bluuebunny/crossref_metadata_2025_split huggingface dataset:
CD45-Deficient Mice Accumulate Pro-B Cells Both In Vivo and In Vitro
Authors: Fleming Heather E. , Milne Craig D. , Paige Christopher J. 
Published: April 2014

Abstract
Efficient generation of mature B lineage cells requires the participation of the BCR, the pre-BCR, accessory coreceptors, and growth factor receptors. Together these receptors integrate cell intrinsic signals with regulatory pathways initiated by surrounding cells and structures. CD45 is a receptor tyrosine phosphatase expressed at high levels on all hemopoietic cells, and has been shown to modulate many signaling cascades in both positive and negative manners. In the absence of B220, the B lineage isoform of CD45, differentiation to the mature B cell stage is incomplete. We demonstrate that CD45-deficient mice also accumulate pro-B cells in the bone marrow. In vitro differentiation is altered in that B lineage populations exhibit prolonged survival in the presence of high concentrations of IL-7. Cell lines derived from CD45-deficient animals experience prolonged JAK/STAT activation in response to IL-7 stimulation, and constitutively elevated levels of phosphorylated src kinases. Aberrant IL-7Rα expression is observed in vivo, and may be responsible for the skewed development present in CD45−/− animals. Demonstrating that CD45-deficient pro-B cells are affected by the absence of B220 highlights a previously unrecognized parallel in B and T lineage precursors, and emphasizes that the presence of normal numbers of peripheral B cells does not assure that the bone marrow compartment is intact.
Mechanisms Regulating the Positioning of Mouse p47 Resistance GTPases LRG-47 and IIGP1 on Cellular Membranes: Retargeting to Plasma Membrane Induced by Phagocytosis
Authors: Martens Sascha , Sabel Katja , Lange Rita , Uthaiah Revathy , Wolf Eva , Howard Jonathan C. 
Published: April 2014

Abstract
The recently identified p47 GTPases are one of the most effective cell-autonomous resistance systems known against intracellular pathogens in the mouse. One member of the family, LRG-47, has been shown to be essential for immune control in vivo of Listeria monocytogenes, Toxoplasma gondii, Mycobacterium tuberculosis, and Mycobacterium avium, possibly by promoting acidification of the phagosome. However, the intracellular localization of LRG-47, and the nature of its association with the phagosomal or any other membrane system is unknown. In this study, we show that LRG-47 is a Golgi-associated protein in the IFN-stimulated cell, which is rapidly recruited to active plasma membrane upon phagocytosis and remains associated with phagosomes as they mature. We show that the Golgi localization of LRG-47 is dependent on the integrity of an amphipathic helix near the C terminus, whereas the plasma membrane localization depends on an unidentified signal associated with the G domain. Unlike LRG-47, but like the published p47 resistance GTPase, IGTP, a further p47 GTPase, IIGP1, is associated with the endoplasmic reticulum. However, unlike IGTP, IIGP1 is associated with the endoplasmic reticulum by an N-terminal myristoylation modification. Thus, the p47 GTPases are a diverse battery of intracellular defense factors dynamically associated with different membrane systems.
Cytoplasmic Entry of Listeria monocytogenes Enhances Dendritic Cell Maturation and T Cell Differentiation and Function
Authors: Brzoza Kristina L. , Rockel Andrea B. , Hiltbold Elizabeth M. 
Published: April 2014

Abstract
Protective immunity to the intracellular bacterial pathogen, Listeria monocytogenes, is mediated by a vigorous T cell response. In particular, CD8+ cytolytic T cells provide essential effector function in the clearance of bacterial infection. The cytoplasmic entry of Listeria facilitated by listeriolysin O is an essential feature not only of the bacteria’s virulence, but of the ability of the bacteria to elicit protective immunity in the host. To determine how cytoplasmic entry of Listeria regulates the development of protective immunity, we examined the effects of this process on the maturation of murine dendritic cells (DC) and on their ability to prime naive CD8+ T cell responses. Costimulatory molecules (CD40, CD80, and CD86) were induced by listerial infection only when the bacteria invaded the cytoplasm. In addition, the production of IL-12, IL-10, IL-6, and TNF-α was most efficiently triggered by cytosolic Listeria. Naive T cells primed by peptide-loaded DC infected with either wild-type or nonhemolytic mutant Listeria proliferated equivalently, but a much larger proportion of those primed by wild-type Listeria monocytogenes produced IFN-γ. Costimulatory molecules induced by cytosolic entry regulated T cell proliferation and, as a result, the number of functional T cells generated. DC-produced cytokines (specifically IL-12 and IL-10) were the major factors determining the proportion of T cells producing IFN-γ. These data highlight the requirement for listerial cytoplasmic invasion for the optimal priming of T cell cytokine production and attest to the importance of this event to the development of protective CTL responses to this pathogen.
Temporin A and Related Frog Antimicrobial Peptides Use Formyl Peptide Receptor-Like 1 as a Receptor to Chemoattract Phagocytes
Authors: Chen Qian , Wade David , Kurosaka Kahori , Wang Zhao Yuan , Oppenheim Joost J. , Yang De 
Published: April 2014

