bluuebunny/crossref_metadata_2025_split huggingface dataset:
Dysregulated Expression of Pre-Tα Reveals the Opposite Effects of Pre-TCR at Successive Stages of T Cell Development
Authors: Lacorazza H. Daniel , Porritt Helen E. , Nikolich-Žugich Janko 
Published: April 2014

AbstractThe pre-TCR complex (TCRβ-pre-TCRα chain (pTα)), first expressed in a fraction of CD8−4−CD44−25+ (DN3) cells, is believed to facilitate or enable an efficient transition from the CD8−4− double-negative (DN) to the CD8+4+ double-positive (DP) developmental stage. Subsequent to pre-TCR expression, DN3 thymocytes receive survival, proliferation, and differentiation signals, although it is still unclear which of these outcomes are directly induced by the pre-TCR. To address this issue, we generated mice bearing a range of pTα transgene copy number under the transcriptional control of the p56lck proximal promoter. All lines exhibited increased DN3 cycling, accelerated DN3/4 transition, and improved DN4 survival. However, the high copy number lines also showed a selective reduction in thymic cellularity due to increased apoptosis of DP thymocytes, which could be reversed by the ectopic expression of Bcl-2. Our results suggest that transgenic pTα likely caused apoptosis of DP thymocytes due to competitive decrease in surface TCRαβ formation. These results highlight the critical importance of precise temporal and stoichiometric regulation of pre-TCR and TCR component expression.
Tolerance, Mixed Chimerism, and Chronic Transplant Arteriopathy
Authors: Russell Paul S. , Chase Catharine M. , Sykes Megan , Ito Hiroshi , Shaffer Juanita , Colvin Robert B. 
Published: April 2014

AbstractMuch evidence supports the conclusion that immunological responses to donor-specific incompatibilities are a major factor in producing “chronic” transplant rejection, including the arteriopathy (atherosclerosis) commonly present. Our experiments explored the effects of altered immunological responsiveness to these Ags on the formation of arteriopathy in transplanted mouse hearts. Specific immunological nonreactivity, or tolerance, was induced either by neonatal administration of allogeneic spleen cells (from F1 donors between class I-mismatched donor and recipient strains), resulting in “classical” immunological tolerance, or by bone marrow infusion to suitably prepared adult recipients, either fully MHC mismatched or class I mismatched, yielding “mixed chimerism.” Both approaches obviated systemic graft-versus-host effects. In both groups, donor-specific skin grafts survived perfectly and donor cell chimerism persisted. Specific Abs were undetectable in all recipients. Most transplants to either group of tolerant recipients developed striking vasculopathy in their coronary arteries (12 of 15 in neonatal tolerance and 15 of 23 in mixed chimeras). Neointimal infiltrates included CD4 and CD8 T cells and macrophages. Only 2 of 29 contemporary isotransplants showed any evidence of vasculopathy. Recipients essentially incapable of T and B cell responses (C.B-17/SCID and RAG1−/−) were also used. Transplants into these animals developed vasculopathy in 16 of 31 instances. Accordingly, in this setting, vasculopathy develops in the presence of H-2 gene-determined incompatibility even with minimal conventional immune reactivity. Perhaps innate responsiveness, that could include NK cell activity, can create such arteriopathic lesions. More evidence is being sought regarding this process.
Immature Human Dendritic Cells Express Asialoglycoprotein Receptor Isoforms for Efficient Receptor-Mediated Endocytosis
Authors: Valladeau Jenny , Duvert-Frances Valérie , Pin Jean-Jacques , Kleijmeer Monique J. , Ait-Yahia Smina , Ravel Odile , Vincent Claude , Vega Felix , Helms Alison , Gorman Dan , Zurawski Sandra M. , Zurawski Gerard , Ford John , Saeland Sem 
Published: April 2014

