bluuebunny/crossref_metadata_2025_split huggingface dataset:
Comparative Analysis of T Lymphocytes Recovered from the Lungs of Mice Genetically Susceptible, Resistant, and Hyperresistant toMycobacterium tuberculosis-Triggered Disease
Authors: Lyadova Irina V. , Eruslanov Evgenyi B. , Khaidukov Sergei V. , Yeremeev Vladimir V. , Majorov Konstantin B. , Pichugin Alexander V. , Nikonenko Boris V. , Kondratieva Tatiana K. , Apt Alexander S. 
Published: April 2014

AbstractGenetic control of susceptibility to tuberculosis (TB) is being intensively studied, and immune responses to mycobacteria are considerably well characterized. However, it remains largely unknown which parameters of response distinguish resistant and susceptible TB phenotypes. Mice of I/St and A/Sn inbred strains and (A/Sn × I/St)F1 hybrids were previously categorized as, respectively, susceptible, resistant, and hyperresistant to Mycobacterium tuberculosis-triggered disease. In the present work we compared parameters of lung T cell activation and response following M. tuberculosis challenge. In all mice, the disease progression was accompanied by a marked accumulation in the lungs of activated CD4+ (CD44high/CD45RBlow) and CD8+ (CD44high/CD45RB+) T cells capable of secreting IFN-γ and of activating macrophages for NO production and mycobacterial growth inhibition. However, significantly more CD8+ T cells were accumulated in the lungs of resistant A/Sn and F1 compared with I/St mice. About 80% A/Sn and F1 CD8+ cells expressed CD44high/CD45RB+ phenotype, while about 40% I/St CD8+ cells did not express CD45RB marker at week 5 of infection. In contrast, in susceptible I/St mice lung CD4+ cells proliferated much more strongly in response to mycobacterial sonicate, and a higher proportion of these cells expressed CD95 and underwent apoptosis compared with A/Sn cells. Unseparated lung cells and T cells of I/St origin produced more IL-5 and IL-10, respectively, whereas their A/Sn and F1 counterparts produced more IFN-γ following infection. F1 cells overall expressed an intermediate phenotype between the two parental strains. Such a more balanced type of immune reactivity could be linked to a better TB defense.
Generation of T Cells Specific for the Wild-Type Sequence p53264–272 Peptide in Cancer Patients: Implications for Immunoselection of Epitope Loss Variants
Authors: Hoffmann Thomas K. , Nakano Koji , Elder Elaine M. , Dworacki Grzegorz , Finkelstein Sydney D. , Appella Ettore , Whiteside Theresa L. , DeLeo Albert B. 
Published: April 2014

AbstractAlterations in the p53 gene occur frequently and can lead to accumulation of p53 protein in squamous cell carcinomas of the head and neck (SCCHN). Since accumulation of p53 is associated with enhanced presentation of wild-type sequence (wt) p53 peptides to immune cells, the development of pan vaccines against SCCHN has focused on wt p53 epitopes. We used the HLA-A2.1-restricted wt p53264–272 epitope to generate CTL from circulating precursor T cells of HLA-A2.1+ healthy donors and patients with SCCHN. Autologous peptide-pulsed dendritic cells were used for in vitro sensitization. CTL specific for the wt p53264–272 peptide were generated from PBMC obtained from two of seven normal donors and three of seven patients with SCCHN. These CTL were HLA class I restricted and responded to T2 cells pulsed with p53264–272 peptide as well as HLA-A2-matched SCCHN cell lines naturally presenting the epitope. Paradoxically, none of the tumors in the three patients who generated CTL could adequately present the epitope; two had a wt p53 genotype and no p53 protein accumulation, while the third tumor expressed a point mutation (R to H) in codon 273 that prevents presentation of the p53264–272 epitope. In contrast, patients who did not generate CTL had tumors that accumulated altered p53 and potentially could present the p53264–272 epitope. These findings suggest that in vivo, CTL specific for the wt p53264–272 peptide might play a role in the elimination of tumor cells expressing this epitope and in immunoselection of epitope-loss tumor cells. Immunoselection of tumors that become resistant to anti-p53 immune responses has important implications for future p53-based vaccination strategies.
Cutting Edge: B Cell Antigen Receptor Signaling Occurs Outside Lipid Rafts in Immature B Cells
Authors: Sproul Tim W. , Malapati Sunil , Kim Julie , Pierce Susan K. 
Published: April 2014

