bluuebunny/crossref_metadata_2025_split huggingface dataset:
A New Population of Cells Lacking Expression of CD27 Represents a Notable Component of the B Cell Memory Compartment in Systemic Lupus Erythematosus
Authors: Wei Chungwen , Anolik Jennifer , Cappione Amedeo , Zheng Bo , Pugh-Bernard Aimee , Brooks James , Lee Eun-Hyung , Milner Eric C. B. , Sanz Iñaki 
Published: April 2014

Abstract
Human memory B cells comprise isotype-switched and nonswitched cells with both subsets displaying somatic hypermutation. In addition to somatic hypermutation, CD27 expression has also been considered a universal memory B cell marker. We describe a new population of memory B cells containing isotype-switched (IgG and IgA) and IgM-only cells and lacking expression of CD27 and IgD. These cells are present in peripheral blood and tonsils of healthy subjects and display a degree of hypermutation comparable to CD27+ nonswitched memory cells. As conventional memory cells, they proliferate in response to CpG DNA and fail to extrude rhodamine. In contrast to other recently described CD27-negative (CD27neg) memory B cells, they lack expression of FcRH4 and recirculate in the peripheral blood. Although CD27neg memory cells are relatively scarce in healthy subjects, they are substantially increased in systemic lupus erythematosus (SLE) patients in whom they frequently represent a large fraction of all memory B cells. Yet, their frequency is normal in patients with rheumatoid arthritis or chronic hepatitis C. In SLE, an increased frequency of CD27neg memory cells is significantly associated with higher disease activity index, a history of nephritis, and disease-specific autoantibodies (anti-dsDNA, anti-Smith (Sm), anti-ribonucleoprotein (RNP), and 9G4). These findings enhance our understanding of the B cell diversification pathways and provide mechanistic insight into the immunopathogenesis of SLE.
B7-H1 Up-Regulation on Myeloid Dendritic Cells Significantly Suppresses T Cell Immune Function in Patients with Chronic Hepatitis B
Authors: Chen Liangen , Zhang Zheng , Chen Weiwei , Zhang Zhidong , Li Yonggang , Shi Ming , Zhang Jiyuan , Chen Lieping , Wang Shengdian , Wang Fu-Sheng 
Published: April 2014

Abstract
Although dysfunctional dendritic cells contribute to inadequate adaptive immunity in chronic hepatitis B (CHB), underlying molecular mechanisms remain largely undefined. In this study, we examined B7-H1 expression on circulating myeloid dendritic cells (mDCs) in 46 CHB patients, 10 autoimmune hepatitis patients, and 10 healthy subjects as control. We found that B7-H1 expression is significantly up-regulated on circulating mDCs of CHB and autoimmune hepatitis patients compared with healthy individuals. The B7-H1 up-regulation was significantly correlated with an elevation of serum alanine aminotransaminase levels and plasma viral load. In addition, in vitro, both IFN-α and IFN-γ could strongly stimulate mDCs to express B7-H1. More importantly, elevated B7-H1 expression is also closely associated with the suppression of T cell immune function. In vitro blockade of B7-H1 signaling could not only down-regulate IL-10 and up-regulate IL-12 production by mDCs, but also enhance mDC-mediated allostimulatory capacity and cytokine production of T cells. Blockade of B7-H1 signaling could improve hepatitis B c Ag-pulsed monocyte-derived DC-induced IFN-γ production by autologous hepatitis B virus-specific T cells. These new findings suggested that chronic inflammation may contribute to B7-H1 up-regulation on mDCs in CHB patients, which potentially cause defective hepatitis B virus-specific T cell function and viral persistence. Our findings further support the notion that the blockade of B7-H1 may represent a novel therapeutic approach for this disease.
Cutting Edge: CNS CD11c+ Cells from Mice with Encephalomyelitis Polarize Th17 cells and Support CD25+CD4+ T cell-Mediated Immunosuppression, Suggesting Dual Roles in the Disease Process
Authors: Deshpande Pratima , King Irah L. , Segal Benjamin M. 
Published: April 2014

