bluuebunny/crossref_metadata_2025_split huggingface dataset:
Mycobacterium tuberculosis Recall Antigens Suppress HIV-1 Replication in Anergic Donor Cells via CD8+ T Cell Expansion and Increased IL-10 Levels
Authors: Ranjbar Shahin , Ly Nary , Thim Sok , Reynes Jean-Marc , Goldfeld Anne E. 
Published: April 2014

Abstract
Mycobacterium tuberculosis (MTb) is the leading cause of death in the setting of AIDS. MTb enhances the pathogenicity and accelerates the course of HIV disease and, furthermore, infection with HIV-1 increases the risk of reactivation or reinfection with MTb. In this study, we show that host-specific recall responses to one pathogen, MTb, has a direct effect upon the regulation of a second pathogen, HIV-1. Using cells from immunocompetent former tuberculosis (TB) patients who displayed either a persistently positive (responsive) or negative (anergic), delayed-type hypersensitivity (DTH) reaction to intradermal injection of purified protein derivative (PPD), we investigated the effect of recall Ags to MTb upon the replication of HIV-1 primary isolates in vitro. We show that HIV-1 replication of a T cell-tropic isolate was significantly impaired in MTb-stimulated PBMC from PPD-anergic donors. Furthermore, these donors displayed a significant increase in CD8+ T cells and IL-10 levels and lower levels of IL-2 and TNF-α relative to PPD-responsive donors in response to PPD stimulation. Strikingly, CD8+ T cell depletion and blocking of IL-10 significantly increased HIV-1 replication in these PPD-anergic donors, indicating that an immunosuppressive response to MTb recall Ags inhibits HIV-1 replication in PPD-anergic individuals. Therefore, immunotherapeutic approaches aimed at recapitulating Ag-specific MTb anergy in vivo could result in novel and effective approaches to inhibit HIV-1 disease progression in MTb/HIV-1 coinfection.
Molecular Analysis of TCR Clonotypes in LGL: A Clonal Model for Polyclonal Responses
Authors: O’Keefe Christine L. , Plasilova Magdalena , Wlodarski Marcin , Risitano Antonio M. , Rodriguez Alexander R. , Howe Evan , Young Neal S. , Hsi Eric , Maciejewski Jaroslaw P. 
Published: April 2014

Abstract
Large granular lymphocytic (LGL) leukemia is a clonal lymphoproliferative disorder of CTL associated with cytopenias resulting from an immune and cytokine attack on hemopoietic progenitor cells. Extreme clonality of CTL expansions seen in LGL leukemia makes it an ideal model to study the role of the T cell repertoire in other less-polarized immune-mediated disorders. Complementarity-determining region 3 (CDR3) of the TCR is a unique Ag-specific region that can serve as a molecular marker, or clonotype, of the disease-specific T cells. We studied the variable portion of the β-chain spectrum in a cohort of LGL leukemia patients. The CDR3 sequences were determined for the immunodominant clones and used to design clonotype-specific primers. By direct and semi-nested amplification, clonotype amplicons were found to be shared by multiple patients and controls. Analysis of the generated sequences demonstrated that the original clonotypes are rarely encountered in normal control samples; however, high levels of homology were found in both controls and patients. Clonotypes derived from individual LGL patients can be used as tumor markers for the malignant clone. More generally, clonotypic analysis and comparison of the variable portion of the β-chain CDR3-specific sequences from a large number of patients may lead to better subclassification of not only LGL but also other immune-mediated disorders.
Cutting Edge: Activation of Toll-Like Receptor 2 Induces a Th2 Immune Response and Promotes Experimental Asthma
Authors: Redecke Vanessa , Häcker Hans , Datta Sandip K. , Fermin Agnes , Pitha Paula M. , Broide David H. , Raz Eyal 
Published: April 2014

Abstract
Recognition of microbial components by APCs and their activation through Toll-like receptors (TLR) leads to the induction of adaptive immune responses. In this study, we show that activation of TLR2 by its synthetic ligand Pam3Cys, in contrast to activation of TLR9 by immunostimulatory DNA (ISS-ODN), induces a prominent Th2-biased immune response. Activation of APCs by Pam3Cys resulted in the induction of Th2-associated effector molecules like IL-13, and IL-1β, GM-CSF and up-regulation of B7RP-1, but low levels of Th1-associated cytokines (IL-12, IFNα, IL-18, IL-27). Accordingly, TLR2 ligands aggravated experimental asthma. These data indicate that the type of TLR stimulation during the initial phase of immune activation determines the polarization of the adaptive immune response and may play a role in the initiation of Th2-mediated immune disorders, such as asthma.
Depletion of CXCR2 Inhibits Tumor Growth and Angiogenesis in a Murine Model of Lung Cancer
Authors: Keane Michael P. , Belperio John A. , Xue Ying Y. , Burdick Marie D. , Strieter Robert M. 
Published: April 2014

