bluuebunny/crossref_metadata_2025_split huggingface dataset:
Mycobacterium tuberculosisInfects Dendritic Cells with High Frequency and Impairs Their Function In Vivo
Authors: Wolf Andrea J. , Linas Beth , Trevejo-Nuñez Giraldina J. , Kincaid Eleanor , Tamura Toshiki , Takatsu Kiyoshi , Ernst Joel D. 
Published: April 2014

AbstractMycobacterium tuberculosis (Mtb) is thought to reside in macrophages, although infected dendritic cells (DCs) have been observed. Thus, although cellular associations have been made, global characterization of the cells harboring Mtb is lacking. We have performed temporal and quantitative characterization of the cells harboring Mtb following aerosol infection of mice by using GFP-expressing bacteria and flow cytometry. We discovered that Mtb infects phagocytic cells of diverse phenotypes, that the predominant infected cell populations change with time, and that myeloid DCs are the major cell population infected with Mtb in the lungs and lymph nodes. We also found that the bacteria in the lung-draining lymph node are transported there from the lungs by a CCL19/21-dependent mechanism and that the transport of bacteria to the lymph node is a transient phenomenon despite chronic infection. In addition, we found that the lymph node cell subsets that are most efficacious in stimulating Mtb-specific, TCR-transgenic CD4+ T lymphocytes are not infected with the bacteria and are scarce or absent from the lungs of infected mice. Finally, we found that the lung cell populations that are infected with Mtb at high frequency are relatively ineffective at stimulating Ag-specific CD4+ T lymphocytes, and we have obtained evidence that live Mtb can inhibit MHC class II Ag presentation without a decrease in the surface expression of MHC class II. These results indicate that Mtb targets DC migration and Ag presentation in vivo to promote persistent infection.
Baseline Viral Load and Immune Activation Determine the Extent of Reconstitution of Innate Immune Effectors in HIV-1-Infected Subjects Undergoing Antiretroviral Treatment
Authors: Chehimi Jihed , Azzoni Livio , Farabaugh Matthew , Creer Shenoa A. , Tomescu Costin , Hancock Aidan , Mackiewicz Agnes , D’Alessandro Lara , Ghanekar Smita , Foulkes Andrea S. , Mounzer Karam , Kostman Jay , Montaner Luis J. 
Published: April 2014

Abstract
We analyzed dendritic cell (DC) and NK cell compartments in relation to CD4 recovery in 21 HIV-infected subjects followed to &lt;50 copies/ml once starting antiretroviral therapy (ART) and observed for 52 wk of sustained suppression. Although CD4 counts increased in all subjects in response to ART, we observed a restoration of functional plasmacytoid DC (PDC) after 52 wk of sustained suppression under ART (from 1850 cells/ml to 4550 cells/ml) to levels comparable to controls (5120 cells/ml) only in subjects with a low baseline viral load, which also rapidly suppressed to &lt;50 copies/ml upon ≤60 days from ART initiation. Recovery of PDC at week 52 correlates with level of CD95 expression on CD8 T cells and PDC frequency following first ART suppression. NK cytotoxic activity increased rapidly upon viral suppression (VS) and correlated with PDC function at week 52. However, restoration of total NK cells was incomplete even after 52 wk on ART (73 cells/μl vs 122 cells/μl in controls). Direct reconstitution experiments indicate that NK cytotoxic activity against virally infected target cells requires DC/NK cooperation, and can be recovered upon sustained VS and recovery of functional PDC (but not myeloid DC) from ART-suppressed subjects. Our data indicate that viremic HIV-infected subjects may have different levels of reconstitution of DC and NK-mediated function following ART, with subjects with lower initial viremia and the greatest reduction of baseline immune activation at VS achieving the greatest level of innate effector cell reconstitution.
African Trypanosomiasis: Naturally Occurring Regulatory T Cells Favor Trypanotolerance by Limiting Pathology Associated with Sustained Type 1 Inflammation
Authors: Guilliams Martin , Oldenhove Guillaume , Noel Wim , Hérin Michel , Brys Lea , Loi Patrizia , Flamand Véronique , Moser Muriel , De Baetselier Patrick , Beschin Alain 
Published: April 2014