Abstract
CD11c+ dendritic cells (DCs) are a prominent component of CNS infiltrates in mice with experimental autoimmune encephalomyelitis. However, their role in immunopathogenesis is controversial. In this study, we report that they originate from peripheral hemopoietic cells and exhibit diverse functions that change during the course of acute disease. CNS DCs stimulate naive T cells to proliferate and polarize Th17 responses when harvested shortly following disease onset but are relatively inefficient APC by the time of peak disability. Conversely, they can support CD4+CD25+ T cell-mediated immunosuppression early during experimental autoimmune encephalomyelitis. Such paradoxical functions might reflect dual roles of CNS DCs in promoting local inflammation while setting the stage for remission.
Cutting Edge: Cross-Regulation by TLR4 and T cell Ig Mucin-3 Determines Sex Differences in Inflammatory Heart Disease
Authors: Frisancho-Kiss Sylvia , Davis Sarah E. , Nyland Jennifer F. , Frisancho J. Augusto , Cihakova Daniela , Barrett Masheka A. , Rose Noel R. , Fairweather DeLisa 
Published: April 2014

Abstract
Recent clinical studies have reinforced the importance of sex-related differences in the pathogenesis of cardiovascular diseases, with an increased incidence and mortality in men. Similar to humans, male BALB/c mice infected with coxsackievirus B3 (CVB3) develop more severe inflammation in the heart even though viral replication is no greater than in females. We show that TLR4 and IFN-γ levels are significantly elevated and regulatory T cell (Treg) populations significantly reduced in the heart of males following CVB3 infection, whereas females have significantly increased T cell Ig mucin (Tim)-3, IL-4 and Treg. Blocking Tim-3 in males significantly increases inflammation and TLR4 expression while reducing Treg. In contrast, defective TLR4 signaling significantly reduces inflammation while increasing Tim-3 expression. Cross-regulation of TLR4 and Tim-3 occurs during the innate and adaptive immune response. This novel mechanism may help explain why inflammatory heart disease is more severe in males.
An Essential Role for TNF in Modulating Thresholds for Survival, Activation, and Tolerance of CD8+ T Cells
Authors: Chatzidakis Ioannis , Fousteri Georgia , Tsoukatou Debbie , Kollias George , Mamalaki Clio 
Published: April 2014

AbstractTNF and its receptors p55 and p75 are known to be important in the homeostasis of the peripheral immune system. Previous studies have presented apparently contradictory evidence for an in vivo role of TNF in T cells. In this study, we analyzed TNF-deficient mice crossed with the F5 TCR-transgenic animals. We show that endogenous TNF modulates several aspects of homeostasis of peripheral F5 CD8 T cells. We found that F5/TNF−/−mice had reduced numbers of peripheral F5 T cells, F5/TNF−/− CD8 T cells exhibited reduced survival potential, and furthermore that T cell-derived TNF is required for optimum recovery of naive CD8 T cells in lymphopenic hosts, suggesting its involvement in the survival of peripheral CD8 T cells. Both peptide activation and ensuing Ag-induced apoptosis are quantitatively reduced in TNF−/− CD8 T cells. The latter observations can be related to decreased binding activities of NF-κB and NF-ATp observed in Ag-stimulated F5/TNF−/− T cells. Finally, in a CD8 T cell tolerance model, endogenous TNF was necessary for several parameters of CD8 T cell tolerance induction. Collectively, our results provide evidence that endogenous TNF modulates thresholds in several ligand-driven T cell responses.
Normal Hemopoiesis and Lymphopoiesis in the Combined Absence of Numb and Numblike
Authors: Wilson Anne , Ardiet Denis-Luc , Saner Catherine , Vilain Nathalie , Beermann Friedrich , Aguet Michel , MacDonald H. Robson , Zilian Olav 
Published: April 2014

Abstract
The mammalian ortholog of the conserved Drosophila adaptor protein Numb (Nb) and its homolog Numblike (Nbl) modulate neuronal cell fate determination at least in part by antagonizing Notch signaling. Because the Notch pathway has been implicated in regulating hemopoietic stem cell self-renewal and T cell fate specification in mammals, we investigated the role of Nb and Nbl in hemopoiesis using conditional gene targeting. Surprisingly simultaneous deletion of both Nb and Nbl in murine bone marrow precursors did not affect the ability of stem cells to self-renew or to give rise to differentiated myeloid or lymphoid progeny, even under competitive conditions in mixed chimeras. Furthermore, T cell fate specification and intrathymic T cell development were unaffected in the combined absence of Nb and Nbl. Collectively our data indicate that the Nb family of adaptor proteins is dispensable for hemopoiesis and lymphopoiesis in mice, despite their proposed role in neuronal stem cell development.
Signal 3 Availability Limits the CD8 T Cell Response to a Solid Tumor
Authors: Curtsinger Julie M. , Gerner Michael Y. , Lins Debra C. , Mescher Matthew F. 
Published: April 2014