Abstract
B cell Ag receptor (BCR) signaling changes dramatically during B cell development, resulting in activation in mature B cells and apoptosis, receptor editing, or anergy in immature B cells. BCR signaling in mature B cells was shown to be initiated by the translocation of the BCR into cholesterol- and sphingolipid-enriched membrane microdomains that include the Src family kinase Lyn and exclude the phosphatase CD45. Subsequently the BCR is rapidly internalized into the cell. Here we show that the BCR in the immature B cell line, WEHI-231, does not translocate into lipid rafts following cross-linking nor is the BCR rapidly internalized. The immature BCR initiates signaling from outside lipid rafts as evidenced by the immediate induction of an array of phosphoproteins and subsequent apoptosis. The failure of the BCR in immature B cells to enter lipid rafts may contribute to the dramatic difference in the outcome of signaling in mature and immature B cells.
BDCA-2, BDCA-3, and BDCA-4: Three Markers for Distinct Subsets of Dendritic Cells in Human Peripheral Blood
Authors: Dzionek Andrzej , Fuchs Anja , Schmidt Petra , Cremer Sabine , Zysk Monika , Miltenyi Stefan , Buck David W. , Schmitz Jürgen 
Published: April 2014

AbstractWe have generated a panel of mAbs that identify three presumably novel human dendritic cell Ags: BDCA-2, BDCA-3, and BDCA-4. In blood, BDCA-2 and BDCA-4 are expressed on CD11c− CD123bright plasmacytoid dendritic cells, whereas BDCA-3 is expressed on small population of CD11c+ CD123− dendritic cells. All three Ags are not detectable on a third blood dendritic cell population, which is CD1c+ CD11cbright CD123dim, or on any other cells in blood. BDCA-4 is also expressed on monocyte-derived and CD34+ cell-derived dendritic cells. Expression of all three Ags dramatically changes once blood dendritic cells undergo in vitro maturation. BDCA-2 is completely down-regulated on plasmacytoid CD11c− CD123bright dendritic cells, expression of BDCA-3 is up-regulated on both plasmacytoid CD11c− CD123bright dendritic cells and CD1c+ CD11cbright CD123dim dendritic cells, and expression of BDCA-4 is up-regulated on CD1c+ CD11cbright CD123dim dendritic cells. BDCA-2 is rapidly internalized at 37°C after mAb labeling. The three presumably novel Ags serve as specific markers for the respective subpopulations of blood dendritic cells in fresh blood and will be of great value for their further analysis and to evaluate their therapeutic potential.
Tumor-Specific CD4+ T Cells Have a Major “Post-Licensing” Role in CTL Mediated Anti-Tumor Immunity
Authors: Marzo Amanda L. , Kinnear Beverley F. , Lake Richard A. , Frelinger Jeffrey J. , Collins Edward J. , Robinson Bruce W. S. , Scott Bernadette 
Published: April 2014