AbstractIn a search for genes expressed by dendritic cells (DC), we have cloned cDNAs encoding different forms of an asialoglycoprotein receptor (ASGPR). The DC-ASGPR represents long and short isoforms of human macrophage lectin, a Ca2+-dependent type II transmembrane lectin displaying considerable homology with the H1 and H2 subunits of the hepatic ASGPR. Immunoprecipitation from DC using an anti-DC-ASGPR mAb yielded a major 40-kDa protein with an isoelectric point of 8.2. DC-ASGPR mRNA was observed predominantly in immune tissues. Both isoforms were detected in DC and granulocytes, but not in T, B, or NK cells, or monocytes. DC-ASGPR species were restricted to the CD14-derived DC obtained from CD34+ progenitors, while absent from the CD1a-derived subset. Accordingly, both monocyte-derived DC and tonsillar interstitial-type DC expressed DC-ASGPR protein, while Langerhans-type cells did not. Furthermore, DC-ASGPR is a feature of immaturity, as expression was lost upon CD40 activation. In agreement with the presence of tyrosine-based and dileucine motifs in the intracytoplasmic domain, mAb against DC-ASGPR was rapidly internalized by DC at 37°C. Finally, intracellular DC-ASGPR was localized to early endosomes, suggesting that the receptor recycles to the cell surface following internalization of ligand. Our findings identify DC-ASGPR/human macrophage lectin as a feature of immature DC, and as another lectin important for the specialized Ag-capture function of DC.
Molecular Evolution of Catalytic Antibodies in Autoimmune Mice
Authors: Sun Jialin , Takahashi Naoko , Kakinuma Hiroyuki , Nishi Yoshisuke 
Published: April 2014

AbstractCatalytic Abs (catAbs) preferentially evolved in autoimmune MRL/MPJ-lpr/lpr (MRL/lpr) mice upon immunization with the phosphonate transition-state analogue (TSA), but this did not happen in normal BALB/c mice. The majority of the catAbs from MRL/lpr mice were from several independent clones of the same family. Most of them had a lysine at position 95 in the heavy chain (H95), which is at the junctional region. This residue, which interacts with the phosphonate moiety of the TSA and presumably is involved in the catalytic activity, was not changed even after expansive evolution following multiple mutations. By contrast, the majority that arose from BALB/c mice were the non-catAbs, which were quite different in the sequence from the catAbs from MRL/lpr mice, but they were clonally related to one another, so most of them were originated from a single clone. In the MRL/lpr mice, the catalytic subsets that existed in the initial repertoire were effectively captured by the phosphonyl oxygens in the TSA by interacting with the lysine at H95. In the BALB/c mice, however, another noncatalytic subset with only the binding capability directed to a moiety other than the phosphonate moiety was alternatively evolved, because of the lowest abundance or elimination of the catalytic subsets.
Comparison of Chimpanzee and Human Leukocyte Ig-Like Receptor Genes Reveals Framework and Rapidly Evolving Genes
Authors: Canavez Flavio , Young Neil T. , Guethlein Lisbeth A. , Rajalingam Raja , Khakoo Salim I. , Shum Benny P. , Parham Peter 
Published: April 2014