Abstract
Tolerance to African trypanosomes requires the production of IFN-γ in the early stage of infection that triggers the development of classically activated macrophages controlling parasite growth. However, once the first peak of parasitemia has been controlled, down-regulation of the type 1 immune response has been described. In this study, we have evaluated whether regulatory T cells (Tregs) contribute to the limitation of the immune response occurring during Trypanosoma congolense infection and hereby influence the outcome of the disease in trypanotolerant C57BL/6 host. Our data show that Foxp3+ Tregs originating from the naturally occurring Treg pool expanded in the spleen and the liver of infected mice. These cells produced IL-10 and limited the production of IFN-γ by CD4+ and CD8+ effector T cells. Tregs also down-regulated classical activation of macrophages resulting in reduced TNF-α production. The Treg-mediated suppression of the type 1 inflammatory immune response did not hamper parasite clearance, but was beneficial for the host survival by limiting the tissue damages, including liver injury. Collectively, these data suggest a cardinal role for naturally occurring Tregs in the development of a trypanotolerant phenotype during African trypanosomiasis.
Regulation of Antibody-Dependent Cellular Cytotoxicity by IgG Intrinsic and Apparent Affinity for Target Antigen
Authors: Tang Yong , Lou Jianlong , Alpaugh R. Katherine , Robinson Matthew K. , Marks James D. , Weiner Louis M. 
Published: April 2014

Abstract
Unconjugated mAbs have emerged as useful cancer therapeutics. Ab-dependent cellular cytotoxicity (ADCC) is believed to be a major antitumor mechanism of some anticancer Abs. However, the factors that regulate the magnitude of ADCC are incompletely understood. In this study, we described the relationship between Ab affinity and ADCC. A series of human IgG1 isotype Abs was created from the anti-HER2/neu (also named c-erbB2) C6.5 single-chain Fv (scFv) and its affinity mutants. The scFv affinities range from 10−7 to 10−11 M, and the IgG Abs retain the affinities of the scFv from which they were derived. The apparent affinity of the Abs ranged from nearly 10−10 M (the lowest affinity variant) to almost 10−11 M (the other variants). The IgG molecules were tested for their ability to elicit ADCC in vitro against three tumor cell lines with differing levels of HER2/neu expression using unactivated human PBMC from healthy donors as the effector cells. The results demonstrated that both the apparent affinity and intrinsic affinity of the Abs studied regulate ADCC. High-affinity tumor Ag binding by the IgGs led to the most efficient and powerful ADCC. Tumor cells expressing high levels of HER2/neu are more susceptible to the ADCC triggered by Abs than the cells expressing lower amounts of HER2/neu. These findings justify the examination of high affinity Abs for ADCC promotion. Because high affinity may impair in vivo tumor targeting, a careful examination of Ab structure to function relationships is required to develop optimized therapeutic unconjugated Abs.
IgE-Antibody-Dependent Immunotherapy of Solid Tumors: Cytotoxic and Phagocytic Mechanisms of Eradication of Ovarian Cancer Cells
Authors: Karagiannis Sophia N. , Bracher Marguerite G. , Hunt James , McCloskey Natalie , Beavil Rebecca L. , Beavil Andrew J. , Fear David J. , Thompson Richard G. , East Nicholas , Burke Frances , Moore Robert J. , Dombrowicz David D. , Balkwill Frances R. , Gould Hannah J. 
Published: April 2014

