bluuebunny/crossref_metadata_2025_split huggingface dataset:
Heterospecific CD4 Help to Rescue CD8 T Cell Killers
Authors: de Goër de Herve Marie-Ghislaine , Cariou Anne , Simonetta Federico , Taoufik Yassine 
Published: April 2014

Abstract
Help from CD4 T cells may be required for optimal generation and maintenance of memory CD8 T cells and also for optimal Ag reactivation. We examined whether the helper cell and the CD8 killer cell need to have the same Ag specificity for help to be effective during interactions of memory T cells with mature APC. This is important because virus and tumor Ag-specific CD4 T cell responses are selectively impaired in several chronic viral infections and malignancies. We performed studies in vitro and in vivo and found that functional memory CD4 T cells generated from a distinct antigenic source (heterospecific helpers) could provide direct and effective help to memory CD8 T cells. Functional heterospecific memory CD4 T cells could also rescue secondary CD8 T cell responses in an experimental tumor model in which homospecific CD4 help was impaired. This could provide a rationale for immunotherapy strategies designed to bypass impaired homospecific help.
Intraclonal Competition Inhibits the Formation of High-Affinity Antibody-Secreting Cells
Authors: Le Thuc-vy L. , Kim Tea Hyun , Chaplin David D. 
Published: April 2014

Abstract
Protective immunity requires a diverse, polyclonal B cell repertoire. We demonstrate that affinity maturation of the humoral response to a hapten is impaired when preexisting clonally restricted cells recognizing the hapten are dominant in the B cell repertoire. B1-8i+/− mice, which feature a high frequency of B cells with nitrophenyl (NP)-binding specificity, respond to NP-haptenated proteins with the production of NP-specific Abs, but affinity maturation is impaired due to insufficient generation of high-affinity Ab-producing cells. We manipulated the frequency of NP-specific B cells by adoptive transfer of B1-8 B cells into naive, wild-type recipients. Remarkably, when 104 B1-8 B cells were transferred, these cells supported efficient affinity maturation and plasma cell differentiation. In contrast, when 106 B1-8 cells were transferred, affinity maturation did not occur. These data indicate that restricting the frequency of clonally related B cells is required to support affinity maturation.
Soluble Frizzled-Related Protein 1 Is Estrogen Inducible in Bone Marrow Stromal Cells and Suppresses the Earliest Events in Lymphopoiesis
Authors: Yokota Takafumi , Oritani Kenji , Garrett Karla P. , Kouro Taku , Nishida Makoto , Takahashi Isao , Ichii Michiko , Satoh Yusuke , Kincade Paul W. , Kanakura Yuzuru 
Published: April 2014

Abstract
It has long been known that lymphopoiesis is transiently suppressed during pregnancy, which can be experimentally simulated by estrogen treatment. We now confirm with Rag1/GFP reporter mice that early lymphoid progenitors in the lineage marker− c-kithigh ScaI+, hematopoietic stem cell-enriched fraction of bone marrow are particularly depressed in these circumstances. Hematopoietic and environmental cells are both potential hormone targets and, because of this complexity, very little is known regarding mechanisms. We have now identified soluble Frizzled-related protein (sFRP)1 as an estrogen-inducible gene in stromal cells, whose expression corresponded to inability to support lymphopoiesis. Bone-lining stromal cells express sFRP1, and the transcripts were elevated by pregnancy or estrogen injection. Estrogen receptor-α was essential for both lymphoid suppression and induction of the sFRP family. SFRP1 has been mainly described as an antagonist for complex Wnt signals. However, we found that sFRP1, like Wnt3a, stabilized β-catenin and blocked early lymphoid progression. Myeloerythroid progenitors were less affected by sFRP1 in culture, which was similar to estrogen with respect to lineage specificity. Hematopoietic stem cells expressed various Frizzled receptors, which markedly declined as they differentiated to lymphoid lineage. Thus, hormonal control of early lymphopoiesis in adults might partly relate to sFRP1 levels.
Polymorphic Sites Away from the Bw4 Epitope That Affect Interaction of Bw4+ HLA-B with KIR3DL1
Authors: Sanjanwala Bharati , Draghi Monia , Norman Paul J. , Guethlein Lisbeth A. , Parham Peter 
Published: April 2014