Abstract
The leukocyte receptor complex (LRC) on human chromosome 19 contains related Ig superfamily killer cell Ig-like receptor (KIR) and leukocyte Ig-like receptor (LIR) genes. Previously, we discovered much difference in the KIR genes between humans and chimpanzees, primate species estimated to have ∼98.8% genomic sequence similarity. Here, the common chimpanzee LIR genes are identified, characterized, and compared with their human counterparts. From screening a chimpanzee splenocyte cDNA library, clones corresponding to nine different chimpanzee LIRs were isolated and sequenced. Analysis of genomic DNA from 48 unrelated chimpanzees showed 42 to have all nine LIR genes, and six animals to lack just one of the genes. In structural diversity and functional type, the chimpanzee LIRs cover the range of human LIRs. Although both species have the same number of inhibitory LIRs, humans have more activating receptors, a trend also seen for KIRs. Four chimpanzee LIRs are clearly orthologs of human LIRs. Five other chimpanzee LIRs have paralogous relationships with clusters of human LIRs and have undergone much recombination. Like the human genes, chimpanzee LIR genes appear to be organized into two duplicated blocks, each block containing two orthologous genes. This organization provides a conserved framework within which there are clusters of faster evolving genes. Human and chimpanzee KIR genes have an analogous arrangement. Whereas both KIR and LIR genes can exhibit greater interspecies differences than the genome average, within each species the LIR gene family is more conserved than the KIR gene family.
Characterization of CDw92 as a Member of the Choline Transporter-Like Protein Family Regulated Specifically on Dendritic Cells
Authors: Wille Stefan , Szekeres Andreas , Majdic Otto , Prager Elisabeth , Staffler Günther , Stöckl Johannes , Kunthalert Duangkamol , Prieschl Eva E. , Baumruker Thomas , Burtscher Helmut , Zlabinger Gerhard J. , Knapp Walter , Stockinger Hannes 
Published: April 2014

Abstract
CDw92 is a 70-kDa surface protein broadly expressed on leukocytes and endothelial cells. In this manuscript, we present the molecular cloning of the CDw92 molecule by using a highly efficient retroviral expression cloning system. Sequence analysis of the CDw92 cDNA revealed a length of 2679 bp. The 1959-bp open reading frame encodes a protein of 652 amino acids. Computational analysis of the CDw92 protein sequence indicates 10 transmembrane domains, three potential N-linked glycosylation sites, and an amino acid stretch in the C-terminal region that is related to the immunoreceptor tyrosine-based inhibitory motif. Comparison of the sequence of the CDw92 clone presented in this study with various database entries show that it is a C-terminal variant of human choline transporter-like protein 1, a member of a recently identified family of multitransmembrane surface proteins. Furthermore, we found that CDw92 is stably expressed on monocytes, PBLs, and endothelial cells, as we did not yet find modulation of expression by various stimuli on these cells. In contrast to this factor-independent expression of CDw92, we detected a specific regulation of CDw92 on monocyte-derived dendritic cells (Mo-DCs). Maturation of Mo-DCs by ionomycin or calcium ionophore resulted in down-regulation of CDw92 and incubation of these cells with IL-10 in a specific re-expression. Moreover, targeting of CDw92 on LPS-treated Mo-DCs by CDw92 mAb VIM15b augmented the LPS-induced IL-10 production 2.8-fold. Together, these data suggest a crucial role of the CDw92 protein in the biology and regulation of the function of leukocytes in particular DCs.
Multiple Carboxyl-Terminal Regions of the EBV Oncoprotein, Latent Membrane Protein 1, Cooperatively Regulate Signaling to B Lymphocytes Via TNF Receptor-Associated Factor (TRAF)-Dependent and TRAF-Independent Mechanisms
Authors: Busch Lisa K. , Bishop Gail A. 
Published: April 2014

AbstractLatent membrane protein 1 (LMP1) is an EBV-encoded transforming protein that strongly mimics the B cell-activating properties of a normal cellular membrane protein, CD40. LMP1 and CD40 both associate with the cytoplasmic adapter proteins called TNFR-associated factors (TRAFs). TRAFs 1, 2, and 3 bind to a region of LMP1 that is essential for EBV to transform B lymphocytes, carboxyl-terminal activating region (CTAR) 1. However, studies of transiently overexpressed LMP1 molecules, primarily in epithelial cells, indicated that a second region, CTAR2, is largely responsible for LMP1-mediated activation of NF-κB and c-Jun N-terminal kinase. To better understand LMP1 signaling in B lymphocytes, we performed a structure-function analysis of the LMP1 C-terminal cytoplasmic domain stably expressed in B cell lines. Our results demonstrate that LMP1-stimulated Ig production, surface molecule up-regulation, and NF-κB and c-Jun N-terminal kinase activation require both CTAR1 and CTAR2, and that these two regions may interact to mediate LMP1 signaling. Furthermore, we find that the function of CTAR1, but not CTAR2, correlates with TRAF binding and present evidence that as yet unidentified cytoplasmic proteins may associate with LMP1 to mediate some of its signaling activities.
Manipulation of Avidity to Improve Effectiveness of Adoptively Transferred CD8+ T Cells for Melanoma Immunotherapy in Human MHC Class I-Transgenic Mice
Authors: Bullock Timothy N. J. , Mullins David W. , Colella Teresa A. , Engelhard Victor H. 
Published: April 2014

