bluuebunny/crossref_metadata_2025_split huggingface dataset:
Attrition of Virus-Specific Memory CD8+ T Cells During Reconstitution of Lymphopenic Environments
Authors: Peacock Craig D. , Kim Sung-Kwon , Welsh Raymond M. 
Published: April 2014

Abstract
Viruses can cause a severe lymphopenia early in infection and a subsequent, lasting loss of pre-existing CD8+ memory T cells. We therefore questioned how well virus Ag-specific memory CD8+ T cells could reconstitute mice rendered lymphopenic as a consequence of genetics, irradiation, or viral or poly(I:C)-induced cytokines. In each case, reconstitution of the CD8+ compartment was associated with limited division of virus-specific memory T cells and a reduction in their proportion. This indicates that foreign Ag-experienced CD44highCD8+ memory T cells may respond differently to homeostatic signals than other CD44highCD8+ cells, and that events inducing lymphopenia may lead to a permanent reduction in T cell memory.
Febrile Temperatures Attenuate IL-1β Release by Inhibiting Proteolytic Processing of the Proform and Influence Th1/Th2 Balance by Favoring Th2 Cytokines
Authors: Boneberg Eva-Maria , Hartung Thomas 
Published: April 2014

Abstract
We investigated possible feedback mechanisms of febrile temperatures on LPS- and staphylococcal enterotoxin B (SEB)-induced cytokine release in human whole blood. LPS-induced IL-1β release was inhibited at temperatures &gt;38°C, whereas intracellular proIL-1β formation as well as the release of other cytokines except IL-18 were only attenuated above 42°C, indicating that febrile temperatures impair the proteolytic processing of proIL-1β. This attenuated processing is not due to either heat inactivation of caspase-1 or structural changes in proIL-1β produced at higher temperatures. Instead, we propose that febrile conditions change cytosolic compartmentation or trafficking, so that synthesized proIL-1β cannot encounter caspase-1. Febrile temperatures also influenced Th1/Th2 cytokine balance. We observed a 3-fold increase in the Th2-cytokines IL-5 and IL-13 and a reduction to 15% of the Th1-cytokine IL-2 when SEB-stimulated whole blood was incubated at 40°C compared with 37°C. These results indicate that fever limits the production of the fever-inducing IL-1β and also influences the adaptive immune response, favoring Th2 cytokine production.
P-Selectin Enhances Generation of CD14+CD16+ Dendritic-Like Cells and Inhibits Macrophage Maturation from Human Peripheral Blood Monocytes
Authors: Li Geling , Kim Young-June , Mantel Charlie , Broxmeyer Hal E. 
Published: April 2014

AbstractEndothelial cells play a critical role in monocyte differentiation. Platelets also affect terminal maturation of monocytes in vitro. P-selectin is an important adhesion molecule expressed on both endothelial cells and activated platelets. We investigated its effects on human peripheral blood monocyte differentiation under the influence of different cytokines. Generation of dendritic-like cells (DLCs) from peripheral blood monocytes was promoted by immobilized P-selectin in the presence of M-CSF and IL-4 as judged by dendritic cell (DC) morphology; increased expression of CD1a, a DC marker; low phagocytic activity; and high alloreactivity to naive T cells. In contrast to typical DCs, DLCs expressed CD14 and FcγRIII (CD16). These features link the possible identity of DLCs to that of an uncommon CD14+CD16+CD64− monocyte subset found to be expanded in a variety of pathological conditions. Functionally, DLCs generated by P-selectin in combination with M-CSF plus IL-4 primed naive allogeneic CD4+ T cells to produce significantly less IFN-γ than cells generated by BSA in the presence of M-CSF and IL-4. P-selectin effects on enhancing CD14+CD16+ DLC generation were completely abrogated by pretreatment of cells with the protein kinase C δ inhibitor rottlerin, but not by classical protein kinase C inhibitor Gö6976. Immobilized P-selectin also inhibited macrophage differentiation in response to M-CSF alone as demonstrated by morphology, phenotype, and phagocytosis analysis. The effects of P-selectin on macrophage differentiation were neutralized by pretreatment of monocytes with Ab against P-selectin glycoprotein ligand 1. These results suggest a novel role for P-selectin in regulating monocyte fate determination.
Late Immature B Cells (IgMhighIgDneg) Undergo a Light Chain Receptor Editing Response to Soluble Self-Antigen
Authors: Tze Lina E. , Hippen Keli L. , Behrens Timothy W. 
Published: April 2014