AbstractKIR3DL1 is a polymorphic, inhibitory NK cell receptor specific for the Bw4 epitope carried by subsets of HLA-A and HLA-B allotypes. The Bw4 epitope of HLA-B*5101 and HLA-B*1513 is determined by the NIALR sequence motif at positions 77, 80, 81, 82, and 83 in the α1 helix. Mutation of these positions to the residues present in the alternative and nonfunctional Bw6 motif showed that the functional activity of the Bw4 epitopes of B*5101 and B*1513 is retained after substitution at positions 77, 80, and 81, but lost after substitution of position 83. Mutation of leucine to arginine at position 82 led to loss of function for B*5101 but not for B*1513. Further mutagenesis, in which B*1513 residues were replaced by their B*5101 counterparts, showed that polymorphisms in all three extracellular domains contribute to this functional difference. Prominent were positions 67 in the α1 domain, 116 in the α2 domain, and 194 in the α3 domain. Lesser contributions were made by additional positions in the α2 domain. These positions are not part of the Bw4 epitope and include residues shaping the B and F pockets that determine the sequence and conformation of the peptides bound by HLA class I molecules. This analysis shows how polymorphism at sites throughout the HLA class I molecule can influence the interaction of the Bw4 epitope with KIR3DL1. This influence is likely mediated by changes in the peptides bound, which alter the conformation of the Bw4 epitope.
A Novel Role of CD30L/CD30 Signaling by T-T Cell Interaction in Th1 Response against Mycobacterial Infection
Authors: Tang Ce , Yamada Hisakata , Shibata Kensuke , Muta Hiromi , Wajjwalku Worawidh , Podack Eckhard R. , Yoshikai Yasunobu 
Published: April 2014

AbstractA CD30 ligand (CD30L, CD153) is a type II membrane-associated glycoprotein belonging to the TNF family. To illustrate the potential role of CD30L in CD4+ Th1 cell responses, we investigated the fate of Ag-specific CD4+ T cells in CD30L-deficient (CD30L−/−) mice after Mycobacterium bovis bacillus Calmette-Guérin (BCG) infection. The number of bacteria was significantly higher in organs of CD30L−/− mice than in wild-type (WT) mice 4 wk postinfection. The numbers of purified protein derivative- or Ag85B-specific-IFN-γ-producing-CD4+ T cells in spleen, lung, or peritoneal exudate cells were significantly fewer in CD30L−/− mice than in WT mice. During the infection, CD30L was expressed mainly by CD44+CD3+CD4+ T cells but not by CD3+CD8+ T cells, B cells, dendritic cells, or macrophages. Costimulation with agonistic anti-CD30 mAb or coculturing with CD30L-transfected P815 cells restored IFN-γ production by CD4+ T cells from BCG-infected CD30L−/− mice. Coculturing with CD30L+/+CD4+ T cells from BCG-infected WT mice also restored the number of IFN-γ+CD30L−/−CD4+ T cells. When transferred into the CD30L+/+ mice, Ag-specific donor CD30L−/− CD4+ T cells capable of producing IFN-γ were restored to the compared level seen in CD30L+/+ CD4+ T cells on day 10 after BCG infection. When naive CD30L+/+ T cells were transferred into CD30L−/− mice, IFN-γ-producing-CD4+ Th1 cells of donor origin were normally generated following BCG infection, and IFN-γ-producing-CD30L−/−CD4+ Th1 cells of host origin were partly restored. These results suggest that CD30L/CD30 signaling executed by CD30+ T-CD30L+ T cell interaction partly play a critical role in augmentation of Th1 response capable of producing IFN-γ against BCG infection.
Tuberculosis Triggers a Tissue-Dependent Program of Differentiation and Acquisition of Effector Functions by Circulating Monocytes
Authors: Sköld Markus , Behar Samuel M. 
Published: April 2014