Abstract
Many mammalian antimicrobial peptides (AMPs) have multiple effects on antimicrobial immunity. We found that temporin A (TA), a representative frog-derived AMP, induced the migration of human monocytes, neutrophils, and macrophages with a bell-shaped response curve in a pertussis toxin-sensitive manner, activated p44/42 MAPK, and stimulated Ca2+ flux in monocytes, suggesting that TA is capable of chemoattracting phagocytic leukocytes by the use of a Giα protein-coupled receptor. TA-induced Ca2+ flux in monocytes was cross-desensitized by an agonistic ligand MMK-1 specific for formyl peptide receptor-like 1 (FPRL1) and vice versa, suggesting that TA uses FPRL1 as a receptor. This conclusion was confirmed by data showing that TA selectively stimulated chemotaxis of HEK 293 cells transfected with human FPRL1 or its mouse ortholog, murine formyl peptide receptor 2. In addition, TA elicited the infiltration of neutrophils and monocytes into the injection site of mice, indicating that TA is also functionally chemotactic in vivo. Examination of two additional temporins revealed that Rana-6 was also able to attract human phagocytes using FPRL1, but temporin 1P selectively induced the migration of neutrophils using a distinct receptor. Comparison of the chemotactic and antimicrobial activities of several synthetic analogues suggested that these activities are likely to rely on different structural characteristics. Overall, the results demonstrate that certain frog-derived temporins have the capacity to chemoattract phagocytes by the use of human FPRL1 (or its orthologs in other species), providing the first evidence suggesting the potential participation of certain amphibian antimicrobial peptides in host antimicrobial immunity.
Partial Activation of Neonatal CD11c+ Dendritic Cells and Induction of Adult-Like CD8+ Cytotoxic T Cell Responses by Synthetic Microspheres
Authors: Regner Matthias , Martinez Xavier , Belnoue Elodie , Sun Cheng-Ming , Boisgerault Florence , Lambert Paul-Henri , Leclerc Claude , Siegrist Claire-Anne 
Published: April 2014

Abstract
Neonatal cytotoxic T cell responses have only been elicited to date with immunogens or delivery systems inducing potent direct APC activation. To define the minimal activation requirements for the induction of neonatal CD8+ cytotoxic responses, we used synthetic microspheres (MS) coated with a single CD8+ T cell peptide from lymphocytic choriomeningitis virus (LCMV) or HIV-1. Unexpectedly, a single injection of peptide-conjugated MS without added adjuvant induced CD4-dependent Ag-specific neonatal murine cytotoxic responses with adult-like CTL precursor frequency, avidity for Ag, and frequency of IFN-γ-secreting CD8+ splenocytes. Neonatal CD8+ T cell responses to MS-LCMV were elicited within 2 wk of a single immunization and, upon challenge, provided similar protection from viral replication as adult CTLs, demonstrating their in vivo competence. As previously reported, peptide-coated MS elicited no detectable activation of adult CD11c+ dendritic cells (DC). In contrast, CTL responses were associated with a partial activation of neonatal CD11c+ DC, reflected by the up-regulation of CD80 and CD86 expression but no concurrent changes in MHC class II or CD40 expression. However, this partial activation of neonatal DC was not sufficient to circumvent the requirement for CD4+ T cell help. The effective induction of neonatal CD8+ T cell responses by this minimal Ag delivery system demonstrates that neonatal CD11c+ DC may mature sufficiently to stimulate naive CD8+ neonatal T cells, even in the absence of strong maturation signals.
Lipopolysaccharide Binding Protein Binds to Triacylated and Diacylated Lipopeptides and Mediates Innate Immune Responses
Authors: Schröder Nicolas W. J. , Heine Holger , Alexander Christian , Manukyan Maria , Eckert Jana , Hamann Lutz , Göbel Ulf B. , Schumann Ralf R. 
Published: April 2014