AbstractA number of tumor studies have indicated a link between CD4 help and the magnitude and persistence of CTL activity; however, the mechanisms underlying this have been largely unclear. To evaluate and determine the mechanisms by which CD4+ T cells synergize with CD8+ T cells to prevent tumor growth, we used the novel technique of monitoring in vivo CTL by labeling target cells with CFSE. This approach was supported by the direct visualization of CTL using peptide-MHC tetramers to follow tumor-specific T cells. The data presented demonstrate that while cotransfer of Ag-specific CD4+ T cells was not required for the generation of CTLs, because adoptive transfer of CD8+ T cells alone was sufficient, CD4+ T cells were required for the maintenance of CD8+ T cell numbers. Our data suggest that there is a correlation among the number of CD8+ T cells, in vivo CTL function, and IFN-γ production, with no evidence of a partial or nonresponsive phenotype among tetramer-positive cells. We also show that CD4+ T cells are required for CD8+ T cell infiltration of the tumor.
Interaction ofMycobacterium avium-Containing Phagosomes with the Antigen Presentation Pathway
Authors: Ullrich Heinz-Joachim , Beatty Wandy L. , Russell David G. 
Published: April 2014

AbstractPathogenic mycobacteria infect macrophages where they replicate in phagosomes that minimize contact with late endosomal/lysosomal compartments. Loading of Ags to MHC class II molecules occurs in specialized compartments with late endosomal characteristics. This points to a sequestration of mycobacteria-containing phagosomes from the sites where Ags meet MHC class II molecules. Indeed, in resting macrophages MHC class II levels decreased strongly in phagosomes containing M. avium during a 4-day infection. Phagosomal MHC class II of early (4 h) infections was partly surface-derived and associated with peptide. Activation of host macrophages led to the appearance of H2-M, a chaperon of Ag loading, and to a strong increase in MHC class II molecules in phagosomes of acute (1 day) infections. Comparison with the kinetics of MHC class II acquisition by IgG-coated bead-containing phagosomes suggests that the arrest in phagosome maturation by mycobacteria limits the intersection of mycobacteria-containing phagosomes with the intracellular trafficking pathways of Ag-presenting molecules.
Evolution of the T Cell Repertoire During Primary, Memory, and Recall Responses to Viral Infection
Authors: Blattman Joseph N. , Sourdive David J. D. , Murali-Krishna Kaja , Ahmed Rafi , Altman John D. 
Published: April 2014

AbstractMany viral infections induce a broad repertoire of CD8+ T cell responses that initiate recognition and elimination of infected cells by interaction of TCRs with viral peptides presented on infected cells by MHC class I proteins. Following clearance of the infection, &gt;90% of activated CD8+ T cells die, leaving behind a stable pool of memory CD8+ T cells capable of responding to subsequent infections with enhanced kinetics. To probe the mechanisms involved in the generation of T cell memory, we compared primary, memory, and secondary challenge virus-specific T cell repertoires using a combination of costaining with MHC class I tetramers and a panel of anti-Vβ Abs, as well as complementarity-determining region 3 length distribution analysis of TCR Vβ transcripts from cells sorted according to tetramer binding. Following individual mice over time, we found identity between primary effector and memory TCR repertoires for each of three immunodominant epitopes from lymphocytic choriomeningitis virus. During secondary responses, we found quantitative changes in epitope-specific T cell hierarchies but little evidence for changes in Vβ usage or complementarity-determining region 3 length distributions within epitope-specific populations. We conclude that 1) selection of memory T cell populations is stochastic and not determined by a distinct step of clonal selection necessary for survival from the acute responding population, and 2) maturation of the T cell repertoire during secondary lymphocytic choriomeningitis virus infection alters the relative magnitudes of epitope-specific responses but does not significantly modify the repertoire of T cells responding to a given epitope.
The Role of CD4+ T Cell Help and CD40 Ligand in the In Vitro Expansion of HIV-1-Specific Memory Cytotoxic CD8+ T Cell Responses
Authors: Ostrowski Mario A. , Justement Shawn J. , Ehler Linda , Mizell Stephanie B. , Lui Shuying , Mican Joan , Walker Bruce D. , Thomas Elaine K. , Seder Robert , Fauci Anthony S. 
Published: April 2014