Abstract
The origin and function of the different myeloid cell subsets that appear in the lung during pulmonary tuberculosis are unknown. Herein we show that adoptively transferred monocytes give rise to many of the macrophage and dendritic cell (DC) subsets that appear following aerosol infection with virulent Mycobacterium tuberculosis. Monocyte differentiation in infected peripheral tissue is surprisingly heterogeneous and results in the formation of five distinct myeloid subsets, including both classically activated macrophages, that produce inducible NO synthase via an IFN-γ-dependent mechanism, and DC. In contrast, monocytes recruited to draining pulmonary lymph nodes are functionally different and acquire a mature DC phenotype. Thus, while monocytes are recruited to the lungs of uninfected mice, their differentiation and acquisition of myeloid effector functions are dramatically altered in the presence of inflammation and bacteria and are dependent on tissue localization. Therefore, our results support a model in which recruited monocytes are well poised to influence multiple aspects of host immunity to infections in the lungs. This report provides the first direct evidence for monocyte differentiation into both the macrophage and DC lineages in vivo following infection with a live human pathogen.
Ly49h-Deficient C57BL/6 Mice: A New Mouse Cytomegalovirus-Susceptible Model Remains Resistant to Unrelated Pathogens Controlled by the NK Gene Complex
Authors: Fodil-Cornu Nassima , Lee Seung-Hwan , Belanger Simon , Makrigiannis Andrew P. , Biron Christine A. , Buller R. Mark , Vidal Silvia M. 
Published: April 2014

Abstract
Cmv1 was the first mouse cytomegalovirus (MCMV) resistance locus identified in C57BL/6 mice. It encodes Ly49H, a NK cell-activating receptor that specifically recognizes the m157 viral protein at the surface of MCMV-infected cells. To dissect the effect of the Ly49h gene in host-pathogen interactions, we generated C57BL/6 mice lacking the Ly49h region. We found that 36 h after MCMV infection, the lack of Ly49h resulted in high viral replication in the spleen and dramatically enhanced proinflammatory cytokine production in the serum and spleen. At later points in time, we observed that MCMV induced a drastic loss in CD8+ T cells in B6.Ly49h−/− mice, probably reflecting severe histological changes in the spleen. Overall, our results indicate that Ly49H+ NK cells contain a systemic production of cytokines that may contribute to the MCMV-induced pathology and play a central role in maintaining normal spleen cell microarchitecture. Finally, we tested the ability of B6.Ly49h−/− mice to control replication of Leishmania major and ectromelia virus. Resistance to these pathogens has been previously mapped within the NK gene complex. We found that the lack of Ly49H+ NK cells is not associated with an altered resistance to L. major. In contrast, absence of Ly49H+ NK cells seems to afford additional protection against ectromelia infection in C57BL/6 mice, suggesting that Ly49H may recognize ectromelia-infected cells with detrimental effects. Taken together, these results confirm the pivotal role of the Ly49H receptor during MCMV infection and open the way for further investigations in host-pathogen interactions.
Signaling through MyD88 Regulates Leukocyte Recruitment after Brain Injury
Authors: Babcock Alicia A. , Toft-Hansen Henrik , Owens Trevor 
Published: April 2014