AbstractCD8 T cells need a third signal, along with Ag and costimulation, for effective survival and development of effector functions, and this can be provided by IL-12 or type I IFN. Adoptively transferred OT-I T cells, specific for H-2Kb and OVA, encounter Ag in the draining lymph nodes of mice with the OVA-expressing E.G7 tumor growing at a s.c. site. The OT-I cells respond by undergoing limited clonal expansion and development of effector functions (granzyme B expression and IFN-γ production), and they migrate to the tumor where they persist but fail to control tumor growth. In contrast, OT-I T cells deficient for both the IL-12 and type I IFN receptors expand only transiently and rapidly disappear. These results suggested that some signal 3 cytokine is available, but that it is insufficient to support a CTL response that can control tumor growth. Consistent with this, administration of IL-12 at day 10 of tumor growth resulted in a large and sustained expansion of wild-type OT-I cells with enhanced effector functions, and tumor growth was controlled. This did not occur when the OT-I cells lacked the IL-12 and type I IFN receptors, demonstrating that the therapeutic effect of IL-12 results from direct delivery of signal 3 to the CD8 T cells responding to tumor Ag in the signal 3-deficient environment of the tumor.
Detection and Long-Term In Vivo Monitoring of Individual Tumor-Specific T Cell Clones in Patients with Metastatic Melanoma
Authors: Michalek Jaroslav , Kocak Ivo , Fait Vuk , Zaloudik Jan , Hajek Roman 
Published: April 2014

Abstract
We investigated the presence of individual melanoma-specific T cell clones in patients with metastatic melanoma. Ten patients were examined for the presence of melanoma-reactive T cells using dendritic cells loaded with autologous tumor cells. Their specificity was tested using nonradioactive cytotoxicity test. Individual immunodominant T cell clones were identified by the clonotypic assay that combines in vitro cell culture, immunomagnetic sorting of activated IFN-γ+ T cells, TCRβ locus-anchored RT-PCR, and clonotypic quantitative PCR. All patients had detectable melanoma-reactive T cells in vitro. Expanded melanoma-reactive T cells demonstrated specific cytotoxic effect against autologous tumor cells in vitro. Three patients experienced objective responses, and their clinical responses were closely associated with the in vivo expansion and long-term persistence of individual CD8+ T cell clones with frequencies of 10−6 to 10−3 of all circulating CD8+ T cells. Five patients with progressive disease experienced no or temporary presence of circulating melanoma-reactive T cell clones. Thus, circulating immunodominant CD8+ T cell clones closely correlate with clinical outcome in patients with metastatic melanoma.
Redundant Role for Early Growth Response Transcriptional Regulators in Thymocyte Differentiation and Survival
Authors: Carter John H. , Lefebvre Juliet M. , Wiest David L. , Tourtellotte Warren G. 
Published: April 2014

Abstract
The early growth response (Egr) family of transcriptional regulators consists of four proteins that share highly conserved DNA-binding domains. In many cell types, they are coexpressed and appear to have cooperative roles in regulating gene expression during growth and differentiation. Three Egr proteins, Egr1, Egr2, and Egr3, are induced during thymocyte differentiation in response to pre-TCR signaling, suggesting they may be critical for some aspects of pre-TCR-mediated differentiation. Indeed, enforced expression of Egr proteins in developing thymocytes can recapitulate some aspects of pre-TCR signaling, but the mechanisms by which they contribute to β-selection are still poorly understood. Egr3 stimulates proliferation of β-selected thymocytes, and Egr3-deficient mice have hypocellular thymuses, defects in proliferation, and impaired progression from double-negative 3 to double-negative 4. Surprisingly, Egr1-deficient mice exhibit normal β-selection, indicating that the functions of Egr1 during β-selection are likely compensated by other Egr proteins. In this study, we show that mice lacking both Egr1 and Egr3 exhibit a more severe thymic atrophy and impairment of thymocyte differentiation than mice lacking either Egr1 or Egr3. This is due to a proliferation defect and cell-autonomous increase in apoptosis, indicating that Egr1 and Egr3 cooperate to promote thymocyte survival. Microarray analysis of deregulated gene expression in immature thymocytes lacking both Egr1 and Egr3 revealed a previously unknown role for Egr proteins in the maintenance of cellular metabolism, providing new insight into the function of these molecules during T cell development.
CD4+CD25+ T Regulatory Cells Dominate Multiple Immune Evasion Mechanisms in Early but Not Late Phases of Tumor Development in a B Cell Lymphoma Model
Authors: Elpek Kutlu G. , Lacelle Chantale , Singh Narendra P. , Yolcu Esma S. , Shirwan Haval 
Published: April 2014