Abstract
LPS binding protein (LBP) is an acute-phase protein synthesized predominantly in the liver of the mammalian host. It was first described to bind LPS of Gram-negative bacteria and transfer it via a CD14-enhanced mechanism to a receptor complex including TLR-4 and MD-2, initiating a signal transduction cascade leading to the release of proinflammatory cytokines. In recent studies, we found that LBP also mediates cytokine induction caused by compounds derived from Gram-positive bacteria, including lipoteichoic acid and peptidoglycan fragments. Lipoproteins and lipopeptides have repeatedly been shown to act as potent cytokine inducers, interacting with TLR-2, in synergy with TLR-1 or -6. In this study, we show that these compounds also interact with LBP and CD14. We used triacylated lipopeptides, corresponding to lipoproteins of Borrelia burgdorferi, mycobacteria, and Escherichia coli, as well as diacylated lipopeptides, corresponding to, e.g., 2-kDa macrophage activating lipopeptide of Mycoplasma spp. Activation of Chinese hamster ovary cells transfected with TLR-2 by both lipopeptides was enhanced by cotransfection of CD14. Responsiveness of human mononuclear cells to these compounds was greatly enhanced in the presence of human LBP. Binding of lipopeptides to LBP as well as competitive inhibition of this interaction by LPS was demonstrated in a microplate assay. Furthermore, we were able to show that LBP transfers lipopeptides to CD14 on human monocytes using FACS analysis. These results support that LBP is a pattern recognition receptor transferring a variety of bacterial ligands including the two major types of lipopeptides to CD14 present in different receptor complexes.
Oral Administration with Papillomavirus Pseudovirus Encoding IL-2 Fully Restores Mucosal and Systemic Immune Responses to Vaccinations in Aged Mice
Authors: Fayad Raja , Zhang Hongtao , Quinn Daniel , Huang Yujun , Qiao Liang 
Published: April 2014

Abstract
Infectious diseases are one of the major threats for the elderly because their immune system is often compromised, and vaccinations to prevent these infections are not effective. A major defect in their immune system seems to be the inability of T cells to produce IL-2. We used papillomavirus (PV) pseudoviruses (PSVs) as a model vaccine and a gene delivery vector to address how to enhance immune responses to vaccinations. We found that oral immunization with PV PSV induced minimal mucosal and systemic Abs and CTLs specific for the PSVs in aged mice compared with young adult mice. In addition, fewer specific Th cells were generated in the aged mice. When aged mice were immunized with PV PSVs encoding human IL-2, specific Th cells were generated, producing murine IL-2, IL-4, and IFN-γ. Further, specific Abs and CTLs were induced, resulting in protection against mucosal viral challenge. Thus, this study provided a basis for clinical trials using PV PSVs encoding IL-2 for vaccination of the elderly.
Mature Human Langerhans Cells Derived from CD34+ Hematopoietic Progenitors Stimulate Greater Cytolytic T Lymphocyte Activity in the Absence of Bioactive IL-12p70, by Either Single Peptide Presentation or Cross-Priming, Than Do Dermal-Interstitial or Monocyte-Derived Dendritic Cells
Authors: Ratzinger Gudrun , Baggers Jan , de Cos Maria A. , Yuan Jianda , Dao Tao , Reagan John L. , Münz Christian , Heller Glenn , Young James W. 
Published: April 2014

AbstractThe emerging heterogeneity of dendritic cells (DCs) mirrors their increasingly recognized division of labor at myriad control points in innate and acquired cellular immunity. We separately generated blood monocyte-derived DCs (moDCs), as well as Langerhans cells (LCs) and dermal-interstitial DCs (DDC-IDCs) from CD34+ hematopoietic progenitor cells. Differential expression of CD11b, CD52, CD91, and the CD1 isoforms proved useful in distinguishing these three DC types. All mature DCs uniformly expressed comparable levels of HLA-DR, CD83, CD80, and CD86, and were potent stimulators of allogeneic T cells after exposure either to recombinant human CD40L trimer or a combination of inflammatory cytokines with PGE2. moDCs, however, required 0.5–1 log greater numbers than LCs or DDC-IDCs to stimulate comparable T cell proliferation. Only moDCs secreted the bioactive heterodimer IL-12p70, and moDCs phagocytosed significantly more dying tumor cells than did either LCs or DDC-IDCs. LCs nevertheless proved superior to moDCs and DDC-IDCs in stimulating CTL against a recall viral Ag by presenting passively loaded peptide or against tumor Ag by cross-priming autologous CD8+ T cells. LCs also secreted significantly more IL-15 than did either moDCs or DDC-IDCs, which is especially important to the generation of CTL. These findings merit further comparisons in clinical trials designed to determine the physiologic relevance of these distinctions in activity between LCs and other DCs.
Characterization and Recruitment of Plasmacytoid Dendritic Cells in Synovial Fluid and Tissue of Patients with Chronic Inflammatory Arthritis
Authors: Lande Roberto , Giacomini Elena , Serafini Barbara , Rosicarelli Barbara , Sebastiani Gian Domenico , Minisola Giovanni , Tarantino Umberto , Riccieri Valeria , Valesini Guido , Coccia Eliana M. 
Published: April 2014

