bluuebunny/crossref_metadata_2025_split huggingface dataset:
T Cell Activity After Dendritic Cell Vaccination Is Dependent on Both the Type of Antigen and the Mode of Delivery
Authors: Serody Jonathan S. , Collins Edward J. , Tisch Roland M. , Kuhns Jennifer J. , Frelinger Jeffrey A. 
Published: April 2014

AbstractPrevious work in both human and animal models has shown that CTL responses can be generated against proteins derived from tumors using either peptide-pulsed dendritic cells (DCs) or nucleic acids from the tumor transfected into autologous DCs. Despite the efficacy of this approach for vaccine therapy, many questions remain regarding whether the route of administration, the frequency of administration, or the type of Ag is critical to generating T cell responses to these Ags. We have investigated methods to enhance CTL responses to a peptide derived from the human proto-oncogene HER-2/neu using mice containing a chimeric HLA A2 and H2Kb allele. Changes in amino acids in the anchor positions of the peptide enhanced the binding of the peptide to HLA-A2 in vitro, but did not enhance the immunogenicity of the peptide in vivo. In contrast, when autologous DCs presented peptides, significant CTL activity was induced with the altered, but not the wild-type, peptide. We found that the route of administration affected the anatomic site and the time to onset of CTL activity, but did not impact on the magnitude of the response. To our surprise, we observed that weekly administration of peptide-pulsed DCs led to diminishing CTL activity after 6 wk of treatment. This was not found in animals injected with DCs every 3 wk for six treatments or in animals initially given DCs weekly and then injected weekly with peptide-pulsed C1R-A2 transfectants.
Cutting Edge: OFF Cycling of TNF Production by Antigen-Specific CD8+ T Cells Is Antigen Independent
Authors: Badovinac Vladimir P. , Corbin Gail A. , Harty John T. 
Published: April 2014

AbstractAlthough they are known for their capacity to kill infected cells, Ag-specific CD8+ T cells elaborate other effector mechanisms, including TNF and IFN-γ, that contribute to defense against infection. Ag-specific CD8+ T cells rapidly turn ON and turn OFF IFN-γ production in direct response to Ag contact, presumably to minimize the potential immunopathology that could result from inappropriate secretion of this inflammatory mediator. In this study, we show, using in vitro propagated and directly ex vivo-analyzed Ag-specific CD8+ T cells, that in contrast to Ag-dependent ON/OFF cycling of IFN-γ production, the cessation of TNF production by the same IFN-γ producing cells is rapid and Ag independent.
Cutting Edge: TLR2-Deficient and MyD88-Deficient Mice Are Highly Susceptible toStaphylococcus aureusInfection
Authors: Takeuchi Osamu , Hoshino Katsuaki , Akira Shizuo 
Published: April 2014

AbstractToll-like receptor (TLR) family acts as pattern recognition receptors for pathogen-specific molecular patterns. We previously showed that TLR2 recognizes Gram-positive bacterial components whereas TLR4 recognizes LPS, a component of Gram-negative bacteria. MyD88 is shown to be an adaptor molecule essential for TLR family signaling. To investigate the role of TLR family in host defense against Gram-positive bacteria, we infected TLR2- and MyD88-deficient mice with Staphylococcus aureus. Both TLR2- and MyD88-deficient mice were highly susceptible to S. aureus infection, with more enhanced susceptibility in MyD88-deficient mice. Peritoneal macrophages from MyD88-deficient mice did not produce any detectable levels of cytokines in response to S. aureus. In contrast, TLR2-deficient macrophages produced reduced, but significant, levels of the cytokines, and TLR4-deficient macrophages produced the same amounts as wild-type cells, indicating that S. aureus is recognized not only by TLR2, but also by other TLR family members except for TLR4.
Cutting Edge: An Essential Role for Notch-1 in the Development of Both Thymus-Independent and -Dependent T Cells in the Gut
Authors: Wilson Anne , Ferrero Isabel , MacDonald H. Robson , Radtke Freddy 
Published: April 2014