Abstract
The Glu-Leu-Arg+ (ELR+) CXC chemokines are potent promoters of angiogenesis and have been demonstrated to induce a significant portion of nonsmall cell lung cancer-derived angiogenic activity and support tumorigenesis. ELR+ CXC chemokines share a common chemokine receptor, CXCR2. We hypothesized that CXCR2 mediates the proangiogenic effects of ELR+ CXC chemokines during tumorigenesis. To test this postulate, we used syngeneic murine Lewis lung cancer (LLC; 3LL, H-2b) heterotopic and orthotopic tumor model systems in C57BL/6 mice replete (CXCR2+/+) and deficient in CXCR2 (CXCR2−/−). We first demonstrated a correlation of the expression of endogenous ELR+ CXC chemokines with tumor growth and metastatic potential of LLC tumors. Next, we found that LLC primary tumors were significantly reduced in growth in CXCR2−/− mice. Moreover, we found a marked reduction in the spontaneous metastases of heterotopic tumors to the lungs of CXCR2−/− mice. Morphometric analysis of the primary tumors in CXCR2−/− mice demonstrated increased necrosis and reduced vascular density. These findings were further confirmed in CXCR2+/+ mice using specific neutralizing Abs to CXCR2. The results of these studies support the notion that CXCR2 mediates the angiogenic activity of ELR+ CXC chemokines in a preclinical model of lung cancer.
Lassa Virus Infection of Human Dendritic Cells and Macrophages Is Productive but Fails to Activate Cells
Authors: Baize Sylvain , Kaplon Jérôme , Faure Caroline , Pannetier Delphine , Georges-Courbot Marie-Claude , Deubel Vincent 
Published: April 2014

AbstractLassa fever is a hemorrhagic fever caused by Lassa virus (LV), an old-world Arenavirus. Little is known about the immune responses that occur during the disease, but protection seems to be linked to the induction of cellular responses specific for viral glycoproteins. Conversely, severe Lassa fever may be associated with immunosuppression. We studied the infection of human dendritic cells (DC) and macrophages (MP) by LV. Both these cell types are susceptible to LV infection. Viral nucleoprotein was detected in DC and MP, and high and moderate viral titers were obtained with culture supernatants of DC and MP, respectively. LV did not induce apoptosis in DC and MP. These cells were not activated by LV infection. No change was observed in the expression of surface molecules involved in activation, costimulation, adhesion, and Ag presentation following LV infection, or in the functional properties of DC. Inflammatory cytokine production was not detected at the mRNA or protein level after LV infection of DC and MP. Thus, MP, and particularly DC, are crucial targets for LV and are probably involved in the early replication of LV from the initial site of infection. The lack of activation and maturation of cells following infection may be associated with the immunosuppression observed in severe LV infection.
Analysis of Autoreactive CD4 T Cells in Experimental Autoimmune Encephalomyelitis after Primary and Secondary Challenge Using MHC Class II Tetramers
Authors: Bischof Felix , Hofmann Matthias , Schumacher Ton N. M. , Vyth-Dreese Florry A. , Weissert Robert , Schild Hansjörg , Kruisbeek Ada M. , Melms Arthur 
Published: April 2014

Abstract
Experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis, is primarily mediated by CD4 T cells specific for Ags in the CNS. Using MHC class II tetramers, we assessed expansion and phenotypic differentiation of polyclonal self-reactive CD4 T cells during EAE after primary and secondary challenge with the specific Ag. After EAE induction in SJL mice with proteolipid protein 139–151, CNS-specific T cells up-regulated activation markers and expanded in the draining lymph nodes and in the spleen. Less than 20% of total autoreactive T cells entered the CNS simultaneously with Th cells of other specificities. Almost all tetramer-positive cells in the CNS were activated and phenotypically distinct from the large peripheral pool. When EAE was induced in Ag-experienced mice, disease symptoms developed earlier and persisted longer; autoreactive T cells were more rapidly activated and invaded the CNS earlier. In striking contrast to specific CTLs that respond after secondary viral challenge, the absolute numbers of autoreactive CD4 T cells were not increased, indicating that the accelerated autoreactivity in Ag-experienced mice is not related to higher frequencies of autoreactive CD4 T cells.
Spontaneous Organ-Specific Th2-Mediated Autoimmunity in TCR Transgenic Mice
Authors: Candon Sophie , McHugh Rebecca S. , Foucras Gilles , Natarajan Kannan , Shevach Ethan M. , Margulies David H. 
Published: April 2014