AbstractCD4+ T cells have been shown to play a critical role in the maintenance of an effective anti-viral CD8+ CTL response in murine models. Recent studies have demonstrated that CD4+ T cells provide help to CTLs through ligation of the CD40 receptor on dendritic cells. The role of CD4+ T cell help in the expansion of virus-specific CD8+ memory T cell responses was examined in normal volunteers recently vaccinated to influenza and in HIV-1 infected individuals. In recently vaccinated normal volunteers, CD4+ T cell help was required for optimal in vitro expansion of influenza-specific CTL responses. Also, CD40 ligand trimer (CD40LT) enhanced CTL responses and was able to completely substitute for CD4+ T cell help in PBMCs from normal volunteers. In HIV-1 infection, CD4+ T cell help was required for optimal expansion of HIV-1-specific memory CTL in vitro in 9 of 10 patients. CD40LT could enhance CTL in the absence of CD4+ T cell help in the majority of patients; however, the degree of enhancement of CTL responses was variable such that, in some patients, CD40LT could not completely substitute for CD4+ T cell help. In those HIV-1-infected patients who demonstrated poor responses to CD40LT, a dysfunction in circulating CD8+ memory T cells was demonstrated, which was reversed by the addition of cytokines including IL-2. Finally, it was demonstrated that IL-15 produced by CD40LT-stimulated dendritic cells may be an additional mechanism by which CD40LT induces the expansion of memory CTL in CD4+ T cell-depleted conditions, where IL-2 is lacking.
Most Marginal Zone B Cells in Rat Express Germline Encoded Ig VH Genes and Are Ligand Selected
Authors: Dammers Peter M. , Visser Annie , Popa Eliane R. , Nieuwenhuis Paul , Kroese Frans G. M. 
Published: April 2014

AbstractThe present study was performed to analyze whether marginal zone B (MZ-B) cells in nondeliberately immunized adult rats are selected on basis of the specificity of their B cell receptor, and to determine to what extent memory B cells contribute to the MZ-B cell subset. To this end, the Ig PC7183 VH gene repertoire was studied among VHDJH-μ transcripts expressed in four sequential stages of B cell development, of two individual untreated adult rats. B cell subsets, i.e., pro/pre-B cells and newly formed B (NF-B) cells from bone marrow, and recirculating follicular B cells and MZ-B cells from spleen were sorted by flow cytometry. In addition, from one these rats, cells were microdissected from follicular and MZ areas of the spleen and productive PC7183 VH gene rearrangements were analyzed for the presence of somatic mutations. Sequence analysis reveals that most MZ-B cells in the adult rat, either defined by flow cytometry or by their anatomical location in the spleen, express germline encoded VH genes (naive MZ-B cells) and a minor fraction (about 20%) of the MZ-B cells carry somatic mutations (memory MZ-B cells). In addition, we show that naive MZ-B cells are a selected population of cells, both based on PC7183 VH gene repertoire and on the length of the Ig heavy (H) chain complementarity-determining region 3 (H-CDR3) region, i.e., PC7183 VHDJH-μ transcripts of MZ-B cells carry significantly shorter H-CDR3 regions than other B cell subsets.
The TNF Receptor Family Member CD30 Is Not Essential for Negative Selection
Authors: DeYoung Andrea Lina , Duramad Omar , Winoto Astar 
Published: April 2014

AbstractCD30 is a member of the TNF receptor superfamily that has been implicated in negative selection and some forms of peripheral tolerance. A previous study of CD30−/− mice in a class I-restricted H-Y TCR-transgenic mouse model showed that CD30 is essential for removal of autoreactive thymocytes. During the course of the studies of CD30 in the class II-restricted TCR-transgenic mice, we found that the absence of CD30 has no effect on negative selection. Surprisingly, we also found that the CD30 mutation does not perturb apoptosis of the autoreactive thymocytes in the class I-restricted H-Y TCR-transgenic model. The minimal role of CD30 in negative selection and other recent data are discussed.
Enteric Infection Acts as an Adjuvant for the Response to a Model Food Antigen
Authors: Shi Hai Ning , Liu Hao Yuan , Nagler-Anderson Cathryn 
Published: April 2014