AbstractWhereas most T cells arise in the thymus, a distinct lineage of extrathymically derived T cells is present in the gut mucosa. The developmental origin of extrathymic T cells is poorly understood. We show here that Notch-1, a transmembrane receptor involved in T cell fate specification of bipotential T/B precursors in the thymus, is absolutely required for the development of extrathymic (as well as thymus-derived) mature T cells in the intestinal epithelium. In the absence of Notch-1, CD117+ T cell precursors are relatively more abundant in the gut than the thymus, whereas immature B cells accumulate in the thymus but not the gut. Collectively, these data demonstrate that Notch-1 is essential for both thymic and extrathymic T cell fate specification and further suggest that bipotential T/B precursors that do not receive a Notch-1 signal adopt a B cell fate in the thymus but become developmentally arrested in the gut.
Cutting Edge: Targeted Disruption of the C3a Receptor Gene Demonstrates a Novel Protective Anti-Inflammatory Role for C3a in Endotoxin-Shock
Authors: Kildsgaard Jens , Hollmann Travis J. , Matthews Kirstin W. , Bian Ka , Murad Ferid , Wetsel Rick A. 
Published: April 2014

AbstractThe complement anaphylatoxin C3a, on binding the C3aR, mediates numerous proinflammatory activities. In addition, recent in vitro studies with C3a have implicated C3aR as a possible anti-inflammatory receptor. Because of its possible dual role in modulating the inflammatory response, it is uncertain whether C3aR contributes to the pathogenesis of endotoxin shock. Here, the targeted-disruption of the C3aR in mice is reported. These mice exhibit an enhanced lethality to endotoxin shock with a pronounced gene dosage effect. In addition, the plasma concentration of IL-1β was significantly elevated in the C3aR−/− mice compared with their littermates following LPS challenge. These findings demonstrate an important protective role for the C3aR in endotoxin shock and indicate that, in addition to its traditionally accepted functions in mediating inflammation, the C3aR also acts in vivo as an anti-inflammatory receptor by attenuating LPS-induced proinflammatory cytokine production.
Lymphocytes Lacking IκB-α Develop Normally, But Have Selective Defects in Proliferation and Function
Authors: Chen Chih-Li , Singh Nagendra , Yull Fiona E. , Strayhorn David , Van Kaer Luc , Kerr Lawrence D. 
Published: April 2014

AbstractNF-κB has been implicated in the development, activation, and function of B and T lymphocytes. We have evaluated the in vivo effects of deletion of IκB-α, a major inhibitor of NF-κB, on lymphocyte development, proliferation, and function. To elucidate the long term role of IκB-α in lymphocytes, fetal liver cells of 14.5-day-old IκB-α−/− or wild-type embryos were transplanted into irradiated recombinase-activating gene-2-deficient mice. Within 4 wk, the IκB-α−/− fetal liver cells reconstitute mature B and T cell populations in the recipients comparable to those produced by wild-type fetal liver cells. However, the proliferative responses of IκB-α−/− B cells are enhanced, whereas those of IκB-α−/− T cells are reduced. The levels of IgG1, IgG2a, IgA, and IgE produced by IκB-α−/− B cells are elevated relative to those produced by IκB-α+/+ or IκB-α+/−. Moreover, the specific immune responses to OVA and the generation of germinal centers are impaired in recipients of IκB-α−/− fetal liver cells. These results indicate that IκB-α plays a vital role in signal transduction pathways regulating lymphocyte proliferation and also in the production of specific Ig isotypes.
Dermal Microvascular Endothelial Cells Express the 180-kDa Macrophage Mannose Receptor In Situ and In Vitro
Authors: Gröger Marion , Holnthoner Wolfgang , Maurer Dieter , Lechleitner Sonja , Wolff Klaus , Mayr Bettina Beate , Lubitz Werner , Petzelbauer Peter 
Published: April 2014