Abstract
Dendritic cells (DCs) are thought to play a key role in driving the immunopathogenic response underlying chronic inflammatory arthritis. In this study, we have examined the presence and phenotype of plasmacytoid DCs (pDCs) in the synovial fluids (SF) of patients with rheumatoid arthritis (RA), psoriatic arthritis (PA), and osteoarthritis (OA) and determined the chemotactic properties of SF from these patients toward pDCs. Flow cytometry analysis showed that the percentage of pDCs, identified as a population of Lin−CD123++ cells, is 4- to 5-fold higher in RA SF and PA SF than in OA SF. The morphological and immunophenotypic characterization of pDCs isolated from PA and RA SF indicates that they are in an immature state, most likely due to inhibitory factors present in RA SF, but are still able to undergo maturation when exposed ex vivo to viral agent or unmethylated DNA. CD123+ and BDCA2+ pDCs were detected by immunohistochemistry in RA synovial tissue in which expression of the IFN-α-inducible protein MxA was also found, suggesting production of type I IFN by maturing pDCs. We also show that CXCR3 and CXCR4 are expressed by both blood-derived pDCs and pDCs isolated from RA and PA SF and that CXCL-10, CXCL-11, and CXCL-12 present in RA and PA SF stimulate chemotaxis of blood-derived pDCs. Altogether, these findings suggest that chemokine-driven recruitment of pDCs from the blood to the inflamed synovium could be important in the regulation of the immune response in chronic inflammatory arthritis.
Epitope-Dependent Inhibition of T Cell Activation by theEaTransgene: An Explanation for Transgene-Mediated Protection from Murine Lupus
Authors: Martinez-Soría Eduardo , Ibnou-Zekri Nabila , Iwamoto Masahiro , Santiago-Raber Marie-Laure , Kikuchi Shuichi , Kosco-Vilbois Marie , Izui Shozo 
Published: April 2014

AbstractA high level expression of the Ead transgene encoding the I-E α-chain is highly effective in the suppression of lupus autoantibody production in mice. To explore the possible modulation of the Ag-presenting capacity of B cells as a result of the transgene expression, we assessed the ability of the transgenic B cells to activate Ag-specific T cells in vitro. By using four different model Ag-MHC class II combinations, this analysis revealed that a high transgene expression in B cells markedly inhibits the activation of T cells in an epitope-dependent manner, without modulation of the I-E expression. The transgene-mediated suppression of T cell responses is likely to be related to the relative affinity of peptides derived from transgenic I-E α-chains (Eα peptides) vs antigenic peptides to individual class II molecules. Our results support a model of autoimmunity prevention based on competition for Ag presentation, in which the generation of large amounts of Eα peptides with high affinity to I-A molecules decreases the use of I-A for presentation of pathogenic self-peptides by B cells, thereby preventing excessive activation of autoreactive T and B cells.
License to Heal: Bidirectional Interaction of Antigen-Specific Regulatory T Cells and Tolerogenic APC
Authors: Vlad George , Cortesini Raffaello , Suciu-Foca Nicole 
Published: April 2014

Abstract
Naturally occurring CD4+CD25+ regulatory T (TR) cells, a component of the innate immune response, which play a key role in the maintenance of self-tolerance, have become the focus of numerous studies over the last decade. These cells inhibit the immune response in an Ag-nonspecific manner, interacting with other T cells. Much less is known about adaptive TR cells, which develop in response to chronic antigenic stimulation, and act directly on professional and nonprofessional APC, rendering them tolerogenic and able to elicit the differentiation of CD8+ and CD4+ T cells with suppressive activity. In this review, we will discuss data pertaining to the bidirectional interaction between Ag-specific TR with APC and their clinical relevance.
Cutting Edge: The Acquisition of TLR Tolerance during Malaria Infection Impacts T Cell Activation
Authors: Perry James A. , Olver Christine S. , Burnett Robert C. , Avery Anne C. 
Published: April 2014

