bluuebunny/crossref_metadata_2025_split huggingface dataset:
Phagocyte‐induced antigen‐specific activation of unprimed CD8+ T cells in vitro
Authors: De Bruijn Marloes L. H. , Jackson Michael R. , Peterson Per A. 
Published: March 2007

AbstractThe strict segregation of the major histocompatibility complex (MHC) class I and class II loading pathways has been challenged by recent reports indicating that MHC class I molecules can acquire antigen in the phagocytic pathway. We now show that this alternative peptide loading pathway can be used efficiently to generate macrophages able to activate unprimed antigen‐specific cytotoxic T cells in vitro. Short peptides (8–11 residues), administered in the phagocytic pathway at nanomolar concentrations, were found to be effective in specifically activating naïve cytotoxic T lymphocytes (CTL) in vitro, but longer peptides or whole protein antigen were not. Whole protein antigen coated on beads did, however, render macrophages susceptible to lysis by an antigen‐specific CTL clone. This indicates that proteolysis in the phagocytic pathway has limited capability for class I‐restricted presentation. We propose a model for class I loading in the phagocytic pathway consisting of direct trafficking of nascent MHC class I from the trans‐Golgi network to the phagosome, prior to appearance at the cell surface, and the use of the narrow cavity between bead and phagosomal membrane as a peptide exchange/loading compartment. Targeting immunogenic class I‐binding peptide to the phagocytic pathway of macrophages facilitates presentation in association with class I. This is a useful tool for CTL response induction in vitro.
T lymphocyte development in p56lck deficient mice: allelic exclusion of the TcR β locus is incomplete but thymocyte development is not restored by TcR β or TcR αβ transgenes
Authors: Wallace Valerie A. , Kawai Kazuhiro , Levelt Christiaan N. , Kishihara Kenji , Molina Thierry , Timms Emma , Pircher Hanspeter , Penninger Josef , Ohashi Pamela S. , Eichmann Klaus , Mak Tak W. 
Published: March 2007

AbstractThe protein tyrosine kinase, p56lck, is involved in signal transduction in mature T cells and in the molecular events controlling early thymocyte differentiation. Thymuses of mice deficient for p56lck expression (p56lck‐/‐) consist of immature CD4‐CD8‐ double‐negative (DN) and CD4+CD8+ double‐positive (DP) thymocytes and are severely reduced in total cell number. In this report we have studied DN thymocytes from p56lck‐/‐ mice and found an increase in the proportion of the CD44−CD25+ subset, suggesting that transit through this stage, which is known to require T cell receptor (TcR) β expression, may be delayed in the absence of p56lck expression. In addition, the expression of a transgenic TcR β chain or TcR αβ pair did not restore thymic development in p56lck‐/‐ mice. However, in contrast to mice expressing a dominant negative isoform of p56lck in which DP thymocytes do not develop, DP thymocytes still develop in nontransgenic and TcR transgenic p56lck‐/‐ mice. These results demonstrate that expansion of the DP subset is impaired in p56lck‐/‐ mice. In contrast, allelic exclusion is not severely compromised. Although there was an increase in the number of peripheral T cells expressing more than one Vβ chain in TcR transgenic p56lck‐/‐ mice, we found that inhibition of endogenous TcR β gene rearrangement was almost complete in thymocytes of Vβ transgenic p56lck‐/‐ mice and we could not detect any peripheral T cells that expressed more than one Vβ chain in non‐transgenic p56lck‐/‐ mice.
Restoration of endogenous antigen processing in Burkitt's lymphoma cells by Epstein‐Barr virus latent membrane protein‐1: coordinate up‐regulation of peptide transporters and HLA‐class I antigen expression
Authors: Rowe Martin , Khanna Rajiv , Jacob Catherine A. , Argaet Victor , Kelly Adrian , Powis Stephen , Belich Monica , Groom‐Carter Deborah , Lee Steve , Burrows Scott R. , Trowsdale John , Moss Denis J. , Rickinson Alan B. 
Published: March 2007