AbstractThe adoptive transfer of tumor-reactive CD8+ T cells into tumor-bearing hosts provides an attractive alternative to vaccination-based active immunotherapy of melanoma. The development of techniques that result in the preferential expansion of tumor-reactive T cells is therefore of great importance. In this study, we report the generation of HLA-A*0201-restricted CD8+ T cell populations that recognize either tyrosinase369–376 or gp100209–217 from tolerant human class I MHC-transgenic mice by using single amino acid-substituted variant peptides. Low peptide concentration or restimulation with the parent peptide was used to enhance the functional avidity, defined by stimulation of IFN-γ accumulation, and cross-reactivity of the resulting T cell populations. We found a direct correlation between the ability of a T cell population to respond in vitro to low concentrations of the precise peptide expressed on the tumor and its ability to delay the outgrowth of B16 melanoma after adoptive transfer. Surprisingly, we found that some T cells that exhibited high functional avidity and were effective in controlling tumor outgrowth exhibited low structural avidity, as judged by MHC-tetramer staining. Our results establish strategies for the development and selection of CD8+ T cell populations that persist despite peripheral tolerance, and that can control melanoma outgrowth. Furthermore, they support the use of human MHC class I-transgenic mice as a preclinical model for developing effective immunotherapies that can be rapidly extended into therapeutic settings.
The Capsular Polysaccharides ofCryptococcus neoformansActivate Normal CD4+ T Cells in a Dominant Th2 Pattern
Authors: Almeida Geisy M. , Andrade Regis M. , Bento Cleonice A. M. 
Published: April 2014

AbstractCapsular components of Cryptococcus neoformans induce several deleterious effects on T cells. However, it is unknown how the capsular components act on these lymphocytes. The present study characterized cellular and molecular events involved in immunoregulation of splenic CD4+ T cells by C. neoformans capsular polysaccharides (CPSs). The results showed that CPSs induce proliferation of normal splenic CD4+ T cells, but not of normal CD8+ T or B lymphocytes. Such proliferation depended on physical contact between CPSs and viable splenic adherent cells (SAC) and CD40 ligand-induced intracellular signal transduction. The absence of lymphoproliferation after fixation of SAC with paraformaldehyde has discarded the hypothesis of a superantigen-like activation. The evaluation of a cytokine pattern produced by the responding CD4+ T lymphocytes revealed that CPSs induce a dominant Th2 pattern, with high levels of IL-4 and IL-10 production and undetectable inflammatory cytokines, such as TNF-α and IFN-γ. Blockade of CD40 ligand by relevant mAb down-regulated the CPS-induced anti-inflammatory cytokine production and abolished the enhancement of fungus growth in cocultures of SAC and CD4+ T lymphocytes. Our findings suggest that CPSs induce proliferation and differentiation of normal CD4+ T cells into a Th2 phenotype, which could favor parasite growth and thus important deleterious effects to the host.
HIV Mucosal Vaccine: Nasal Immunization with rBCG-V3J1 Induces a Long Term V3J1 Peptide-Specific Neutralizing Immunity in Th1- and Th2-Deficient Conditions
Authors: Hiroi Takachika , Goto Hironobu , Someya Kenji , Yanagita Manabu , Honda Mitsuo , Yamanaka Noboru , Kiyono Hiroshi 
Published: April 2014