AbstractTumors use a complex set of direct and indirect mechanisms to evade the immune system. Naturally arising CD4+CD25+FoxP3+ T regulatory (Treg) cells have been implicated recently in tumor immune escape mechanism, but the relative contribution of these cells to overall tumor progression compared with other immune evasion mechanisms remains to be elucidated. Using the A20 B cell lymphoma as a transplantable tumor model, we demonstrate that this tumor employs multiple direct (expression of immunoinhibitory molecule PD-L1, IDO, and IL-10, and lack of expression of CD80 costimulatory molecule) and indirect (down-regulation of APC function and induction of Treg cells) immune evasion mechanisms. Importantly, Treg cells served as the dominant immune escape mechanism early in tumor progression because the physical elimination of these cells before tumor challenge resulted in tumor-free survival in 70% of mice, whereas their depletion in animals with established tumors had no therapeutic effect. Therefore, our data suggest that Treg cells may serve as an important therapeutic target for patients with early stages of cancer and that more vigorous combinatorial approaches simultaneously targeting multiple immune evasion as well as immunosurveillance mechanisms for the generation of a productive immune response against tumor may be required for effective immunotherapy in patients with advanced disease.
CD103− and CD103+ Bronchial Lymph Node Dendritic Cells Are Specialized in Presenting and Cross-Presenting Innocuous Antigen to CD4+ and CD8+ T Cells
Authors: del Rio Maria-Luisa , Rodriguez-Barbosa Jose-Ignacio , Kremmer Elisabeth , Förster Reinhold 
Published: April 2014

Abstract
Dendritic cells (DC) are able to capture, process, and present exogenous Ag to CD8+ T lymphocytes through MHC class I, a process referred to as cross-presentation. In this study, we demonstrate that CD103+ (CD11chighCD11blow) and CD103− (CD11cintCD11bhigh) DC residing in the lung-draining bronchial lymph node (brLN) have evolved to acquire opposing functions in presenting innocuous inhaled Ag. Thus, under tolerogenic conditions, CD103− DC are specialized in presenting innocuous Ag to CD4+ T cells, whereas CD103+ DC, which do not express CD8α, are specialized in presenting Ag exclusively to CD8+ T cells. In CCR7-deficient but not in plt/plt mice, Ag-carrying CD103+ DC are largely absent in the brLN, although CD103+ DC are present in the lung of CCR7-deficient mice. As a consequence, adoptively transferred CD8+ T cells can be activated under tolerizing conditions in plt/plt but not in CCR7-deficient mice. These data reveal that CD103+ brLN DC are specialized in cross-presenting innocuous inhaled Ag in vivo. Because these cells are largely absent in CCR7−/− mice, our findings strongly suggest that brLN CD103+ DC are lung-derived and that expression of CCR7 is required for their migration from the lung into its draining lymph node.
Murine Dendritic Cell Type I IFN Production Induced by Human IgG-RNA Immune Complexes Is IFN Regulatory Factor (IRF)5 and IRF7 Dependent and Is Required for IL-6 Production
Authors: Yasuda Kei , Richez Christophe , Maciaszek Joseph W. , Agrawal Neerja , Akira Shizuo , Marshak-Rothstein Ann , Rifkin Ian R. 
Published: April 2014

Abstract
Dendritic cell (DC) activation by nucleic acid-containing IgG complexes is implicated in systemic lupus erythematosus (SLE) pathogenesis. However, it has been difficult to definitively examine the receptors and signaling pathways by which this activation is mediated. Because mouse FcγRs recognize human IgG, we hypothesized that IgG from lupus patients might stimulate mouse DCs, thereby facilitating this analysis. In this study, we show that sera and purified IgG from lupus patients activate mouse DCs to produce IFN-α, IFN-β, and IL-6 and up-regulate costimulatory molecules in a FcγR-dependent manner. This activation is only seen in sera with reactivity against ribonucleoproteins and is completely dependent on TLR7 and the presence of RNA. As anticipated, IFN regulatory factor (IRF)7 is required for IFN-α and IFN-β production. Unexpectedly, however, IRF5 plays a critical role in IFN-α and IFN-β production induced not only by RNA-containing immune complexes but also by conventional TLR7 and TLR9 ligands. Moreover, DC production of IL-6 induced by these stimuli is dependent on a functional type I IFNR, indicating the need for a type I IFN-dependent feedback loop in the production of inflammatory cytokines. This system may also prove useful for the study of receptors and signaling pathways used by immune complexes in other human diseases.
The CD28/CTLA-4-B7 Signaling Pathway Is Involved in Both Allergic Sensitization and Tolerance Induction to Orally Administered Peanut Proteins
Authors: van Wijk Femke , Nierkens Stefan , de Jong Wilco , Wehrens Ellen J. M. , Boon Louis , van Kooten Peter , Knippels Léon M. J. , Pieters Raymond 
Published: April 2014