AbstractGroup I Burkitt lymphoma (BL) lines retaining the original BL tumor cell phenotype are unable to present endogenously expressed antigens to HLA class I‐restricted cytotoxic T cells (CTL) but can be recognized if the relevant HLA class I/peptide epitope complex is reconstituted at the cell surface by exogenous addition of synthetic target peptide. Endogenous antigen‐processing function is restored in BL lines that have undergone Epstein‐Barr virus (EBV)‐induced drift in culture to the group III phenotype typically displayed by EBV‐transformed lymphoblastoid cell lines (LCL) of normal B cell origin. We compared group I versus group III cells for their expression of proteasome components, transporter proteins and HLA‐class I antigens, all of which are thought to be involved in the endogenous antigen processing pathway. By Western blot analysis, there were not consistent differences in the low molecular mass protein subunits of proteasomes (lmp)‐2, lmp‐7 and δ, although the mb‐1 proteasome subunit was regularly present at higher levels in group I BL lines relative to group III lines or LCL. By contrast there were marked differences in the expression of peptide transporter‐associated proteins (Tap), with down‐regulation of Tap‐1 and Tap‐2 in 8/8 and 7/8 group I BL lines, respectively. Surface levels of HLA class I antigens were also consistently lower in group I cells; this was not associated with an intracellular accumulation of free HLA heavy chains, such as is seen in the Tap‐deficient T2 processing‐mutant line, but instead reflected a reduced rate of HLA class I synthesis in group I cells. Analysis of EBV gene transfectants of the B lymphoma lines BJAB and BL41 showed that the virus‐encoded latent membrane protein‐1 (LMP1), which is one of several EBV antigens expressed in group III but not in group I cells, was uniquely able to up‐regulate expression both of the Tap proteins and HLA class I. Furthermore, this was accompanied by a restoration of antigen‐processing function as measured by the ability of these cells to present an endogenously expressed viral antigen to CTL. These effects of LMP1 were similar to those induced in the same cell lines by interferon‐γ treatment. The results implicate both Tap and HLA class I expression as factors limiting the antigen‐processing function of BL cells, and suggest that the accessibility of other EBV‐associated malignancies to CTL surveillance may be critically dependent upon their LMP1 status.
Oral tolerance to haptens: intestinal epithelial cells from 2,4‐dinitrochlorobenzene‐fed mice inhibit hapten‐specific T cell activation in vitro
Authors: Galliaerde Veronique , Desvignes Cyril , Peyron Eric , Kaiserlian Dominique 
Published: March 2007

AbstractThe mechanisms underlying the induction of immunological tolerance after feeding soluble exogenous antigens, including proteins and haptens, are still unclear. Using a model of oral tolerance to the contact‐sensitizing hapten 2,4‐dinitrochlorobenzene (DNCB), we have compared the ability of intestinal epithelial cells and of Peyer's patch APC to present DNCB in vitro or ex vivo after oral feeding, to specific peripheral lymph node T cells from DNCB‐sensitized mice. In contrast to Peyer's patch APC, which induce efficient hapten‐specific T cell activation upon exposure to the hapten either in vitro or in vivo, mature MHC class‐II‐positive intestinal epithelial cells were unable to induce T cell activation in either case. Interestingly, enterocytes from DNCB‐fed mice exerted a dramatic inhibitory effect on the proliferative response of hapten‐primed T cells in response to dinitrobenzene sulfonate presented by syngeneic spleen cells. This inhibitory effect, which was also observed with supernatant of intestinal epithelial cells from DNCB‐fed mice, could be reversed by neutralizing anti‐transforming growth factor (TGF)‐β antibodies. In addition, pre‐incubation of hapten‐sensitized T cells with enterocytes from DNCB‐fed mice induced T cell anergy, which could be reversed by exogenous interleukin‐2 or interleukin‐4. These data demonstrate that intestinal epithelial cells activated in vivo by oral administration of DNCB are able to block proliferation of activated T cells through secretion of immunosuppressive cytokines such as TGF‐β. It is proposed that intestinal epithelial cells may play a significant role in oral tolerance by limiting T cell‐mediated hypersensitivity responses.
CD28/CTLA‐4 ligands: the gene encoding CD86 (B70/B7.2) maps to the same region as CD80 (B7/B7.1) gene in human chromosome 3q13‐q23
Authors: Fernández‐Ruiz Elena , Somoza Chamorro , Sánchez‐Madrid Francisco , Lanier Lewis L. 
Published: March 2007