Abstract
Receptor editing is an important mechanism to modify the Ag specificity of newly developing B cells that are reactive with self-Ags. Previous studies have suggested that late immature B cells, bearing high levels of IgM on their cell surface, are unable to initiate receptor editing and instead are deleted by apoptosis. Using the hen egg lysozyme transgenic system, we show that IgMhigh late-immature B cells are fully capable of receptor editing to soluble self-Ag. This was demonstrated by the induction of new endogenous light chain locus rearrangements and by a single-cell flow cytometric assay using a recombination-activating gene 2-green fluorescence protein reporter transgene. These studies suggest that the developmental window available for immature B cells to edit their Ig receptors, at least in response to certain soluble Ags, extends through the IgMhigh late immature B cell stage.
IL-15-Mediated Induction of LFA-1 Is a Late Step Required for Cytotoxic Differentiation of Human NK Cells from CD34+Lin− Bone Marrow Cells
Authors: Barao Isabel , Hudig Dorothy , Ascensao Joao L. 
Published: April 2014

AbstractOptimal differentiation of cytotoxic NK cells is important to provide protective innate immunity to patients after bone marrow transplantation. In vitro differentiation of CD56+CD3− NK cells takes weeks and is supported by several cytokines, including IL-2, IL-7, and IL-15, and thus can be useful for immunotherapy. However, IL-2 therapy is problematic in vivo, and NK cells differentiated in vitro with only IL-7 lack cytotoxicity. We assessed whether human NK cells initially differentiated in vitro from CD34+Lin− bone marrow cells with IL-7 could acquire cytotoxicity after exposure to additional cytokines and what changes promoted cytotoxicity. The cells cultured with IL-7 already had granzyme B as well as perforin, as previously reported, the proteins of cytotoxic granules. The cells also lacked LFA-1. After 1 wk of secondary culture with either IL-2 or IL-15, but not with IL-12 or IL-18, the IL-7-cultured cells acquired cytotoxicity. IL-2 or IL-15 also induced LFA-1. Ab to the LFA-1 subunits CD11a and CD18 blocked lysis by the NK cells, indicating that the new LFA-1 correlated with, and was essential for, the cytotoxic function of the in vitro generated cells. The LFA-1 also participated in target cell binding by the in vitro differentiated cells. In this study, we demonstrated a new function for IL-15, the induction of LFA-1 in NK progenitor cells, and that IL-15 does more than merely support NK progenitor cell proliferation. The efficacy after only 1 wk of IL-15 administration is a positive practical feature that may apply to human therapy.
Immune Modulation by Silencing IL-12 Production in Dendritic Cells Using Small Interfering RNA
Authors: Hill Jonathan A. , Ichim Thomas E. , Kusznieruk Kornel P. , Li Mu , Huang Xuyan , Yan Xiaotao , Zhong Robert , Cairns Ewa , Bell David A. , Min Wei-Ping 
Published: April 2014

Abstract
RNA interference is a mechanism of posttranscriptional gene silencing that functions in most eukaryotic cells, including human and mouse. Specific gene silencing is mediated by short strands of duplex RNA of ∼21 nt in length (termed small interfering RNA or siRNA) that target the cognate mRNA sequence for degradation. We demonstrate here that RNAi can be used for immune modulation by targeting dendritic cell (DC) gene expression. Transfection of DC with siRNA specific for the IL-12 p35 gene resulted in potent suppression of gene expression and blockade of bioactive IL-12 p70 production without affecting unrelated genes or cellular viability. Inhibition of IL-12 was associated with increased IL-10 production, which endowed the DC with the ability to stimulate production of Th2 cytokines from allogenic T cells in vitro. Furthermore, siRNA-silenced DC lacking IL-12 production were poor allostimulators in MLR. IL-12-silenced and KLH-pulsed DC polarized the immune response toward a Th2 cytokine profile in an Ag-specific manner. These data are the first to demonstrate that RNA interference is a potent and specific tool for modulating DC-mediated immune responses.
In Vivo Ligation of CD40 Enhances Priming Against the Endogenous Tumor Antigen and Promotes CD8+ T Cell Effector Function in SV40 T Antigen Transgenic Mice
Authors: Staveley-O’Carroll Kevin , Schell Todd D. , Jimenez Marcela , Mylin Lawrence M. , Tevethia M. Judith , Schoenberger Stephen P. , Tevethia Satvir S. 
Published: April 2014

