice and phenotypically normal congenic mice, 16 sarcomas, 8 having developed in nude BALB/c mice and 8 having developed in congenic normal (nu/+) mice, were transplanted to normal BALB/c recipients and the rates of rejection or acceptance were registered. The 16 tumors were chosen randomly from a panel of 39 sarcomas induced with 0.5% or 0.1% 3‐methylcholanthrene and maintained as cell lines in culture. Out of the tumors originating from nude mice, 66% were rejected by the normal BALB/c recipients, while only 30% of the tumors originating from normal mice were rejected. Tumors with short induction times from normal mice were more readily accepted than tumors with long induction times. Tumors originating from nude mice had significantly longer mean latency times after transplantation to both normal and nude recipients than tumors originating from normal mice. Contrary to what has been reported by others, there was no correlation between the rejection rates of the individual tumors and their Kd, Dd or Ld major histocompatibility complex (MHC) class I surface expression as measured by flow cytometric analysis of cultured tumor cells. The Kd, Dd and Ld proteins of the transplanted tumor lines were analyzed by isoelectric focusing for the occurrence of mutations resulting in altered charge of the MHC protein. No such mutations were found, ruling out MHC mutations of that kind as the source of immunogenicity in the cell lines used in these experiments. Our results suggest the existence of a T cell‐mediated selection in the original tumor cell mass of tumors induced in normal mice, adapting the tumor to growth in a host with a functional T cell system, but apparently there is no connection between this loss of immunogenicity and loss of MHC class I expression.
Heterogeneous effects of B7‐1 and B7‐2 in the induction of both protective and therapeutic anti‐tumor immunity against different mouse tumors
Authors: Martin‐Fontecha Alfonso , Cavallo Federica , Bellone Matteo , Heltai Silvia , Iezzi Giandomenica , Tornaghi Paola , Nabavi Nasrin , Forni Guido , Dellabona Paolo , Casorati Giulia 
Published: March 2007

AbstractExperimental mouse tumors are classified as intrinsically immunogenic when, after a single injection into syngeneic mice as nonreplicating cell vaccines, they elicit a protective immune response against a subsequent lethal challenge. Tumors that do not retain this residual immunogenicity are defined as poorly immunogenic or nonimmunogenic. The expression of the B7‐1 co‐stimulatory molecule on immunogenic tumors can further increase their capacity to induce a T cell‐dependent anti‐tumor immunity, whereas it has limited effects on nonimmunogenic tumors. Recently, B7‐2, a second molecule with an apparently similar co‐stimulatory activity, has been cloned. In this report, we compare the efficiency of nonreplicating cells from one immunogenic and two nonimmunogenic mouse tumors transfected with B7‐1 or B7‐2 in the induction of protective and curative anti‐tumor immunity. Immunogenic lymphoma cells expressing B7‐1 or B7‐2 are equally effective in both protecting against a subsequent challenge and curing established tumors. By contrast, nonimmunogenic adenocarcinoma and melanoma cells expressing B7‐2 provide superior protective immunity, and only B7‐2+ adenocarcinoma cells induce an efficient curative immunity. CD8+ and polymorphonuclear cells, but not CD4+ T cells, are critically involved in the rejection of the adenocarcinoma elicited by both B7‐1+ and B7‐2+ vaccines. These data indicate that B7‐1 and B7‐2 are not redundant co‐stimulatory molecules and that, in these experimental models, B7‐2 is superior to B7‐1 in the induction of an efficient immunity when the immunogenicity of a tumor is a limiting factor.
Restricted onset of T cell receptor α gene rearrangement in fetal and neonatal thymocytes
Authors: Rytkönen Marja A. , Hurwitz Julia L. , Thompson Susan D. , Pelkonen Jukka 
Published: March 2007

AbstractThe initial T cell receptor (TCR) α gene rearrangements were analyzed in fetal and neonatal thymocyte hybridomas by Southern blotting. Interestingly, in 30% of all thymocyte hybridomas and in all fetal day 16 thymocyte hybridomas the most proximal Jα50 (ΨJα) gene was rearranged. This rearrangement was found on one chromosome only and mostly in association with a δ rearrangement on the homologous chromosome. Jα50 was rearranged to multiple target genes based on the variable size of the restriction fragments. In addition, δ rearrangement was found with a concomitant α rearrangement in the majority of hybridomas and it was not only associated with Jα50 but with several other rearranged Jα genes as well. Our results clearly demonstrate that T cell precursors are not pre‐committed to either δ or α rearrangement but a flexible progenitor responds to multiple regulatory signals during T cell differentiation and they do not support the notion that δrec‐ΨJα rearrangement is required for cell commitment to TCR α gene rearrangement.