Abstract
CD4+ T cells that lead to autoimmune gastritis (AIG) in BALB/c mice are either Th1 or Th2 cells. To test whether the phenotype of disease is related to the particular TCR expressed by the pathogenic cell, we have generated several lines of TCR transgenic mice using receptors cloned from pathogenic Th1 or Th2 cells. We previously described spontaneous inflammatory AIG in A23 mice, caused by the transgenic expression of the TCR from a Th1 clone, TXA23. In this study we describe the generation of A51 mouse lines, transgenic for the TCR of a CD4+ self-reactive Th2 clone, TXA51. A proportion of A51 mice spontaneously develop AIG by 10 wk of age, with a disease characterized by eosinophilic infiltration of the gastric mucosa and Th2 differentiation of transgenic T cells in the gastric lymph node. The Th2 phenotype of this autoimmune response seems to be related to a low availability of MHC class II-self peptide complexes. This in vivo model of spontaneous Th2-mediated, organ-specific autoimmunity provides a unique example in which the clonotypic TCR conveys the Th2 disease phenotype.
A Regulatory Role for CD37 in T Cell Proliferation
Authors: van Spriel Annemiek B. , Puls Kirsten L. , Sofi Mariam , Pouniotis Dodie , Hochrein Hubertus , Orinska Zane , Knobeloch Klaus-Peter , Plebanski Magdalena , Wright Mark D. 
Published: April 2014

Abstract
CD37 is a leukocyte-specific protein belonging to the tetraspanin superfamily. Previously thought to be predominantly a B cell molecule, CD37 is shown in this study to regulate T cell proliferation. CD37-deficient (CD37−/−) T cells were notably hyperproliferative in MLR, in response to Con A, or CD3-TCR engagement particularly in the absence of CD28 costimulation. Hyperproliferation was not due to differences in memory to naive T cell ratios in CD37−/− mice, apoptosis, or TCR down-modulation. Division cycle analyses revealed CD37−/− T cells to enter first division earlier than wild-type T cells. Importantly, proliferation of CD37−/− T cells was preceded by enhanced early IL-2 production. We hypothesized CD37 to be involved in TCR signaling and this was supported by the observation that CD4/CD8-associated p56Lck kinase activity was increased in CD37−/− T cells. Remarkably, CD37 cross-linking on human T cells transduced signals that led to complete inhibition of CD3-induced proliferation. In the presence of CD28 costimulation, CD37 engagement still significantly reduced proliferation. Taken together, these results demonstrate a regulatory role for CD37 in T cell proliferation by influencing early events of TCR signaling.
Physical and Functional Interactions between Daxx and DNA Methyltransferase 1-Associated Protein, DMAP1
Authors: Muromoto Ryuta , Sugiyama Kenji , Takachi Akie , Imoto Seiyu , Sato Noriko , Yamamoto Tetsuya , Oritani Kenji , Shimoda Kazuya , Matsuda Tadashi 
Published: April 2014

Abstract
Daxx has been shown to play an essential role in type I IFN-αβ-mediated suppression of B cell development and apoptosis. Recently, we demonstrated that Tyk2 is directly involved in IFN signaling for the induction and translocation of Daxx, which may result in growth arrest and/or apoptosis of B lymphocyte progenitors. To clarify how Daxx regulates B cell development, we examined Daxx interacting partners by yeast two-hybrid screening. DNA methyltransferase 1 (DNMT1)-associated protein (DMAP1) was identified and demonstrated to interact with Daxx. The interaction regions in both proteins were mapped, and the cellular localization of the interaction was examined. Both Daxx and DMAP1 formed a complex with DNMT1 and colocalized in the nucleus. DMAP1 enhanced Daxx-mediated repression of glucocorticoid receptor transcriptional activity. Furthermore, Daxx protected protein degradation of DMAP1 in vivo. These results provide the novel molecular link between Daxx and DNMT1, which establishes a repressive transcription complex in the nucleus.
A Peptide That Antagonizes TCR-Mediated Reactions with Both Syngeneic and Allogeneic Agonists: Functional and Structural Aspects
Authors: Rudolph Markus G. , Shen Lucy Q. , Lamontagne Stephen A. , Luz John G. , Delaney Joseph R. , Ge Qing , Cho Bryan K. , Palliser Deborah , McKinley Carol A. , Chen Jianzhu , Wilson Ian A. , Eisen Herman N. 
Published: April 2014