Abstract
Abs have a paramount place in the treatment of certain, mainly lymphoid, malignancies, although tumors of nonhemopoietic origin have proved more refractory ones. We have previously shown that the efficacy of immunotherapy of solid tumors, in particular ovarian carcinoma, may be improved by the use of IgE Abs in place of the conventional IgG. An IgE Ab (MOv18 IgE) against an ovarian-tumor-specific Ag (folate binding protein), in combination with human PBMC, introduced into ovarian cancer xenograft-bearing mice, greatly exceeded the analogous IgG1 in promoting survival. In this study, we analyzed the mechanisms by which MOv18 IgE may exert its antitumor activities. Monocytes were essential IgE receptor-expressing effector cells that mediated the enhanced survival of tumor-bearing mice by MOv18 IgE and human PBMC. Monocytes mediated MOv18 IgE-dependent ovarian tumor cell killing in vitro by two distinct pathways, cytotoxicity and phagocytosis, acting respectively through the IgE receptors FcεRI and CD23. We also show that human eosinophils were potent effector cells in MOv18 IgE Ab-dependent ovarian tumor cell cytotoxicity in vitro. These results demonstrate that IgE Abs can engage cell surface IgE receptors and activate effector cells against ovarian tumor cells. Our findings offer a framework for an improved immunotherapeutic strategy for combating solid tumors.
Altered Immune Function during Long-Term Host-Tumor Interactions Can Be Modulated to Retard Autochthonous Neoplastic Growth
Authors: Stewart Trina J. , Abrams Scott I. 
Published: April 2014

Abstract
Ag-specific and generalized forms of immunosuppression have been documented in animal tumor models. However, much of our knowledge on tumor-induced immunosuppression was acquired using tumor implant models, which do not reiterate the protracted nature of host-tumor interactions. Therefore, a transgenic mouse model of autochthonous mammary tumor development and progression was chosen to investigate the long-term consequences of neoplastic growth on the immune system. In vitro proliferation of unfractionated splenocytes from tumor-bearing mice, as assessed by [3H]thymidine uptake, was inhibited by the presence of suppressor cells within these splenocyte preparations, because purifying the T cells restored their biological activity. However, the level of inhibition did not correlate with either tumor load or the percentage of myeloid-derived CD11b+Gr1+ cells. To evaluate tumor-specific immune dysfunction, transgenic mice were challenged with autologous tumor cells. Mice with extensive, but not minimal autochthonous tumor burdens demonstrated a significantly enhanced rate of autologous tumor growth compared with age-matched controls. In contrast, an allogeneic tumor challenge was efficiently rejected from both groups of transgenic mice. It was also noted that allogeneic tumor challenge of mice with minimal disease significantly inhibited autochthonous primary tumor growth. We therefore demonstrated that 1) a generalized form of immunosuppression occurred, but not as a result of permanent alterations to T cell function, because purified T cell subsets retained normal biological activity following polyclonal or allostimulation; and 2) tumor-specific immunosuppression emerged as a consequence of tumor progression, but could be modulated to enhance antitumor responses against autochthonous primary neoplastic growth.
Targeting Molecular and Cellular Inhibitory Mechanisms for Improvement of Antitumor Memory Responses Reactivated by Tumor Cell Vaccine
Authors: Webster W. Scott , Thompson R. Houston , Harris Kimberley J. , Frigola Xavier , Kuntz Susan , Inman Brant A. , Dong Haidong 
Published: April 2014