AbstractExpression of the 180-kDa mannose receptor (MR) is mainly found on cells of the macrophage lineage. MR mediates the uptake of micro-organisms and host-derived glycoproteins. We demonstrate that endothelium of the human skin in situ and dermal microvascular endothelial cells (DMEC) in vitro expressed MR at both the protein and mRNA levels. In contrast, HUVEC were consistently negative for MR expression. DMEC internalized dextran as well as Escherichia coli by the way of MR into acidic phagosomes, only a few of which fused with CD63- and lysosomal-associated membrane glycoprotein-2-positive lysosomes. This contrasts with the situation in monocyte-derived dendritic cells, where almost all of the MR-Ag complexes reached CD63- and lysosomal-associated membrane glycoprotein-2-positive compartments, indicating differences in the phagolysosomal fusion rate between DMEC and dendritic cells. In conclusion, DMEC express functional MR, a finding that corroborates a role of skin endothelium in Ag capture/clearing.
Immature CD4+CD8+ Thymocytes Do Not Polarize Lipid Rafts in Response to TCR-Mediated Signals
Authors: Ebert Peter J. R. , Baker Josh F. , Punt Jennifer A. 
Published: April 2014

AbstractTCR-mediated stimulation induces activation and proliferation of mature T cells. When accompanied by signals through the costimulatory receptor CD28, TCR signals also result in the recruitment of cholesterol- and glycosphingolipid-rich membrane microdomains (lipid rafts), which are known to contain several molecules important for T cell signaling. Interestingly, immature CD4+CD8+ thymocytes respond to TCR/CD28 costimulation not by proliferating, but by dying. In this study, we report that, although CD4+CD8+ thymocytes polarize their actin cytoskeleton, they fail to recruit lipid rafts to the site of TCR/CD28 costimulation. We show that coupling of lipid raft mobilization to cytoskeletal reorganization can be mediated by phosphoinositide 3-kinase, and discuss the relevance of these findings to the interpretation of TCR signals by immature vs mature T cells.
Thymocytes Express thegolliProducts of the Myelin Basic Protein Gene and Levels of Expression Are Stage Dependent
Authors: Feng Ji-Ming , Givogri Irene M. , Bongarzone Ernesto R. , Campagnoni Celia , Jacobs Erin , Handley Vance W. , Schonmann Vilma , Campagnoni Anthony T. 
Published: April 2014

AbstractThe golli products of the myelin basic protein gene have been shown to be expressed in mouse thymus and brain. The full repertoire of thymic cell types expressing golli products has not yet been determined, although immunoreactivity has been found in some macrophages. We have analyzed the cellular expression of golli mRNAs and proteins in the thymus. The results showed that MTS5+ cortical/MTS10+ medullary epithelial cells and NLDC145+ dendritic cells did not express golli, while some macrophages did exhibit strong immunoreactivity. Golli mRNAs were not detected in macrophages by in situ hybridization. Thymocytes expressed significant levels of golli mRNAs and proteins by in situ hybridization and immunohistochemistry. Interestingly, golli immunoreactivity varied with thymocyte stage of differentiation. For example, CD4−CD8− (double-negative) thymocytes expressed relatively high levels of golli. Upon further differentiation into CD4−CD8− (double-positive) thymocytes, golli protein expression declined dramatically. When thymocytes developed into CD8− or CD4+ (single-positive) thymocytes, golli protein expression increased again, but it never achieved the levels found in double-negative thymocytes. Thus, the altered levels of expression of golli proteins in developing thymocytes correlated with the transitions from double-negative to double-positive and double-positive to single-positive stages. The lack of significant golli expression in thymic stromal cells may offer an alternative explanation for the mechanism of inefficient negative selection of those autoreactive thymocytes with specificity for myelin basic proteins.
Commitment of B Lymphocytes to a Plasma Cell Fate Is Associated with Blimp-1 Expression In Vivo
Authors: Angelin-Duclos Cristina , Cattoretti Giorgio , Lin Kuo-I , Calame Kathryn 
Published: April 2014