Abstract
We identify and consider some characteristics of a peptide antagonist for the Ag-specific receptor on 2C cells (the 2C TCR). The peptide, GNYSFYAL (called GNY), binds to H-2Kb, and a very high-resolution crystal structure of the GNY-Kb complex at 1.35 Å is described. Although the GNY peptide does not bind to Ld, the potency of GNY-Kb as an antagonist is evident from its ability to specifically inhibit 2C TCR-mediated reactions to an allogenic agonist complex (QLSPFPFDL-Ld), as well as to a syngeneic agonist complex (SIYRYYGL-Kb). The crystal structure and the activities of alanine-substituted peptide variants point to the properties of the peptide P4 side chain and the conformation of the Tyr-P6 side chain as the structural determinants of GNYSFYAL antagonist activity.
The Classical Activation Pathway of the Human Complement System Is Specifically Inhibited by Calreticulin from Trypanosoma cruzi
Authors: Ferreira Viviana , Valck Carolina , Sánchez Gittith , Gingras Alexandre , Tzima Sotiria , Molina María Carmen , Sim Robert , Schwaeble Wilhelm , Ferreira Arturo 
Published: April 2014

Abstract
The high resistance of Trypanosoma cruzi trypomastigotes, the causal agent of Chagas’ disease, to complement involves several parasite strategies. In these in vitro studies, we show that T. cruzi calreticulin (TcCRT) and two subfragments thereof (TcCRT S and TcCRT R domains) bind specifically to recognition subcomponents of the classical and lectin activation pathways (i.e., to collagenous tails of C1q and to mannan-binding lectin) of the human complement system. As a consequence of this binding, specific functional inhibition of the classical pathway and impaired mannan-binding lectin to mannose were observed. By flow cytometry, TcCRT was detected on the surface of viable trypomastigotes and, by confocal microscopy, colocalization of human C1q with surface TcCRT of infective trypomastigotes was visualized. Taken together, these findings imply that TcCRT may be a critical factor contributing to the ability of trypomastigotes to interfere at the earliest stages of complement activation.
Hemozoin-Inducible Proinflammatory Events In Vivo: Potential Role in Malaria Infection
Authors: Jaramillo Maritza , Plante Isabelle , Ouellet Nathalie , Vandal Karen , Tessier Philippe A. , Olivier Martin 
Published: April 2014

Abstract
During malaria infection, high levels of proinflammatory molecules (e.g., cytokines, chemokines) correlate with disease severity. Even if their role as activators of the host immune response has been studied, the direct contribution of hemozoin (HZ), a parasite metabolite, to such a strong induction is not fully understood. Previous in vitro studies demonstrated that both Plasmodium falciparum HZ and synthetic HZ (sHZ), β-hematin, induce macrophage/monocyte chemokine and proinflammatory cytokine secretion. In the present study, we investigated the proinflammatory properties of sHZ in vivo. To this end, increasing doses of sHZ were injected either i.v. or into an air pouch generated on the dorsum of BALB/c mice over a 24-h period. Our results showed that sHZ is a strong modulator of leukocyte recruitment and more specifically of neutrophil and monocyte populations. In addition, evaluation of chemokine and cytokine mRNA and protein expression revealed that sHZ induces the expression of chemokines, macrophage-inflammatory protein (MIP)-1α/CCL3, MIP-1β/CCL4, MIP-2/CXCL2, and monocyte chemoattractant protein-1/CCL2; chemokine receptors, CCR1, CCR2, CCR5, CXCR2, and CXCR4; cytokines, IL-1β and IL-6; and myeloid-related proteins, S100A8, S100A9, and S100A8/A9, in the air pouch exudates. Of interest, chemokine and cytokine mRNA up-regulation were also detected in the liver of i.v. sHZ-injected mice. In conclusion, our study demonstrates that sHZ is a potent proinflammatory agent in vivo, which could contribute to the immunopathology related to malaria.
The Group B Streptococcal β and Pneumococcal Hic Proteins Are Structurally Related Immune Evasion Molecules That Bind the Complement Inhibitor Factor H in an Analogous Fashion
Authors: Jarva Hanna , Hellwage Jens , Jokiranta T. Sakari , Lehtinen Markus J. , Zipfel Peter F. , Meri Seppo 
Published: April 2014