Abstract
The ability to initiate and sustain CD8+ T cell responses to tumors in vivo is hindered by the development of peripheral T cell tolerance against tumor-associated Ags. Approaches that counter the onset of T cell tolerance may preserve a pool of potentially tumor-reactive CD8+ T cells. Administration of agonist Ab to the CD40 molecule, expressed on APCs, can enhance immunization approaches targeting T lymphocytes in an otherwise tolerance-prone environment. In this report, the effects of anti-CD40 administration on priming of naive CD8+ T cells against an endogenous tumor Ag were investigated. Line 501 mice express the SV40 large T Ag oncoprotein as a transgene from the α-amylase promoter, resulting in the development of peripheral CD8+ T cell tolerance to the H-2-Db-restricted immunodominant epitope I of T Ag by 6 mo of age, before the appearance of osteosarcomas. We demonstrate that naive epitope I-specific TCR transgenic (TCR-I) T cells undergo peripheral tolerance following adoptive transfer into 6-mo-old 501 mice. In contrast, administration of agonistic anti-CD40 Ab led to increased expansion of TCR-I T cells in 501 mice, the acquisition of effector function by TCR-I T cells and the establishment of T cell memory. Importantly, this enhanced priming effect of anti-CD40 administration did not require immunization and was effective even if administered after naive TCR-I T cells had encountered the endogenous T Ag. Thus, anti-CD40 administration can block the onset of peripheral tolerance and enhance the recruitment of functionally competent effector T cells toward an endogenous tumor Ag.
Regulation of Murine Inflammatory Bowel Disease by CD25+ and CD25− CD4+ Glucocorticoid-Induced TNF Receptor Family-Related Gene+ Regulatory T Cells
Authors: Uraushihara Koji , Kanai Takanori , Ko Kwibeom , Totsuka Teruji , Makita Shin , Iiyama Ryoichi , Nakamura Tetsuya , Watanabe Mamoru 
Published: April 2014

Abstract
CD4+CD25+ regulatory T cells in normal animals are engaged in the maintenance of immunological self-tolerance and prevention of autoimmune disease. However, accumulating evidence suggests that a fraction of the peripheral CD4+CD25− T cell population also possesses regulatory activity in vivo. Recently, it has been shown glucocorticoid-induced TNFR family-related gene (GITR) is predominantly expressed on CD4+CD25+ regulatory T cells. In this study, we show evidence that CD4+GITR+ T cells, regardless of the CD25 expression, regulate the mucosal immune responses and intestinal inflammation. SCID mice restored with the CD4+GITR− T cell population developed wasting disease and severe chronic colitis. Cotransfer of CD4+GITR+ population prevented the development of CD4+CD45RBhigh T cell-transferred colitis. Administration of anti-GITR mAb-induced chronic colitis in mice restored both CD45RBhigh and CD45RBlow CD4+ T cells. Interestingly, both CD4+CD25+ and CD4+CD25− GITR+ T cells prevented wasting disease and colitis. Furthermore, in vitro studies revealed that CD4+CD25−GITR+ T cells as well as CD4+CD25+GITR+ T cells expressed CTLA-4 intracellularly, showed anergic, suppressed T cell proliferation, and produced IL-10 and TGF-β. These data suggest that GITR can be used as a specific marker for regulatory T cells controlling mucosal inflammation and also as a target for treatment of inflammatory bowel disease.
Role of the Phosphatidylinositol 3 Kinase-Akt Pathway in the Regulation of IL-10 and IL-12 byPorphyromonas gingivalisLipopolysaccharide
Authors: Martin Michael , Schifferle Robert E. , Cuesta Natalia , Vogel Stefanie N. , Katz Jannet , Michalek Suzanne M. 
Published: April 2014

AbstractStimulation of the APC by Porphyromonas gingivalis LPS has been shown to result in the production of certain pro- and anti-inflammatory cytokines. However, the signaling pathways that regulate these processes are currently unknown. In the present study, the role of the phosphatidylinositol 3 kinase (PI3K)-Akt pathway in regulating P. gingivalis LPS-induced production of IL-10, IL-12 p40, and IL-12 p70 by human monocytes was investigated. P. gingivalis LPS selectively activates the PI3K-Akt pathway via Toll-like receptor 2, and inhibition of this pathway results in an abrogation of extracellular signal-regulated kinase 1/2 phosphorylation, whereas the activation of p38 and c-Jun N-terminal kinase 1/2 kinases were unaffected. Analysis of cytokine production following stimulation of monocytes with P. gingivalis LPS revealed that inhibition of the PI3K pathway differentially regulated IL-10 and IL-12 synthesis. IL-10 production was suppressed, whereas IL-12 levels were enhanced. Inhibition of P. gingivalis LPS-mediated activation of the PI3K-Akt pathway resulted in a pronounced augmentation of NF-κB p65 that was independent of IκB-α degradation. Furthermore, the ability of the PI3K-Akt pathway to modulate IL-10 and IL-12 production appears to be mediated by the selective suppression of extracellular signal-regulated kinase 1/2 activity, as the MEK1 inhibitor PD98059 closely mimicked the effects of wortmannin and LY294002 to differentially regulate IL-10 and IL-12 production by P. gingivalis LPS-stimulated monocytes. These studies provide new insight into how engagement of the PI3K-Akt pathway by P. gingivalis LPS affects the induction of key immunoregulatory cytokines that control both qualitative and quantitative aspects of innate and adaptive immunity.
Gr-1+ Myeloid Cells Lacking T Cell Protein Tyrosine Phosphatase Inhibit Lymphocyte Proliferation by an IFN-γ- and Nitric Oxide-Dependent Mechanism
Authors: Dupuis Maryse , de Jesús Ibarra-Sánchez María , Tremblay Michel L. , Duplay Pascale 
Published: April 2014