AbstractB lymphocyte-induced maturation protein-1 (Blimp-1) is a transcriptional repressor that is sufficient to trigger terminal differentiation in the B cell lymphoma BCL-1. In this study, we have determined the expression pattern of Blimp-1 in vivo in primary and secondary lymphoid organs of humans and immunized mice. Blimp-1 is expressed in plasma cells derived from either a T-independent or T-dependent response in plasma cells that have undergone isotype switching and those resulting from secondary immunization. Blimp-1 is also present in long-lived plasma cells residing in the bone marrow. However, Blimp-1 was not detected in memory B cells. This expression pattern provides further evidence of a critical role for Blimp-1 in plasma cell development, supporting earlier studies in cultured lines. Significantly, Blimp-1 was also found in a fraction (4–15%) of germinal center B cells in murine spleen and human tonsils. Blimp-1 expression in the germinal center is associated with an interesting subset of cells with a phenotype intermediate between germinal center B cells and plasma cells. In the mouse, Blimp-1+ germinal center B cells peak at day 12 postimmunization and disappear soon thereafter. They are not apoptotic, some are proliferating, they express germinal center markers peanut agglutinin or CD10 but not Bcl-6, and most express CD138 (syndecan-1), IRF4, and cytoplasmic Ig. Together, these data support a model in which B cell fate decisions occur within the germinal center and Blimp-1 expression is critical for commitment to a plasma cell, rather than a memory cell, fate.
IFN-γ and IFN-α Posttranscriptionally Down-Regulate the IL-4-Induced IL-4 Receptor Gene Expression
Authors: So Eui-Young , Park Hyun-Hee , Lee Choong-Eun 
Published: April 2014

AbstractAs Th1 and Th2 cytokines, IFN-γ/α and IL-4 counterregulate diverse immune functions. In particular, IFN-γ and IFN-α have been reported to markedly suppress the IL-4-induced IgE production and type II IgE receptor (FcεRII/CD23) expression. Because modulation of IL-4R may be an important mechanism in the regulation of IL-4 response, we have investigated the effect of IFN-γ/α on IL-4R expression and signal transduction mechanisms involved in this process. In human mononuclear cells and B cells isolated from tonsil or peripheral blood, IL-4 up-regulates IL-4R(α) expression at surface protein and mRNA levels, and the IL-4-induced IL-4R(α) is significantly down-regulated by both IFN-γ and IFN-α to a similar extent. The inhibitory effects of IFN-γ/α on the IL-4R mRNA expression require a lag period of about 8 h, and are sensitive to cycloheximide treatment, which suggests that the suppressive effect of IFNs on IL-4R gene expression is a secondary response requiring de novo synthesis of IFN-induced factors. Under such conditions that the inhibitory effects of IFNs are observed, IFNs do not affect the IL-4-induced STAT6 activation and IL-4R transcription, as analyzed by EMSA and nuclear run-on assays, respectively. Subsequently, mRNA stability studies have indicated that the action of IFN-γ/α is primarily mediated by an accelerated decay of IL-4-induced IL-4R mRNA. Thus, it appears that, as already shown in the case of the IL-4-induced FcεRII regulation, posttranscriptional inhibition of IL-4-inducible genes by mRNA destabilization is a common mechanism by which type I and II IFNs antagonize the IL-4 response in human immune cells.
CD95 (Fas) Ligand-Expressing Vesicles Display Antibody-Mediated, FcR-Dependent Enhancement of Cytotoxicity
Authors: Jodo Satoshi , Hohlbaum Andreas M. , Xiao Sheng , Chan Derek , Strehlow David , Sherr David H. , Marshak-Rothstein Ann , Ju Shyr-Te 
Published: April 2014