AbstractIn the vaccine strategy against HIV, bacillus Calmette-Guérin (BCG), a live attenuated strain of Mycobacterium bovis, is considered to be one of potential vectors for mucosal delivery of vaccine Ag. We analyzed the induction of the Ag-specific Ab response by nasal immunization with recombinant BCG vector-based vaccine (rBCG-V3J1) that can secrete the V3 principal neutralizing epitope of HIV. Mice were nasally immunized with rBCG-V3J1 (10 μg) three times at weekly intervals. Four weeks after the initial immunization, high titers of V3J1-specific IgG Abs were seen in serum. These high levels of HIV-specific serum IgG responses were maintained for &gt;12 mo following nasal immunization without any booster immunization. V3J1-specific IgG-producing cells were detected in mononuclear cells isolated from spleen, nasal cavity, and salivary gland of the nasally vaccinated mice. Nasal rBCG-V3J1 also induced high levels of prolonged HIV-specific serum IgG responses in Th1 (IFN-γ−/−)- or Th2 (IL-4−/−)-immunodeficient mice. Further, IgG3 was highest among V3 peptide-specific IgG subclass Ab responses in these immunodeficient mice as well as in wild-type mice. In addition, this Ag-specific serum IgG Abs induced by nasal immunization with rBCG-V3J1 possessed the ability to neutralize clinical isolate of HIV in vitro. These results suggested that the nasal rBCG-V3J1 system might be used as a therapeutic vaccine in addition to a prophylaxis vaccine for the control of AIDS.
Surfactant Protein D Enhances Clearance of Influenza A Virus from the Lung In Vivo
Authors: LeVine Ann Marie , Whitsett Jeffrey A. , Hartshorn Kevan L. , Crouch Erika C. , Korfhagen Thomas R. 
Published: April 2014

AbstractMice lacking surfactant protein surfactant protein D (SP-D−/−) and wild-type mice (SP-D+/+) were infected with influenza A virus (IAV) by intranasal instillation. IAV infection increased the endogenous SP-D concentration in wild-type mice. SP-D-deficient mice showed decreased viral clearance of the Phil/82 strain of IAV and increased production of inflammatory cytokines in response to viral challenge. However, the less glycosylated strain of IAV, Mem/71, which is relatively resistant to SP-D in vitro, was cleared efficiently from the lungs of SP-D−/− mice. Viral clearance of the Phil/82 strain of IAV and the cytokine response were both normalized by the coadministration of recombinant SP-D. Since the airway is the usual portal of entry for influenza A virus and other respiratory pathogens, SP-D is likely to play an important role in innate defense responses to IAV.
The Development of a Th1-Type Response and Resistance toLeishmania majorInfection in the Absence of CD40-CD40L Costimulation
Authors: Padigel Udaikumar M. , Perrin Peter J. , Farrell Jay P. 
Published: April 2014