AbstractThe T cell protein tyrosine phosphatase is involved in the immune system regulation, as evidenced by defective function and development of several hemopoietic cell populations in T cell protein tyrosine phosphatase (TC-PTP)-deficient mice. In particular, B and T cell proliferation is greatly inhibited when total splenocytes are stimulated by LPS or anti-CD3 mAb. To define the functional defect of TC-PTP−/− lymphocytes, we isolated T and B cells from the spleen of TC-PTP−/− mice. We show that the proliferative response of lymphocytes was greatly increased when cultured as a purified population, indicating that an inhibitory population is present in TC-PTP−/− spleen. However, TC-PTP−/− lymphocytes have a 2- to 3-fold lower proliferation rate compared with TC-PTP+/+ lymphocytes, suggesting that, as shown previously in embryonic fibroblasts, TC-PTP is involved in the control of cell cycle in lymphocytes. We have characterized phenotypically and functionally the inhibitory population present in the spleen of TC-PTP−/− mice. We show that a Gr-1+-enriched cell population isolated from TC-PTP−/− mice suppresses the CD3-induced proliferation of T cells in coculture in vitro. The specific inhibition of NO synthesis with NG-monomethyl-l-arginine.monoacetate restored splenocyte responses, and there is a strict correlation between NO levels and the degree of suppression. Neutralization of IFN-γ with specific mAb almost completely abolished the inhibitory activity of Gr-1+ cells and concomitantly high levels of NO secretion. Moreover, inhibition of lymphocyte proliferative responses required cell-cell contact to achieve sufficient levels of NO. These findings demonstrate an important function of TC-PTP in the induction of the NO pathway that mediates inhibition of T cell proliferation.
Induction of Autoantigen-Specific Th2 and Tr1 Regulatory T Cells and Modulation of Autoimmune Diabetes
Authors: Chen Cyndi , Lee Wen-Hui , Yun Pen , Snow Peter , Liu Chih-Pin 
Published: April 2014

AbstractAutoantigen-based immunotherapy can modulate autoimmune diabetes, perhaps due to the activation of Ag-specific regulatory T cells. Studies of these regulatory T cells should help us understand their roles in diabetes and aid in designing a more effective immunotherapy. We have used class II MHC tetramers to isolate Ag-specific T cells from nonobese diabetic (NOD) mice and BALB/c mice treated with glutamic acid decarboxylase 65 peptides (p206 and p221). Based on their cytokine secretion profiles, immunization of NOD mice with the same peptide induced different T cell subsets than in BALB/c mice. Treatment of NOD mice induced not only Th2 cells but also IFN-γ/IL-10-secreting T regulatory type 1 (Tr1) cells. Adoptive transfer experiments showed that isolated tetramer+ T cells specific for p206 or p221 could inhibit diabetes development. These cells were able to suppress the in vitro proliferation of other NOD mouse T cells without cell-cell contact. They performed their regulatory functions probably by secreting cytokines, and Abs against these cytokines could block their suppressive effect. Interestingly, the presence of both anti-IL-10 and anti-IFN-γ could enhance the target cell proliferation, suggesting that Tr1 cells play an important role. Further in vivo experiments showed that the tetramer+ T cells could block diabetogenic T cell migration into lymph nodes. Therefore, treatment of NOD mice with autoantigen could induce Th2 and Tr1 regulatory cells that can suppress the function and/or block the migration of other T cells, including diabetogenic T cells, and inhibit diabetes development.
CD49d Overexpression and T Cell Autoimmunity
Authors: Mo Ru-Ran , Eisenbraun Julie K. , Sonstein Joanne , Craig Ronald A. , Curtis Jeffrey L. , Stoolman Lloyd M. , Chen Jun , Yung Raymond L. 
Published: April 2014