Abstract
Development of effective vaccination approaches to treat established tumors represents a focus of intensive research because such approaches offer the promise of enhancing immune system priming against tumor Ags via restimulation of pre-existing (memory) antitumoral helper and effector immune cells. However, inhibitory mechanisms, which function to limit the recall responses of tumor-specific immunity, remain poorly understood and interfere with therapies anticipated to induce protective immunity. The mouse renal cell carcinoma (RENCA) tumor model was used to investigate variables affecting vaccination outcomes. We demonstrate that although a whole cell irradiated tumor cell vaccine can trigger a functional antitumor memory response in the bone marrows of mice with established tumors, these responses do not culminate in the regression of established tumors. In addition, a CD103+ regulatory T (Treg) cell subset accumulates within the draining lymph nodes of tumor-bearing mice. We also show that B7-H1 (CD274, PD-L1), a negative costimulatory ligand, and CD4+ Treg cells collaborate to impair the recall responses of tumor-specific memory T cells. Specifically, mice bearing large established RENCA tumors were treated with tumor cell vaccination in combination with B7-H1 blockade and CD4+ T cell depletion (triple therapy treatment) and monitored for tumor growth and survival. Triple treatment therapy induced complete regression of large established RENCA tumors and raised long-lasting protective immunity. These results have implications for developing clinical antitumoral vaccination regimens in the setting in which tumors express elevated levels of B7-H1 in the presence of abundant Treg cells.
T Cells Express α7-Nicotinic Acetylcholine Receptor Subunits That Require a Functional TCR and Leukocyte-Specific Protein Tyrosine Kinase for Nicotine-Induced Ca2+ Response
Authors: Razani-Boroujerdi Seddigheh , Boyd R. Thomas , Dávila-García Martha I. , Nandi Jayashree S. , Mishra Neerad C. , Singh Shashi P. , Pena-Philippides Juan Carlos , Langley Raymond , Sopori Mohan L. 
Published: April 2014

AbstractAcute and chronic effects of nicotine on the immune system are usually opposite; acute treatment stimulates while chronic nicotine suppresses immune and inflammatory responses. Nicotine acutely raises intracellular calcium ([Ca2+]i) in T cells, but the mechanism of this response is unclear. Nicotinic acetylcholine receptors (nAChRs) are present on neuronal and non-neuronal cells, but while in neurons, nAChRs are cation channels that participate in neurotransmission; their structure and function in nonexcitable cells are not well-defined. In this communication, we present evidence that T cells express α7-nAChRs that are critical in increasing [Ca2+]i in response to nicotine. Cloning and sequencing of the receptor from human T cells showed a full-length transcript essentially identical to the neuronal α7-nAChR subunit (&gt;99.6% homology). These receptors are up-regulated and tyrosine phosphorylated by treatment with nicotine, anti-TCR Abs, or Con A. Furthermore, knockdown of the α7-nAChR subunit mRNA by RNA interference reduced the nicotine-induced Ca2+ response, but unlike the neuronal receptor, α-bungarotoxin and methyllycaconitine not only failed to block, but also actually raised [Ca2+]i in T cells. The nicotine-induced release of Ca2+ from intracellular stores in T cells did not require extracellular Ca2+, but, similar to the TCR-mediated Ca2+ response, required activation of protein tyrosine kinases, a functional TCR/CD3 complex, and leukocyte-specific tyrosine kinase. Moreover, CD3ζ and α7-nAChR coimmunoprecipitated with anti-CD3ζ or anti-α7-nAChR Abs. These results suggest that in T cells, α7-nAChR, despite its close sequence homology with neuronal α7-nAChR, fails to form a ligand-gated Ca2+ channel, and that the nicotine-induced rise in [Ca2+]i in T cells requires functional TCR/CD3 and leukocyte-specific tyrosine kinase.
Viral Replication Capacity as a Correlate of HLA B57/B5801-Associated Nonprogressive HIV-1 Infection
Authors: Navis Marjon , Schellens Ingrid , van Baarle Debbie , Borghans José , van Swieten Peter , Miedema Frank , Kootstra Neeltje , Schuitemaker Hanneke 
Published: April 2014