Abstract
Injury to the CNS provokes an innate inflammatory reaction that engages infiltrating leukocytes with the capacity to repair and/or exacerbate tissue damage. The initial cues that orchestrate leukocyte entry remain poorly defined. We have used flow cytometry to investigate whether MyD88, an adaptor protein that transmits signals from TLRs and receptors for IL-1 and IL-18, regulates leukocyte infiltration into the stab-injured entorhinal cortex (EC) and into sites of axonal degeneration in the denervated hippocampus. We have previously established the kinetics of leukocyte entry into the denervated hippocampus. We now show that significant leukocyte entry into the EC occurs within 3–12 h of stab injury. Whereas T cells showed small, gradual increases over 8 days, macrophage infiltration was pronounced and peaked within 12–24 h. MyD88 deficiency significantly reduced macrophage and T cell recruitment to the stab-injured EC and the denervated hippocampus at 5 days post-injury. Whereas macrophage and T cell entry remained impaired into the denervated hippocampus of MyD88-deficient mice at 8 days, leukocyte infiltration into the stab-injured EC was restored to levels observed in wild-type mice. Transcripts for TNF-α, IL-1β, and CCL2, which increased &gt;50-fold after stab injury in C57BL/6 mice at the time of peak expression, were severely reduced in injured MyD88 knockout mice. Leukocyte recruitment and gene expression were unaffected in TLR2-deficient or TLR4 mutant mice. No significant differences in gene expression were observed in mice lacking IL-1R or IL-18R. These data show that MyD88-dependent signaling mediates proinflammatory gene expression and leukocyte recruitment after CNS injury.
12/15-Lipoxygenase Regulates the Inflammatory Response to Bacterial Products In Vivo
Authors: Dioszeghy Vincent , Rosas Marcela , Maskrey Benjamin H. , Colmont Chantal , Topley Nicholas , Chaitidis Pavlos , Kühn Hartmut , Jones Simon A. , Taylor Philip R. , O'Donnell Valerie B. 
Published: April 2014

Abstract
The peritoneal macrophage (Mφ) is the site of greatest 12/15-lipoxygenase (12/15-LOX) expression in the mouse; however, its immunoregulatory role in this tissue has not been explored. Herein, we show that 12/15-LOX is expressed by 95% of resident peritoneal CD11bhigh cells, with the remaining 5% being 12/15-LOX−. 12/15-LOX+ cells are phenotypically defined by high F4/80, SR-A, and Siglec1 expression, and enhanced IL-10 and G-CSF generation. In contrast, 12/15-LOX− cells are a dendritic cell population. Resident peritoneal Mφ numbers were significantly increased in 12/15-LOX−/− mice, suggesting alterations in migratory trafficking or cell differentiation in vivo. In vitro, Mφ from 12/15-LOX−/− mice exhibit multiple abnormalities in the regulation of cytokine/growth factor production both basally and after stimulation with Staphylococcus epidermidis cell-free supernatant. Resident adherent cells from 12/15-LOX−/− mice generate more IL-1, IL-3, GM-CSF, and IL-17, but less CCL5/RANTES than do cells from wild-type mice, while Staphylococcus epidermidis cell-free supernatant-elicited 12/15-LOX−/− adherent cells release less IL-12p40, IL-12p70, and RANTES, but more GM-CSF. This indicates a selective effect of 12/15-LOX on peritoneal cell cytokine production. In acute sterile peritonitis, 12/15-LOX+ cells and LOX products were cleared, then reappeared during the resolution phase. The peritoneal lavage of 12/15-LOX−/− mice showed elevated TGF-β1, along with increased immigration of monocytes/Mφ, but decreases in several cytokines including RANTES/CCL5, MCP-1/CCL2, G-CSF, IL-12-p40, IL-17, and TNF-α. No changes in neutrophil or lymphocyte numbers were seen. In summary, endogenous 12/15-LOX defines the resident MΦ population and regulates both the recruitment of monocytes/Mφ and cytokine response to bacterial products in vivo.
Reversal of Thymic Stromal Lymphopoietin-Induced Airway Inflammation through Inhibition of Th2 Responses
Authors: Zhou Baohua , Headley Mark B. , Aye Theingi , Tocker Joel , Comeau Michael R. , Ziegler Steven F. 
Published: April 2014