AbstractBioactive Fas ligand (FasL)-expressing vesicles were generated (vesicle preparation, VP) from two cell lines overexpressing FasL. The effect of NOK-1 anti-FasL mAb (mouse IgG1) on the cytotoxicity of FasL VP against various targets was determined. At high concentrations (1–10 μg/ml), NOK-1 inhibited the cytotoxicity. By contrast, NOK-1 in the dose range of 1–100 ng/ml significantly enhanced cytotoxicity against the FcR+ LB27.4, M59, and LF+ targets, but not the FcR− Jurkat and K31H28 hybridoma T cell targets. The ability to enhance FasL VP-mediated cytotoxicity could be blocked by the FcR-specific mAb 2.4G2. Enhancement was also observed with FcR+ A20 B lymphoma but not with the FcR− A20 variant. Enhancement of FasL VP cytotoxicity was observed with five IgG anti-FasL mAbs, but not with an IgM anti-FasL mAb. Inhibition was observed with high doses of all mAb except the IgG anti-FasL mAb G247-4, which is specific to a segment outside the FasL binding site. Interestingly, under identical conditions but in the presence of 2.4G2, G247-4 inhibited the cytotoxicity of FasL VP. In addition, G247-4 inhibited the FasL VP-mediated killing of FcR− Jurkat. The data demonstrate that FasL-expressing bioactive vesicles display a property heretofore unknown in bioactive agents that express FasL-mediated cytotoxicity. The mechanism of the Ab-mediated, FcR-dependent enhancement of cytotoxicity of bioactive vesicles and its physiological significance are discussed.
Th1 and Th2 Cell Clones to a Poorly Immunogenic Tumor Antigen Initiate CD8+ T Cell-Dependent Tumor Eradication In Vivo
Authors: Fallarino Francesca , Grohmann Ursula , Bianchi Roberta , Vacca Carmine , Fioretti Maria C. , Puccetti Paolo 
Published: April 2014

Abstract
Although CD8+ T cells play a central role as immune effectors, CD4+ T cells act to control the activation and persistence of the CD8+ T cell response in autoimmune disease, antiviral immunity, and experimental systems with immunogenic model tumor Ag. However, little information is available on the effects of CD4+ T cells on the function of endogenous CD8+ T lymphocytes recognizing authentic tumor rejection Ag with limited immunogenicity. We report here that the prophylactic or postchallenge administration of T helper Th1-type and Th2-type CD4+ clones specific for an unmutated rejection Ag (murine P815AB, resembling tumor-specific shared Ag in humans) leads to the induction of P815AB-specific reactivity in vivo and concomitant tumor destruction, with quantitative rather than qualitative differences characterizing the antitumor activity of Th1 vs Th2 cells. Because the transferred CD4+ cells lacked direct antitumor activity in vitro and required the de novo generation of P815AB-specific CD8+ T cells in vivo, these findings suggest that CD4+ lymphocytes can enhance the ability of host APC to initiate an endogenous CD8+ T cell response to authentic, poorly immunogenic tumor rejection Ag.
IFN-γ Can Promote Tumor Evasion of the Immune System In Vivo by Down-Regulating Cellular Levels of an Endogenous Tumor Antigen
Authors: Beatty Gregory L. , Paterson Yvonne 
Published: April 2014