AbstractCD86 (B70/B7.2) is an antigen of the immunoglobulin superfamily expressed on monocytes, dendritic cells and activated B,T, and natural killer cells. CD86 was recently identified as a second ligand for the T cell antigens CD28 and CTLA‐4, and plays an important role in the co‐stimulation of T cells in a primary immune response. We report here the assignment of the CD86 gene to human chromosome 3 using Southern blot analysis on a panel of hamster × human somatic cell hybrid genomic DNA. Fluorescence hybridization in situ on metaphase chromosomes coupled with GTG banding (G‐bands by trypsin using Giemsa staining) confirmed this assignment and localized the CD86 gene to 3q13‐q23 region. The CD86 gene is, therefore, located in the proximity of the CD80 (B7/B7.1) gene, the first identified ligand for CD28 and CTLA‐4, previously mapped to chromosome 3q13.3‐q21. Deletions, inversions and insertions of chromosome 3q21‐q26, as well as translocations of 3q21 with other chromosomes have been described in many cases of acute myeloid leukemia (AML), acute nonlymphocytic leukemia (ANLL), chronic myeloid leukemia (CML) and myelodisplastic syndromes (MDS), suggesting that this region contains several genes involved in the leukemic process.
Selection of T cell receptor variable gene‐encoded amino acids on the third binding site loop: a factor influencing variable chain selection in a T cell response
Authors: Callan Margaret F. C. , Reyburn Hugh T. , Bowness Paul , Rowland‐Jones Sarah , Bell John I. , McMichael Andrew J. 
Published: March 2007

AbstractThe 3′ end of the T cell receptor Vβ7.1 gene contains the five nucleotides CAAGA between the broadly conserved consensus sequence of nucleotides TGC/T GCC AGC AGC (which encode cysteine, alanine, serine and serine at positions 92–95 of the β chain) and the heptamer that signals rearrangement. These nucleotides are frequently preserved during gene rearrangement, resulting in the common presence of glutamine at position 96 and of aspartate or glutamate at position 97 of the Vβ7.1 chain CDR3 loop in peripheral blood lymphocytes. There is selection of Vβ7.1 and of the Vβ7.1 gene‐encoded glutamate at position 97 of the β chain CDR3 loop in the cytotoxic T lymphocyte response to the HLA B2705‐restricted influenza A nucleoprotein epitope SRYWAIRTR. Our results indicate that selection of Vβ7.1 gene‐encoded amino acid residues on CDR3 loops may be one factor driving selection of Vβ7.1 in this response.
Phosphotyrosine‐dependent association between CD22 and protein tyrosine phosphatase 1C
Authors: Campbell Mary‐Ann , Klinman Norman R. 
Published: March 2007

AbstractCD22 is a B lymphocyte‐specific cell surface glycoprotein that becomes tyrosine phosphorylated upon B cell activation. To determine if tyrosine phosphorylated CD22 couples signaling through membrane immunoglobulin (mIg) to downstream elements, we looked for molecules coprecipitating with CD22 after anti‐Ig stimulation. We found that a 60‐kDa molecule was stably associated with CD22 following cross‐linking of mIg and have identified this molecule as protein tyrosine phosphatase 1C (PTP1C). The association between PTP1C and CD22 is dependent upon tyrosine phosphorylation of CD22, but does not appear to require tyrosine phosphorylation of PTP1C.
The interaction of beta 2‐microglobulin (β2m) with mouse class I major histocompatibility antigens and its ability to support peptide binding. A comparison of human and mouse β2m
Authors: Pedersen Lars Ø. , Stryhn Anette , Holtet Thor L. , Etzerodt Mikael , Gerwien Jens , Nissen Mogens H. , Thøgersen Hans C. , Buus Seren 
Published: March 2007