AbstractOral administration of soluble protein Ags typically induces Ag-specific systemic nonresponsiveness. However, we have found that feeding a model food protein, OVA, to helminth-infected mice primes for a systemic OVA-specific Th2 response. In this report we show that, in addition to creating a Th2-priming cytokine environment, helminth infection up-regulates costimulatory molecule expression on mucosal, but not peripheral, APCs. To examine the consequences of mucosal infection for the T cell response to orally administered Ag, we adoptively transferred transgenic, OVA-specific, T cells into normal mice. We found that helminth infection enhances the expansion and survival of transgenic T cells induced by Ag feeding. Transfer of 5,6-carboxyfluorescein diacetate succinimidyl ester-labeled donor cells showed that T cell proliferation in response to Ag feeding takes place primarily in the mesenteric lymph nodes. Upon subsequent peripheral exposure to Ag in adjuvant, the proliferative capacity of the transferred transgenic T cells was reduced in noninfected mice that had been fed OVA. Helminth infection abrogated this reduction in proliferative capacity. Our data suggests that enteric infection can act as an adjuvant for the response to dietary Ags and has implications for allergic responses to food and the efficacy of oral vaccination.
Role of TNF Receptor-Associated Factor 2 and p38 Mitogen-Activated Protein Kinase Activation During 4-1BB-Dependent Immune Response
Authors: Cannons Jennifer L. , Choi Yongwon , Watts Tania H. 
Published: April 2014

Abstract4-1BB is a costimulatory member of the TNFR family, expressed on activated CD4+ and CD8+ T cells. Previous results showed that 4-1BB-mediated T cell costimulation is CD28-independent and involves recruitment of TNFR-associated factor 2 (TRAF2) and activation of the stress-activated protein kinase cascade. Here we describe a role for the p38 mitogen-activated protein kinase (MAPK) pathway in 4-1BB signaling. Aggregation of 4-1BB alone induces p38 activation in a T cell hybridoma, whereas, in normal T cells, p38 MAPK is activated synergistically by immobilized anti-CD3 plus immobilized 4-1BB ligand. 4-1BB-induced p38 MAPK activation is inhibited by the p38-specific inhibitor SB203580 in both a T cell hybridoma and in murine T cells. T cells from TRAF2 dominant-negative mice are impaired in 4-1BB-mediated p38 MAPK activation. A link between TRAF2 and the p38 cascade is provided by the MAPK kinase kinase, apoptosis-signal-regulating kinase 1. A T cell hybrid transfected with a kinase-dead apoptosis-signal-regulating kinase 1 fails to activate p38 MAPK in response to 4-1BB signaling. To assess the role of p38 activation in an immune response, T cells were stimulated in an MLR in the presence of SB203580. In a primary MLR, SB203580 blocked IL-2, IFN-γ, and IL-4 secretion whether the costimulatory signal was delivered via 4-1BB or CD28. In contrast, following differentiation into Th1 or Th2 cells, p38 inhibition blocked IL-2 and IFN-γ without affecting IL-4 secretion. Nevertheless, IL-4 secretion by Th2 cells remained costimulation-dependent. Thus, critical T cell signaling events diverge following Th1 vs Th2 differentiation.
APC Stimulated by CpG Oligodeoxynucleotide Enhance Activation of MHC Class I-Restricted T Cells
Authors: Warren Thomas L. , Bhatia Sudershan K. , Acosta Anna M. , Dahle Christopher E. , Ratliff Timothy L. , Krieg Arthur M. , Weiner George J. 
Published: April 2014