Abstract
Although IFN-γ has been generally thought to enhance antitumor immune responses, we found that IFN-γ can promote tumor escape in the CT26 colon carcinoma by down-regulating the protein expression of an endogenous tumor Ag. gp70, the env product of the endogenous ecotropic murine leukemia virus, has been reported to be the immunodominant Ag of CT26. We show that IFN-γ down-regulates intracellular and surface levels of gp70 protein resulting in a reduced lysis by CTL, which is restored by pulsing IFN-γ-treated CT26 with the Ld-restricted immunodominant AH1 epitope derived from gp70. To investigate the role of CT26 sensitivity to IFN-γ in vivo, we constructed two variants of CT26, CT26.mugR and CT26.IFN, that are unresponsive to IFN-γ or express IFN-γ, respectively. We demonstrate using these variants that tumor responsiveness to IFN-γ promotes a reduction in tumor immunogenicity in vivo that is correlated with an increased tumor incidence in immune mice. Analysis of the tumors from mice challenged with CT26 or CT26.mugR revealed infiltration of CD8 T cells secreting IFN-γ. We conclude that IFN-γ secreted by tumor-infiltrating T cells promotes tumor escape through the down-regulation of the endogenous tumor Ag gp70. These findings have impact on the design of effective antitumor vaccine strategies.
Eosinophil Major Basic Protein-1 Does Not Contribute to Allergen-Induced Airway Pathologies in Mouse Models of Asthma
Authors: Denzler Karen L. , Farmer Steven C. , Crosby Jeffrey R. , Borchers Michael , Cieslewicz Grzegorz , Larson Kirsten A. , Cormier-Regard Stephania , Lee Nancy A. , Lee James J. 
Published: April 2014

AbstractThe relationship between eosinophils and the development of Ag-induced pulmonary pathologies, including airway hyper-responsiveness, was investigated using mice deficient for the secondary granule component, major basic protein-1 (mMBP-1). The loss of mMBP-1 had no effect on OVA-induced airway histopathologies or inflammatory cell recruitment. Lung function measurements of knockout mice demonstrated a generalized hyporeactivity to methacholine-induced airflow changes (relative to wild type); however, this baseline phenotype was observable only with methacholine; no relative airflow changes were observed in response to another nonspecific stimulus (serotonin). Moreover, OVA sensitization/aerosol challenge of wild-type and mMBP-1−/− mice resulted in identical dose-response changes to either methacholine or serotonin. Thus, the airway hyper-responsiveness in murine models of asthma occurs in the absence of mMBP-1.
Inhibition of IgG1 and IgE Production by Stimulation of the B Cell CTLA-4 Receptor
Authors: Pioli Claudio , Gatta Lucia , Ubaldi Vanessa , Doria Gino 
Published: April 2014

AbstractAlthough a large amount of information is available on the activity of CTLA-4 in T cells, the role of this receptor in B cells has not been previously characterized. Our results show that CD40 or LPS stimulation in the presence of IL-4 induces CTLA-4 expression in purified B cells; the maximum level is reached in both membrane and intracellular compartments after 48–72 h. Engagement of the B cell CTLA-4 by immobilized mAb inhibits IgG1 and IgE production and reduces the frequency of IgG1- and IgE-expressing B cells. Cε and Cγ1 germline mRNA expression as well as NF-κB and STAT6 activation, events required for isotype switching, are also inhibited by CTLA-4 engagement. Together these findings show the critical role of CTLA-4 in the control of IL-4-driven isotype switching and suggest new approaches for modulating immediate-type hypersensitivity responses.
Fas Ligand Costimulates the In Vivo Proliferation of CD8+ T Cells
Authors: Suzuki Ivy , Martin Stefan , Boursalian Tamar E. , Beers Courtney , Fink Pamela J. 
Published: April 2014

AbstractFas ligand (FasL/CD95L/APO-1L) is one of a growing number of TNF family members whose triggering costimulates maximal proliferation of activated T cells. In this study we show that maximal Ag-dependent accumulation of transferred TCR-transgenic CD8+ T cells requires Fas (CD95/APO-1) expression by the adoptive hosts. Additionally, adoptively transferred FasL+ CD8+ T cells demonstrate a 2-fold advantage in Ag-driven expansion over their FasL−counterparts. This study illustrates the in vivo role of TCR-dependent FasL costimulation in the Ag-specific proliferation of both heterogeneous and homogeneous populations of primary CD8+ T cells and long-term CTL lines. Thus, cross-linking FasL on naive and Ag-experienced CD8+ T cells whose Ag-specific TCRs are engaged is required to drive maximal cellular proliferation in vivo.