Abstract
HLA B57 and the closely related HLA B5801 are over-represented among HIV-1 infected long-term nonprogressors (LTNPs). It has been suggested that this association between HLA B57/5801 and asymptomatic survival is a consequence of strong CTL responses against epitopes in the viral Gag protein. Moreover, CTL escape mutations in Gag would coincide with viral attenuation, resulting in low viral load despite evasion from immune control. In this study we compared HLA B57/5801 HIV-1 infected progressors and LTNPs for sequence variation in four dominant epitopes in Gag and their ability to generate CTL responses against these epitopes and the autologous escape variants. Prevalence and appearance of escape mutations in Gag epitopes and potential compensatory mutations were similar in HLA B57/5801 LTNPs and progressors. Both groups were also indistinguishable in the magnitude of CD8+ IFN-γ responses directed against the wild-type or autologous escape mutant Gag epitopes in IFN-γ ELISPOT analysis. Interestingly, HIV-1 variants from HLA B57/5801 LTNPs had much lower replication capacity than the viruses from HLA B57/5801 progressors, which did not correlate with specific mutations in Gag. In conclusion, the different clinical course of HLA B57/5801 LTNPs and progressors was not associated with differences in CTL escape mutations or CTL activity against epitopes in Gag but rather with differences in HIV-1 replication capacity.
Neisseria meningitidis PorB, a TLR2 Ligand, Induces an Antigen-Specific Eosinophil Recall Response: Potential Adjuvant for Helminth Vaccines?
Authors: Burke Jennifer M. , Ganley-Leal Lisa M. , Khatri Asma , Wetzler Lee M. 
Published: April 2014

Abstract
Efficacious adjuvants are important components of new vaccines. The neisserial outer membrane protein, PorB, is a TLR2 ligand with unique adjuvant activity. We demonstrate that PorB promotes Th2-skewed cellular immune response to the model Ag, OVA, in mice, including Ag-specific recall eosinophil recruitment to the peritoneum. PorB induces chemokine secretion by myeloid cells using both TLR2-dependent and -independent mechanisms, suggesting that anatomical distribution of TLR2+ cells may not be a limiting factor for potential vaccine strategies. The results from this study suggest that PorB, and other TLR2 ligands, may be ideal for use against pathogens where eosinophilia may be protective, such as parasitic helminths.
Dendritic Cell Type Determines the Mechanism of Bystander Suppression by Adaptive T Regulatory Cells Specific for the Minor Antigen HA-1
Authors: Derks Richard A. , Jankowska-Gan Ewa , Xu Qingyong , Burlingham William J. 
Published: April 2014

Abstract
One hallmark of acquired tolerance is bystander suppression, a process whereby Ag-specific (adaptive) T regulatory cells (TR) inhibit the T effector cell response both to specific Ag and to a colocalized third-party Ag. Using peripheral blood T cells from recipients of HLA-identical kidney transplants as responders in the trans vivo-delayed type hypersensitivity assay, we found that dendritic cells (DC), but not monocyte APCs, could mediate bystander suppression of EBV-specific recall response. When HA-1H peptide was added to mixtures of plasmacytoid DC (pDC) and T cells, bystander suppression of the response to a colocalized recall Ag occurred primarily via indolamine-2,3-dioxygenase (IDO) production. Similarly, addition of HA-1H peptide to cocultures of T cells and pDC, but not myeloid DC (mDC), induced IDO activity in vitro. When mDC presented HA-1H peptide to Ag-specific CD8+ TR, cytokine release (TGF-β, IL-10, or both) was the primary mode of bystander suppression. Bystander suppression via mDC was reversed not only by Ab to TGF-β and its receptor on T cells, but also by Ab to thrombospondin-1. EBV addition did not induce IDO or thrombospondin-1 in T-DC cocultures, suggesting that these DC products are not induced by T effector cells, but only by TR cells. These results shed light upon the mechanism of bystander suppression by donor Ag-specific TR in patients with organ transplant tolerance and underscores the distinct and critical roles of mDC and pDCs in this phenomenon.
Invariant NKT Cells Biased for IL-5 Production Act as Crucial Regulators of Inflammation
Authors: Sakuishi Kaori , Oki Shinji , Araki Manabu , Porcelli Steven A. , Miyake Sachiko , Yamamura Takashi 
Published: April 2014