AbstractComplement evasion by different mechanisms is important for microbial virulence and survival in the host. One strategy used by pathogenic bacteria is to bind the soluble complement inhibitor factor H (fH) to their surfaces. In group B streptococci and pneumococci, fH binding has been shown to be mediated by the surface proteins β and Hic, respectively. We showed previously that Hic binds to the middle region of fH and protects the pneumococcus from opsonophagocytosis. As the β protein and Hic are structurally closely related, we wanted to compare the fH binding characteristics of these two proteins. By using direct binding assays with radiolabeled proteins and surface plasmon resonance analysis we show that both β and Hic bind to the short consensus repeats 8–11 and 12–14 in the middle region of fH. Peptide mapping analysis suggested that the fH-binding sites on β and Hic were composed of discontinuous and partially homologous sequences. Thus, the bacterial virulence proteins use multiple binding sites on fH to secure high avidity. Also, the functionally active sites on fH are thereby left free to inhibit C3b deposition and opsonophagocytosis. These results reveal the evolutionary conservation of an analogous immune evasion strategy in different types of pathogenic streptococci. Importantly, the respective virulence factors could be exploited in the development of protein-based vaccines against these pathogens.
The Pathogenesis of Schistosomiasis Is Controlled by Cooperating IL-10-Producing Innate Effector and Regulatory T Cells
Authors: Hesse Matthias , Piccirillo Ciriaco A. , Belkaid Yasmine , Prufer Jeannette , Mentink-Kane Margaret , Leusink Mary , Cheever Allen W. , Shevach Ethan M. , Wynn Thomas A. 
Published: April 2014

Abstract
IL-10 reduces immunopathology in many persistent infections, yet the contribution of IL-10 from distinct cellular sources remains poorly defined. We generated IL-10/recombination-activating gene (RAG)2-deficient mice and dissected the role of T cell- and non-T cell-derived IL-10 in schistosomiasis by performing adoptive transfers. In this study, we show that IL-10 is generated by both the innate and adaptive immune response following infection, with both sources regulating the development of type-2 immunity, immune-mediated pathology, and survival of the infected host. Importantly, most of the CD4+ T cell-produced IL-10 was confined to a subset of T cells expressing CD25. These cells were isolated from egg-induced granulomas and exhibited potent suppressive activity in vitro. Nevertheless, when naive, naturally occurring CD4+CD25+ cells were depleted in adoptive transfers, recipient IL-10/RAG2-deficient animals were more susceptible than RAG2-deficient mice, confirming an additional host-protective role for non-T cell-derived IL-10. Thus, innate effectors and regulatory T cells producing IL-10 cooperate to reduce morbidity and prolong survival in schistosomiasis.
Persistent and Selective Deficiency of CD4+ T Cell Immunity to Cytomegalovirus in Immunocompetent Young Children
Authors: Tu Wenwei , Chen Sharon , Sharp Margaret , Dekker Corry , Manganello Anne Marie , Tongson Eileen C. , Maecker Holden T. , Holmes Tyson H. , Wang Zhaoti , Kemble George , Adler Stuart , Arvin Ann , Lewis David B. 
Published: April 2014

Abstract
Healthy young children who acquire CMV have prolonged viral shedding into the urine and saliva, but whether this is attributable to limitations in viral-specific immune responses has not been explored. In this study, we found that otherwise immunocompetent young children after recent primary CMV infection accumulated markedly fewer CMV-specific CD4+ T cells that produced IFN-γ than did adults. These differences in CD4+ T cell function persisted for more than 1 year after viral acquisition, and did not apply to CMV-specific IFN-γ production by CD8+ T cells. The IFN-γ-producing CD4+ T cells of children or adults that were reactive with CMV Ags were mainly the CCR7low cell subset of memory (CD45R0highCD45RAlow) cells. The decreased IFN-γ response to CMV in children was selective, because their CCR7low memory CD4+ T cells and those of adults produced similar levels of this cytokine after stimulation with staphylococcal enterotoxin B superantigen. CD4+ T cells from children also had reduced CMV-specific IL-2 and CD154 (CD40 ligand) expression, suggesting an early blockade in the differentiation of viral-specific CD4+ T cells. Following CMV acquisition, children, but not adults, persistently shed virus in urine, and this was observable for at least 29 mo postinfection. Thus, CD4+ T cell-mediated immunity to CMV in humans is generated in an age-dependent manner, and may have a substantial role in controlling renal viral replication and urinary shedding.