AbstractCD40-CD40L interactions have been shown to be essential for the production of IL-12 and IFN-γ and control of L. major infection. In contrast, C57BL/6 mice deficient in CD28 develop a dominant Th1-type response and heal infection. In this study, we investigate the effects of a deficiency in both CD40L and CD28 molecules on the immune response and the course of L. major infection. We compared infection in mice genetically lacking CD40L (CD40L−/−), CD28 (CD28−/−), or both (CD40L−/−CD28−/−), and in C57BL/6 mice, all on a resistant background. Although CD40L−/− mice failed to control infection, CD28−/− and CD40L−/−CD28−/− mice, as well as C57BL/6 mice, spontaneously resolved their infections. Healing mice had reduced numbers of lesion parasites compared with nonhealing CD40L−/− mice. At wk 9 of infection, we detected similar levels of IL-4, IFN-γ, IL-12p40, and IL-12Rβ2 mRNA in draining lymph nodes of healing C57BL/6, CD28−/−, and CD40L−/−CD28−/− mice, whereas CD40L−/− mice had increased mRNA levels for IL-4 but reduced levels for IFN-γ, IL-12p40, and IL-12Rβ2. In a separate experiment, blocking of the CD40-CD40L pathway using Ab to CD40L led to an exacerbation of infection in C57BL/6 mice, but had little or no effect on infection in CD28−/− mice. Together, these results demonstrate that in the absence of CD28 costimulation, CD40-CD40L interaction is not required for the development of a protective Th1-type response. The expression of IL-12p40, IL-12Rβ2, and IFN-γ in CD40L−/−CD28−/− mice further suggests the presence of an additional stimulus capable of regulating IL-12 and its receptors in absence of CD40-CD40L interactions.
Therapeutic Administration of Anti-PcrV F(ab′)2 in Sepsis Associated with Pseudomonas aeruginosa
Authors: Shime Nobuaki , Sawa Teiji , Fujimoto Junichi , Faure Karine , Allmond Leonard R. , Karaca Timur , Swanson Britta L. , Spack Edward G. , Wiener-Kronish Jeanine P. 
Published: April 2014

Abstract
The effects of rabbit-derived polyclonal Ab against PcrV, a protein involved in the translocation of type III secreted toxins of Pseudomonas aeruginosa, was investigated in two animal models of P. aeruginosa sepsis. In a mouse survival study, the i.v. administration of anti-PcrV IgG after the airspace instillation of a lethal dose of P. aeruginosa resulted in the complete survival of the animals. In a rabbit model of septic shock associated with Pseudomonas-induced lung injury, animals treated with anti-PcrV IgG intratracheally or i.v. had significant decreases in lung injury, bacteremia, and plasma TNF-α and significant improvement in the hemodynamic parameters associated with shock compared with animals treated in a similar manner with nonspecific control IgG. The administration of anti-PcrV F(ab′)2 showed protective effects comparable to those of whole anti-PcrV IgG. These results document that the therapeutic administration of anti-PcrV IgG blocks the type III secretion system-mediated virulence of P. aeruginosa and prevents septic shock and death, and that these protective effects are largely Fc independent. We conclude that Ab therapy neutralizing the type III secretion system has significant potential against lethal P. aeruginosa infections.
Inhibition of Nitric Oxide Synthase Initiates Relapsing Remitting Experimental Autoimmune Encephalomyelitis in Rats, Yet Nitric Oxide Appears to be Essential for Clinical Expression of Disease
Authors: O’Brien Nikki C. , Charlton Brett , B. Cowden William , Willenborg David O. 
Published: April 2014

AbstractMyelin basic protein-CFA-induced experimental autoimmune encephalomyelitis (EAE) in Lewis rats is an acute monophasic disease from which animals recover. In this model, spontaneous relapses do not occur and rats develop a resistance to further active reinduction of disease. Previously, we reported that oral administration of the NO synthase inhibitor N-methyl-l-arginine acetate (l-NMA) to recovered rats precipitated a second episode of disease in 100% of animals. Further studies now show that this second clinical episode is actually a chronic relapsing disease that persists for months. This occurs only in rats that have recovered from actively induced EAE and not in rats recovered from passively induced EAE, suggesting the need for a peripheral Ag depot to induce secondary disease. We have also determined that clinical signs of EAE in l-NMA-treated recovered rats do not appear until l-NMA treatment has stopped. This is despite the fact that, at the same time point, CNS inflammatory lesions in symptomless animals receiving l-NMA are qualitatively and quantitatively similar to those with severe disease symptoms from whom l-NMA treatment has been withdrawn. The latter animals have significantly higher levels of reactive nitrogen intermediates in the cerebrospinal fluid than the former group. This study examines the mechanism of reinduction of disease by l-NMA treatment, and the findings suggest a dual role for NO in regulation of pathology in EAE that is dependent on site and timing of NO production.