Abstract
Although invariant NKT (iNKT) cells play a regulatory role in the pathogenesis of autoimmune diseases and allergy, an initial trigger for their regulatory responses remains elusive. In this study, we report that a proportion of human CD4+ iNKT cell clones produce enormous amounts of IL-5 and IL-13 when cocultured with CD1d+ APC in the presence of IL-2. Such IL-5 bias was never observed when we stimulated the same clones with α-galactosylceramide or anti-CD3 Ab. Suboptimal TCR stimulation by plate-bound anti-CD3 Ab was found to mimic the effect of CD1d+ APC, indicating the role of TCR signaling for selective induction of IL-5. Interestingly, DNA microarray analysis identified IL-5 and IL-13 as the most highly up-regulated genes, whereas other cytokines produced by iNKT cells, such as IL-4 and IL-10, were not significantly induced. Moreover, iNKT cells from BALB/c mice showed similar IL-5 responses after stimulation with IL-2 ex vivo or in vivo. The iNKT cell subset producing IL-5 and IL-13 could play a major role in the development of allergic disease or asthma and also in the immune regulation of Th1 inflammation.
A Y Chromosome-Linked Factor Impairs NK T Development
Authors: Wesley Johnna D. , Tessmer Marlowe S. , Paget Christophe , Trottein François , Brossay Laurent 
Published: April 2014

Abstract
Vα14 invariant (Vα14i) NK T cell development is unique from mainstream T cell selection, and the polygenic factors that influence NK T cell ontogeny are still unclear. In this study, we report the absence of Vα14i NK T cells in B6.IFN-αβR1−/− male mice, whereas both the conventional T and NK cell populations are relatively unaffected. The lack of Vα14i NK T cells in the B6.IFN-αβR1−/− males is not due to an insufficient level of CD1d1 or a defect in CD1d1-Ag presentation, but it is intrinsic to the male Vα14i NK T cells. This surprising defect displays ≥99% penetrance in the male population, whereas female mice remain unaffected, indicating the deficiency is not X linked. Analysis of the Vα14i NK T cell compartment in B6.Tyk2−/−, B6.STAT1−/−, 129.IFN-αβR1−/−, and B6.IFN-αβR1−/+ mice demonstrate that the deficiency is linked to the Y chromosome, but independent of IFN-αβ. This is the first study demonstrating that Y-linked genes can exclusively impact Vα14i NK T development and further highlight the unique ontogeny of these innate T cells.
Characterization of Early Stages of Human B Cell Development by Gene Expression Profiling
Authors: Hystad Marit E. , Myklebust June H. , Bø Trond H. , Sivertsen Einar A. , Rian Edith , Forfang Lise , Munthe Else , Rosenwald Andreas , Chiorazzi Michael , Jonassen Inge , Staudt Louis M. , Smeland Erlend B. 
Published: April 2014

Abstract
We have characterized several stages of normal human B cell development in adult bone marrow by gene expression profiling of hemopoietic stem cells, early B (E-B), pro-B, pre-B, and immature B cells, using RNA amplification and Lymphochip cDNA microarrays (n = 6). Hierarchical clustering of 758 differentially expressed genes clearly separated the five populations. We used gene sets to investigate the functional assignment of the differentially expressed genes. Genes involved in VDJ recombination as well as B lineage-associated transcription factors (TCF3 (E2A), EBF, BCL11A, and PAX5) were turned on in E-B cells, before acquisition of CD19. Several transcription factors with unknown roles in B lymphoid cells demonstrated interesting expression patterns, including ZCCHC7 and ZHX2. Compared with hemopoietic stem cells and pro-B cells, E-B cells had increased expression of 18 genes, and these included IGJ, IL1RAP, BCL2, and CD62L. In addition, E-B cells expressed T/NK lineage and myeloid-associated genes including CD2, NOTCH1, CD99, PECAM1, TNFSF13B, and MPO. Expression of key genes was confirmed at the protein level by FACS analysis. Several of these Ags were heterogeneously expressed, providing a basis for further subdivision of E-B cells. Altogether, these results provide new information regarding expression of genes in early stages of human B cell development.