AbstractOligonucleotides containing unmethylated CpG motifs (cytosine-phosphorothioate-guanine oligodeoxynucleotide (CpG ODN)) are potent immunostimulatory agents capable of enhancing the Ag-specific Th1 response when used as immune adjuvants. We evaluated the cellular mechanisms responsible for this effect. Development of a CTL response was enhanced when mice were immunized with peptide-pulsed dendritic cells (DCs) treated with CpG ODN. However, in vitro, CpG ODN had no direct effect on highly purified T cells. In vitro, CpG ODN treatment of peptide- or protein-pulsed DCs enhanced the ability of the DCs to activate class I-restricted T cells. The presence of helper T cells enhanced this effect, indicating that treatment with CpG ODN does not obviate the role of T cell help. The enhanced ability of CpG ODN-treated DCs to activate T cells was present but blunted when DCs derived from IL-12 knockout mice were used. Fixation of Ag-pulsed, CpG ODN-treated DCs limited their ability to activate T cells. In contrast, fixation had little effect on DC activation of T cells when DCs were not exposed to CpG ODN. This indicates that production of soluble factors by DCs stimulated with CpG ODN plays a particularly important role in their ability to activate class I-restricted T cells. We conclude that CpG ODN enhances the development of a cellular immune response by stimulating APCs such as DCs, to produce IL-12 and other soluble factors.
The Quantity of TCR Signal Determines Positive Selection and Lineage Commitment of T Cells
Authors: Watanabe Norihiko , Arase Hisashi , Onodera Makoto , Ohashi Pamela S. , Saito Takashi 
Published: April 2014

AbstractIt is generally accepted that the avidity of TCR for self Ag/MHC determines the fate of immature thymocytes. However, the contribution of the quantity of TCR signal to T cell selection has not been well established, particularly in vivo. To address this issue, we analyzed DO-TCR transgenic CD3ζ-deficient (DO-Tg/ζKO) mice in which T cells have a reduced TCR on the cell surface. In DO-Tg/ζKO mice, very few CD4 single positive (SP) thymocytes developed, indicating that the decrease in TCR signaling resulted in a failure of positive selection of DO-Tg thymocytes. Administration of the peptide Ag to DO-Tg/ζKO mice resulted in the generation of functional CD4 SP mature thymocytes in a dose-dependent manner, and, unexpectedly, DO-Tg CD8 SP cells emerged at lower doses of Ag. TCR signal-dependent, sequential commitment from CD8+ SP to CD4+ SP was also shown in a class I-restricted TCR-Tg system. These in vivo analyses demonstrate that the quantity of TCR signal directly determines positive and negative selection, and further suggest that weak signal directs positively selected T cells to CD8 lineage and stronger signal to CD4 lineage.
The VλJλ Repertoire in Human Fetal Spleen: Evidence for Positive Selection and Extensive Receptor Editing
Authors: Lee Jisoo , Monson Nancy L. , Lipsky Peter E. 
Published: April 2014

AbstractVλJλ rearrangements obtained from genomic DNA of individual IgM+ B cells from human fetal spleen were analyzed. A nonrandom pattern of λ gene rearrangements that differed from the adult Vλ repertoire was found. The Vλ distal genes 8A and 4B were absent from the nonproductive fetal repertoire, whereas 2E and 3L were overrepresented and 1B was underrepresented in the productive fetal repertoire. Positive selection of the Vλ gene, 2E, along with Vλ rearrangements employing homologous VλJλ joins were observed in the fetal, but not in the adult Vλ repertoire. Overrepresentation of Jλ distal cluster C genes rearranging to the Vλ distal J segment, Jλ7, in both productive and nonproductive fetal repertoires suggested that receptor editing/replacement was more active in the fetus than in adults. Numerous identical VλJλ junctions were observed in both the productive and nonproductive repertoire of the fetus and adult, but were significantly more frequent in the productive repertoire of the fetus, suggesting expansion of B cells expressing particular λ-light chains in both stages of development, with more profound expansion in the fetal repertoire. Notably, B cells expressing identical λ-light chains expressed diverse heavy chains. These data demonstrate that three mechanisms strongly influence the shaping of the human fetal λ-chain repertoire that are less evident in the adult: positive selection, receptor editing, and expansion of B cells expressing specific λ-light chains. These events imply that the expressed fetal repertoire is shaped by exposure to self Ags.