AbstractThe function of major histocompatibility complex (MHC) class I molecules is to sample peptides derived from intracellular proteins and to present these peptides to CD8+ cytotoxic T lymphocytes. In this paper, biochemical assays addressing MHC class I binding of both peptide and β2‐microglobulin (β2m) have been used to examine the assembly of the trimolecular MHC class I/β2m/peptide complex. Recombinant human β2m and mouse β2m2 have been generated to compare the binding of the two β2m to mouse class I. It is frequently assumed that human β2m binds to mouse class I heavy chain with a much higher affinity than mouse β2m itself. We find that human β2m only binds to mouse class I heavy chain with slightly (about 3‐fold) higher affinity than mouse β2m. In addition, we compared the effect of the two β2m upon peptide binding to mouse class I. The ability of human β2m to support peptide binding correlated well with its ability to saturate mouse class I heavy chains. Surprisingly, mouse β2m only facilitated peptide binding when mouse β2m was used in excess (about 20‐fold) of what was needed to saturate the class I heavy chains. The inefficiency of mouse β2m to support peptide binding could not be attributed to a reduced affinity of mouse β2m/MHC class I complexes for peptides or to a reduction in the fraction of mouse β2m/MHC class I molecules participating in peptide binding. We have previously shown that only a minor fraction of class I molecules are involved in peptide binding, whereas most of class I molecules are involved in β2m binding. We propose that mouse β2m interacts with the minor peptide binding (i.e. the “empty”) fraction with a lower affinity than human β2m does, whereas mouse and human β2m interact with the major peptide‐occupied fraction with almost similar affinities. This would explain why mouse β2m is less efficient than human β2m in generating the peptide binding moiety, and identifies the empty MHC class I heavy chain as the molecule that binds human β2m preferentially.
Soluble form of the human high‐affinity receptor for IgE inhibits recurrent allergic reaction in a novel mouse model of type I allergy
Authors: Naito Koji , Hirama Minoru , Okumura Ko , Ra Chisei 
Published: March 2007

AbstractThe recombinant soluble form of the human high‐affinity receptor for IgE α subunit (sFcϵRIα) is able to block the binding of IgE to the cell surface FcϵRI and prevent the activation of mast cells and basophils. To evaluate its anti‐allergic effects in vivo, we established a novel model for type I allergy by transplanting antigen‐specific IgE‐secreting hybridomas into syngeneic mice. The hybridomas continuously produced anti‐2,4,6‐trinitrophenyl IgE in vivo, and ear swelling responses could be elicited upon applying picryl chloride to the ears of these mice, which reached their maximum 1–2 h after the antigen challenge. The second swelling response, in extent comparable to the first response, was induced by the second antigen challenge several days later. When the sFcϵRIα was intravenously administered before the first challenge and periodically betweeen the first and the second challenges, the ear swelling response to the second challenge, but not to the first challenge, was suppressed almost completely. Immunohistochemical examination revealed that treatment with the sFcϵRIα blocked the binding of IgE to the cell surface IgE receptors after the first challenge. Thus, our results indicate that the sFcϵRIα suppresses recurrent allergic reactions by preventing IgE binding to the cell surface FcϵRI.
Invriant chain peptides enhancing or inhibiting the presentation of antigenic peptides by major histocompatibility complex class II molecules
Authors: Adams Sharlene , Humphreys Robert E. 
Published: March 2007