AbstractD10.G4.1 (D10) cells, a murine conalbumin-reactive Th2 cell line, made to overexpress the β2 integrin LFA-1 by pharmacological manipulation or by transfection become autoreactive and are capable of inducing in vivo autoimmunity. However, whether this is specific to LFA-1 and whether overexpression of other T cell integrin molecules has the same effect are unknown. We examined the functional consequences of T cell CD49d (α4 integrin) overexpression by transfecting murine CD49d cDNA into D10 cells. Similar to the LFA-1-transfected cells, the CD49d-overexpressing T cells are autoreactive and proliferate in response to APCs in an MHC class II-dependent manner in the absence of nominal Ag. Additionally, CD49d overexpression is associated with increased in vitro adhesion to endothelial cells and increased in vivo splenic homing. However, in contrast to LFA-1 overexpression, increased T cell CD49d expression is not associated with autoreactive cytotoxicity or the ability to induce in vivo autoimmunity. In addition to the novel observation that CD49d overexpression is sufficient to induce T cell autoreactivity, our results also support the hypothesis that the ability to induce in vivo autoimmunity is related to T cell cytotoxicity and not to T cell proliferation function in the D10 murine adoptive transfer model of autoimmunity.
The Slc11a1 (Nramp1) Gene Controls Efficacy of Mycobacterial Treatment of Allergic Asthma
Authors: Smit Joost J. , Van Loveren Henk , Hoekstra Maarten O. , Karimi Khalil , Folkerts Gert , Nijkamp Frans P. 
Published: April 2014

Abstract
Genes controlling antibacterial resistance may be important in the hygiene hypothesis, which states that lack of bacterial infections during childhood would favor development of allergic disease. We, therefore, studied whether Nramp1 (Slc11a1) alleles, which determine susceptibility (Nramp1s) or resistance (Nramp1r) to intracellular bacteria, affect the efficacy of heat-killed Mycobacterium vaccae in the treatment of allergic asthma in a mouse model. Treatment of OVA-sensitized Nramp1s mice with M. vaccae suppressed airway hyperresponsiveness, airway eosinophilia, Ag-specific IgE, and IL-4 and IL-5 production after OVA aerosol challenge. In contrast, M. vaccae hardly affected these parameters in Nramp1r mice. In addition, The Nramp1 gene affected both T cell-mediated responses to M. vaccae in vivo and the level of macrophage activation after stimulation with M. vaccae in vitro. In conclusion, the efficacy of M. vaccae in preventing allergic and asthmatic manifestations in a mouse model is strongly affected by Nramp1 alleles. These findings could have important implications for the future use of mycobacteria and their components in the prevention or treatment of allergic asthma. A new link is described between genes, the environment, and the development of allergy, in which the Nramp1 gene fine tunes the hygiene hypothesis.
NF-κB1 p50 Is Required for BLyS Attenuation of Apoptosis but Dispensable for Processing of NF-κB2 p100 to p52 in Quiescent Mature B Cells
Authors: Hatada Eunice N. , Do Richard K. G. , Orlofsky Amos , Liou Hsiou-Chi , Prystowsky Michael , MacLennan Ian C. M. , Caamano Jorge , Chen-Kiang Selina 
Published: April 2014

Abstract
B lymphocyte stimulator (BLyS), a TNF family protein essential for peripheral B cell development, functions primarily through attenuation of B cell apoptosis. In this study, we show that BLyS activates NF-κB through both classical and alternative pathways with distinct kinetics in quiescent mature B cells. It rapidly and transiently enhances the p50/p65 DNA binding activity and induces phosphorylation of IκBα characteristic of the classical NF-κB pathway, albeit maintaining IκBα at a constant level through ongoing protein synthesis and proteasome-mediated destruction. With delayed kinetics, BLyS promotes the processing of p100 to p52 and sustained formation of p52/RelB complexes via the alternative NF-κB pathway. p50 is dispensable for p100 processing. However, it is required to mediate the initial BLyS survival signals and concomitant activation of Bcl-xL in quiescent mature B cells ex vivo. Although also a target of BLyS activation, at least one of the A1 genes, A1-a, is dispensable for the BLyS survival function. These results suggest that BLyS mediates its survival signals in metabolically restricted quiescent B cells, at least in part, through coordinated activation of both NF-κB pathways and selective downstream antiapoptotic genes.