Abstract
Lung-specific thymic stromal lymphopoietin (TSLP) expression is sufficient for the development of an asthma-like chronic airway inflammatory disease. However, the nature of the downstream pathways that regulate disease development are not known. In this study, we used IL-4- and Stat6-deficient mice to establish the role of Th2-type responses downstream of TSLP. IL-4 deficiency greatly reduced, but did not eliminate, TSLP-induced airway hyperresponsiveness, airway inflammation, eosinophilia, and goblet cell metaplasia, while Stat6 deficiency eliminated these asthma-like symptoms. We further demonstrate, using the chronic model of TSLP-mediated airway inflammation, that blockade of both IL-4 and IL-13 responses, through administration of an anti-IL-4Rα mAb, reversed asthma-like symptoms, when given to mice with established disease. Collectively these data provide insight into the pathways engaged in TSLP-driven airway inflammation and demonstrate that simultaneous blockade of IL-4 and IL-13 can reverse established airway disease, suggesting that this may be an effective approach for the therapy of Th2-mediated inflammatory respiratory disease.
Analysis of CD97 Expression and Manipulation: Antibody Treatment but Not Gene Targeting Curtails Granulocyte Migration
Authors: Veninga Henrike , Becker Susann , Hoek Robert M. , Wobus Manja , Wandel Elke , van der Kaa Jos , van der Valk Martin , de Vos Alex F. , Haase Hannelore , Owens Bronwyn , van der Poll Tom , van Lier René A. W. , Verbeek J. Sjef , Aust Gabriela , Hamann Jörg 
Published: April 2014

Abstract
The heptahelical receptor CD97 is a defining member of the EGF-TM7 family of adhesion class receptors. In both humans and mice, CD97 isoforms are expressed with variable numbers of tandemly arranged N-terminal epidermal growth factor-like domains that facilitate interactions with distinct cellular ligands. Results from treatment of mice with mAbs in various disease models have suggested a role for CD97 in leukocyte trafficking. Here, we aimed to thoroughly characterize the expression profile of CD97, and delineate its biological function. To this end, we applied a novel polyclonal Ab, which is the first antiserum suitable for immunohistochemistry, and combined this analysis with the study of Cd97-lacZ knock-in mice. We show that similar to the situation in humans, hematopoietic, epithelial, endothelial, muscle, and fat cells expressed CD97. Despite this broad expression pattern, the Cd97−/− mouse that we created had no overt phenotype, except for a mild granulocytosis. Furthermore, granulocyte accumulation at sites of inflammation was normal in the absence of CD97. Interestingly, application of CD97 mAbs blocked granulocyte trafficking after thioglycollate-induced peritonitis in wild-type but not in knock-out mice. Hence, we conclude that CD97 mAbs actively induce an inhibitory effect that disturbs normal granulocyte trafficking, which is not perturbed by the absence of the molecule.
αβ T Cell Receptor Transfer to γδ T Cells Generates Functional Effector Cells without Mixed TCR Dimers In Vivo
Authors: van der Veken Lars T. , Coccoris Miriam , Swart Erwin , Falkenburg J. H. Frederik , Schumacher Ton N. , Heemskerk Mirjam H. M. 
Published: April 2014

Abstract
The successful application of T cell-based immunotherapeutic applications depends on the availability of large numbers of T cells with the desired Ag specificity and phenotypic characteristics. Engineering of TCR-transferred T lymphocytes is an attractive strategy to obtain sufficient T cells with an Ag specificity of choice. However, the introduction of additional TCR chains into T cells leads to the generation of T cells with unknown specificity, due to the formation of mixed dimers between the endogenous and introduced TCR chains. The formation of such potentially autoaggressive T cells may be prevented by using γδ T cells as recipient cells, but the in vivo activity of such TCR-engineered γδ T cells has not been established. In the present study, we have investigated the in vivo functionality of TCR-transduced γδ T cells, in particular their Ag specific proliferative capacity, Ag specific reactivity, in vivo persistence, and their capacity to mount recall responses. The results demonstrate that αβ TCR engineering of γδ T cells forms a feasible strategy to generate Ag-specific effector T cells that do not express mixed TCR dimers. In view of increasing concerns on the potential autoimmune consequences of mixed TCR dimer formation, the testing of αβ TCR engineered γδ T cells in clinical trials seems warranted.
CCR5 Expression Levels Influence NFAT Translocation, IL-2 Production, and Subsequent Signaling Events during T Lymphocyte Activation
Authors: Camargo Jose F. , Quinones Marlon P. , Mummidi Srinivas , Srinivas Sowmya , Gaitan Alvaro A. , Begum Kazi , Jimenez Fabio , VanCompernolle Scott , Unutmaz Derya , Ahuja Seema S. , Ahuja Sunil K. 
Published: April 2014