Abstract
An effective immune response to infection requires control of pathogen growth while minimizing inflammation-associated pathology. During malaria infection, this balance is particularly important. Murine malaria is characterized by early production of proinflammatory cytokines, which declines in the face of continuing parasitemia. The mechanism by which this occurs remains poorly understood. In this study, we investigated the role of dendritic cells (DCs) in regulating pro- and anti-inflammatory cytokine responses. As malaria infection progresses, DCs become refractory to TLR-mediated IL-12 and TNF-α production, while increasing their ability to produce IL-10 and retaining the capacity for activation of naive T cells. IL-12-secreting DCs from early infection stimulate an IFN-γ-dominated T cell response, whereas IL-10-secreting DCs from later stages induce an IL-10-dominated T cell response. We suggest that phenotypic changes in DCs during Plasmodium yoelii infection represent a mechanism of controlling host inflammation while maintaining effective adaptive immunity.
Cutting Edge: Emergence of CD127high Functionally Competent Memory T Cells Is Compromised by High Viral Loads and Inadequate T Cell Help
Authors: Fuller Michael J. , Hildeman David A. , Sabbaj Steffanie , Gaddis Dalia E. , Tebo Anne E. , Shang Liang , Goepfert Paul A. , Zajac Allan J. 
Published: April 2014

Abstract
In this report we have inspected whether difficulties in controlling viral infections negatively impacts the generation of CD127high memory T cells. Using both MHC class I and II tetramers we reveal that CD127low T cells are not necessarily rapidly deleted but can persist in a pseudoeffector state in which they display the hallmarks of activated effector cells but are functionally inferior. CD127high cells can, however, emerge if the infection is contained. We also show that in the absence of CD4 T cell help significant populations of CD127high CD8 T cells fail to emerge. Analyses of cytokine-producing activities by both mouse and human CD8 T cells further document that the extended maintenance of T cells in a CD127low state has functional consequences which manifest as an impairment of IL-2 production.
Cutting Edge: The SLAM Family Receptor Ly108 Controls T Cell and Neutrophil Functions
Authors: Howie Duncan , Laroux F. Stephen , Morra Massimo , Satoskar Abhay R. , Rosas Lucia E. , Faubion William A. , Julien Aimee , Rietdijk Svend , Coyle Anthony J. , Fraser Christopher , Terhorst Cox 
Published: April 2014

AbstractLy108, a glycoprotein of the signaling lymphocytic activation molecule family of cell surface receptors expressed by T, B, NK, and APCs has been shown to have a role in NK cell cytotoxicity and T cell cytokine responses. In this study, we describe that CD4+ T cells from mice with a targeted disruption of exons 2 and 3 of Ly108 (Ly108ΔE2+3) produce significantly less IL-4 than wild-type CD4+ cells, as judged by in vitro assays and by in vivo responses to cutaneous infection with Leishmania mexicana. Surprisingly, neutrophil functions are controlled by Ly108. Ly108ΔE2+3 mice are highly susceptible to infection with Salmonella typhimurium, bactericidal activity of Ly108ΔE2+3 neutrophils is defective, and their production of IL-6, IL-12, and TNF-α is increased. The aberrant bactericidal activity by Ly108ΔE2+3 neutrophils is a consequence of severely reduced production of reactive oxygen species following phagocytosis of bacteria. Thus, Ly108 serves as a regulator of both innate and adaptive immune responses.
Cutting Edge: Re-evaluating the In Vivo Cytokine Responses of CD8+ T Cells during Primary and Secondary Viral Infections
Authors: Liu Fei , Whitton J. Lindsay 
Published: April 2014

Abstract
Virus-specific CD8+ T cells produce IFN-γ after Ag contact and, in the absence of this cytokine, the host often cannot eradicate infection. However, our ability to identify cells that are actively expressing this critical effector function in vivo is limited, because the protein is rapidly secreted. In this study, we describe a simple approach that circumvents the need for ex vivo Ag stimulation and allows the enumeration of CD8+ T cells that are actively synthesizing IFN-γ in vivo during primary and secondary virus infections. The proportion of Ag-specific primary CD8+ T cells producing IFN-γ peaks at 5 days postinfection, when the T cell population is still expanding exponentially. In vivo IFN-γ synthesis by memory cells is explosive, peaking at ∼12 h after secondary infection and terminating hours thereafter. This technique will be useful when evaluating in vivo immune cell activity in many situations, including a variety of noninfectious (e.g., autoimmune) diseases.