AbstractTwo soluble invariant chain (Ii) peptides with overlapping sequences had contrasting effects on the presentation of antigenic peptides by murine Ad, Ak, Ed, and Ek major histocompatibility complex (MHC) class II molecules. Naturally produced class II‐associated invariant chain peptides human (h)Ii81–104/murine (m)Ii80–103 inhibited antigen presentation on these MHC class II alleles in a manner consistent with competitive inhibition. The Ii‐4 peptides hIi77–92/mIi76–91 enhanced presentation of antigenic peptides on I‐E class II alleles by promoting the exchange of peptides at the cell surface. Treatment of antigenpresenting cells (APC) with Ii‐4 before the addition of antigenic peptide greatly enhanced subsequent T cell responses, while treatment of APC with Ii–4 after antigenic peptide binding decreased subsequent T cell responses. The hIi81–104 and mIi80–103 peptides inhibited T cell responses in both types of assays. The binding of biotinylated antigenic peptide to MHC class II‐transfected L cells, as measured by flow cytometry, was inhibited by mIi80‐103 and enhanced by mIi‐4. Segments of Ii fragments remaining associated with MHC class II, or released Ii peptides, appear to regulate the formation of stable antigenic peptide/MHC class II complexes either positively or negatively through interactions at or near the antigenic peptide binding site. These findings open a pathway for the design of novel therapeutics based on the structure and function of natural and rationally designed fragments of Ii.
Expression and functional significance of an activation‐dependent epitope of the β1 integrins in chronic inflammatory diseases
Authors: Arroyo Alicia G. , García‐Vicuña Rosario , Marazuela Mónica , Yednock Ted A. , González‐Amaro Roberto , Sánchez‐Madrid Francisco 
Published: March 2007

AbstractThe avidity of VLA integrins for their ligands can be increased by their transition to an active conformational state. This conformational change can be detected with a novel monoclonal antibody (mAb), termed 15/7, that recognizes an activation‐dependent conformational epitope on the common β1 polypeptide of different VLA αβ1 integrins. In an attempt to understand the possible role of the active conformational state of β1 integrins in vivo, we first investigated the expression of 15/7 epitope on T lymphocytes from patients with chronic inflammatory joint diseases. An enhanced expression of the 15/7 epitope was found in the synovial fluid (SF) T lymphocytes from these patients as compared to their peripheral blood (PB) T cells. The effect of different cytokines on the appearance of the 15/7 activation epitope in PB T lymphocytes was subsequently analyzed; interferon‐γ, interleukin‐2 and, to a lower extent, tumor necrosis factor‐α were able to induce an increased expression of the 15/7 epitope. This enhanced 15/7 expression correlated with a higher binding ability to fibronectin of cytokine‐activated T cells. The presence of this activation epitope was detected in a small proportion of T lymphocytes scattered within inflammatory foci of synovial membrane from rheumatoid arthritis and thyroid glands from Hashimoto's chronic thyroiditis. We then analyzed the possible role of 15/7 epitope expression on cell adhesion in vitro. Immunofluorescence studies showed that the 15/7 epitope displayed a spot‐like distribution, selectively decorating adhesive contacts of U‐937 myelomonocytic cells attached to the 80 kDa proteolytic fragment of fibronectin (FN80). Furthermore, the anti‐β1 15/7 mAb was able to induce both T lymphocyte, Jurkat and U‐937 cellular binding and spreading on FN80. Altogether these results indicate that an activated conformation of β1 integrins is detected in vivo in lymphocyte infiltrates from chronic inflammatory conditions. The active conformations of β1 integrins are regulated by physiologic mediators such as cytokines, play an important role in cellular attachment and spreading, and appear to be involved in the development of inflammatory processes.
TAP1‐independent loading of class I molecules by exogenous viral proteins
Authors: Bachmann Martin F. , Oxenius Annette , Pircher Hanspeter , Hengartner Hans , Ashton‐Richardt Philip A. , Tonegawa Susumu , Zinkernagel Rolf M. 
Published: March 2007