AbstractLigands of CCR5, the major coreceptor of HIV-1, costimulate T lymphocyte activation. However, the full impact of CCR5 expression on T cell responses remains unknown. Here, we show that compared with CCR5+/+, T cells from CCR5−/− mice secrete lower amounts of IL-2, and a similar phenotype is observed in humans who lack CCR5 expression (CCR5-Δ32/Δ32 homozygotes) as well as after Ab-mediated blockade of CCR5 in human T cells genetically intact for CCR5 expression. Conversely, overexpression of CCR5 in human T cells results in enhanced IL-2 production. CCR5 surface levels correlate positively with IL-2 protein and mRNA abundance, suggesting that CCR5 affects IL-2 gene regulation. Signaling via CCR5 resulted in NFAT transactivation in T cells that was blocked by Abs against CCR5 agonists, suggesting a link between CCR5 and downstream pathways that influence IL-2 expression. Furthermore, murine T cells lacking CCR5 had reduced levels of intranuclear NFAT following activation. Accordingly, CCR5 expression also promoted IL-2-dependent events, including CD25 expression, STAT5 phosphorylation, and T cell proliferation. We therefore suggest that by influencing a NFAT-mediated pathway that regulates IL-2 production and IL-2-dependent events, CCR5 may play a critical role in T cell responses. In accord with our prior inferences from genetic-epidemiologic studies, such CCR5-dependent responses might constitute a viral entry-independent mechanism by which CCR5 may influence HIV-AIDS pathogenesis.
Genomic Instability Resulting from Blm Deficiency Compromises Development, Maintenance, and Function of the B Cell Lineage
Authors: Babbe Holger , McMenamin Jennifer , Hobeika Elias , Wang Jing , Rodig Scott J. , Reth Michael , Leder Philip 
Published: April 2014

Abstract
The RecQ family helicase BLM is critically involved in the maintenance of genomic stability, and BLM mutation causes the heritable disorder Bloom’s syndrome. Affected individuals suffer from a predisposition to a multitude of cancer types and an ill-defined immunodeficiency involving low serum Ab titers. To investigate its role in B cell biology, we inactivated murine Blm specifically in B lymphocytes in vivo. Numbers of developing B lymphoid cells in the bone marrow and mature B cells in the periphery were drastically reduced upon Blm inactivation. Of the major peripheral B cell subsets, B1a cells were most prominently affected. In the sera of Blm-deficient naive mice, concentrations of all Ig isotypes were low, particularly IgG3. Specific IgG Ab responses upon immunization were poor and mutant B cells exhibited a generally reduced Ab class switch capacity in vitro. We did not find evidence for a crucial role of Blm in the mechanism of class switch recombination. However, a modest shift toward microhomology-mediated switch junction formation was observed in Blm-deficient B cells. Finally, a cohort of p53-deficient, conditional Blm knockout mice revealed an increased propensity for B cell lymphoma development. Impaired cell cycle progression and survival as well as high rates of chromosomal structural abnormalities in mutant B cell blasts were identified as the basis for the observed effects. Collectively, our data highlight the importance of BLM-dependent genome surveillance for B cell immunity by ensuring proper development and function of the various B cell subsets while counteracting lymphomagenesis.