AbstractPresentation of peptides derived from endogenous proteins on class I molecules needs functional TAP peptide transporters. To reveal whether class I‐associated presentation of exogenous proteins also required the presence of TAP transporters, we assessed in vitro the ability of spleen cells and macrophages from TAP1‐deficient mice (TAP1−/−) to present peptides derived from exogenous recombinant viral proteins on their class I molecules. We found that recombinant glycoand nucleoprotein from lymphocytic choriomeningitis virus and nucleoprotein of vesicular stomatitis virus were presented as efficiently by TAP1 −/− cells as by control cells. Peptide regurgitation was not involved. Since particulate, nonreplicating antigens can efficiently prime anti‐viral cytotoxic T cells in vivo, this new, TAP‐independent pathway of class I‐associated antigen presentation may be applicable for vaccine strategies.
Cloning of ATAC, an activation‐induced, chemokine‐related molecule exclusively expressed in CD8+ T lymphocytes
Authors: Müller Sabine , Dorner Brigitte , Korthäuer Ulf , Mages Hans W. , D'Apuzzo Massimo , Senger Gabriele , Kroczek Richard A. 
Published: March 2007

AbstractA cDNA clone, designated ATAC, was isolated from a collection of human T cell activation genes. Analysis of tissue distribution determined that ATAC mRNA of approxiamtely 0.9 kb is exclusively expressed in activated CD8+ T cells. Induction of the ATAC gene requires stimulation by both phorbol 12‐myristate 13‐acetate and Ca2+ ionophore A23187 (“two‐signal gene”) and is fully abrogated by the immunosuppressive agent cyclosporin A. Upon stimulation, ATAC mRNA is detectable within 30 min, maximal expression is seen after 4 h. The polypeptide encoded by the open reading frame of ATAC mRNA is 114 amino acids long with a calculated Mr of 12.52 kDa. The structural features predict the cleavage and secretion of a mature ATAC protein of approximately 10 kDa from the 12.52‐kDa precursor. ATAC is highly similar to a very recently identified murine molecule designated lymphotactin both at the cDNA (73.8% identity) and the protein (61.4% identity) levels, and related to members of the C‐C and C‐X‐C chemokine families. Two variants of the ATAC protein were expressed and tested for chemotaxis and Ca2+ release on a variety of target cells. The ATAC gene was located to chromosome 1q23.
A soluble form of TRAP (CD40 ligand) is rapidly released after T cell activation
Authors: Graf Daniel , Müller Sabine , Korthäuer Ulf , van Kooten Cees , Weise Christoph , Kroczek Richard A. 
Published: March 2007

AbstractTRAP is a tumor necrosis factor (TNF)‐related, 33‐kDa type II transmembrane protein almost exclusively expressed on the surface of activated CD4+ T lymphocytes. Interaction of TRAP with CD40 on B cells is of paramount importance for immunoglobulin class switching and subsequent synthesis of IgG, IgA or IgE in vivo. We now provide evidence that activated T cells not only express cell membrane‐associated TRAP but also a soluble form of TRAP (sTRAP). After generating monoclonal antibodies against TRAP and establishing a TRAP‐specific enzyme‐linked immunosorbent assay we were able to detect substantial amounts of sTRAP in the supernatants of activated T cells. The onset and rate of sTRAP release was found to parallel the expression of TRAP on the cell surface. sTRAP, an 18‐kDa protein, is generated by proteolytic proccessing of full‐length TRAP in an intracellular compartment. Starting with methionine 113 of fulllength TRAP, sTRAP lacks the transmembrane region and a part of the extracellular domain but contains the entire TNF‐α homology region and can, therefore, bind to CD40. Like other members of the TNF superfamily (e.g. TNF‐α, Fas/APO‐1 ligand), TRAP thus has the potential to be biologically active not only in a transmembrane form but also as a soluble molecule.