AbstractDendritic cells are believed to play an essential role in regulating the balance between immunogenic and tolerogenic responses to mucosal Ags by controlling T cell differentiation and activation via costimulatory and coinhibitory signals. The CD28/CTLA-4-CD80/CD86 signaling pathway appears to be one of the most important regulators of T cell responses but its exact role in responses to orally administered proteins remains to be elucidated. In the present study, the involvement of the CD28/CTLA-4-CD80/CD86 costimulatory pathway in the induction of allergic sensitization and oral tolerance to peanut proteins was investigated. In both an established C3H/HeOuJ mouse model of peanut hypersensitivity and an oral tolerance model to peanut, CD28/CTLA-4-CD80/CD86 interactions were blocked using the fusion protein CTLA-4Ig. To examine the relative contribution of CD80- and CD86-mediated costimulation in these models, anti-CD80 and anti-CD86 blocking Abs were used. In the hypersensitivity model, CTLA-4Ig treatment prevented the development of peanut extract-induced cytokine responses, peanut extract-specific IgG1, IgG2a, and IgE production and peanut extract-induced challenge responses. Blocking of CD80 reduced, whereas anti-CD86 treatment completely inhibited, the induction of peanut extract-specific IgE. Normal tolerance induction to peanut extract was found following CTLA-4Ig, anti-CD86, or anti-CD80 plus anti-CD86 treatment, whereas blockade of CD80 impaired the induction of oral tolerance. We show that CD28/CTLA-4-CD80/CD86 signaling is essential for the development of allergic responses to peanut and that CD86 interaction is most important in inducing peanut extract-specific IgE responses. Additionally, our data suggest that CD80 but not CD86 interaction with CTLA-4 is crucial for the induction of low dose tolerance to peanut.
Functional Gap Junctions Facilitate Melanoma Antigen Transfer and Cross-Presentation between Human Dendritic Cells
Authors: Mendoza-Naranjo Ariadna , Saéz Pablo J. , Johansson C. Christian , Ramírez Marcos , Mandaković Dinka , Pereda Cristian , López Mercedes N. , Kiessling Rolf , Sáez Juan C. , Salazar-Onfray Flavio 
Published: April 2014

Abstract
Previously, we found that human dendritic cells (hDCs) pulsed with a melanoma cell lysate (MCL) and stimulated with TNF-α (MCL/TNF) acquire a mature phenotype in vitro and are able to trigger tumor-specific immune responses when they are used in melanoma immunotherapy in patients. In this study, we describe that MCL/TNF induces gap junction (GJ)-mediated intercellular communications and promotes melanoma Ag transfer between ex vivo produced hDCs from melanoma patients. hDCs also exhibit increased expression of the GJ-related protein connexin 43, which contributes to GJ plaque formation after MCL/TNF stimulation. The addition of GJ inhibitors suppresses intercellular tumor Ag transfer between hDCs, thus reducing melanoma-specific T cell activation. In summary, we demonstrate that MCL/TNF-stimulated hDCs can establish functional GJ channels that participate in melanoma Ag transfer, facilitating Ag cross-presentation and an effective dendritic cell-mediated melanoma-specific T cell response. These results suggest that GJs formed between hDCs used in cancer vaccination protocols could be essentials for the establishment of a more efficient antitumor response.
Parallel Loss of Myeloid and Plasmacytoid Dendritic Cells from Blood and Lymphoid Tissue in Simian AIDS
Authors: Brown Kevin N. , Trichel Anita , Barratt-Boyes Simon M. 
Published: April 2014

AbstractThe loss of myeloid (mDC) and plasmacytoid dendritic cells (pDC) from the blood of HIV-infected individuals is associated with progressive disease. It has been proposed that DC loss is due to increased recruitment to lymph nodes, although this has not been directly tested. Similarly as in HIV-infected humans, we found that lineage-negative (Lin−) HLA-DR+CD11c+CD123− mDC and Lin−HLA-DR+CD11c−CD123+ pDC were lost from the blood of SIV-infected rhesus macaques with AIDS. In the peripheral lymph nodes of SIV-naive monkeys the majority of mDC were mature cells derived from skin that expressed high levels of HLA-DR, CD83, costimulatory molecules, and the Langerhans cell marker CD1a, whereas pDC expressed low levels of HLA-DR and CD40 and lacked costimulatory molecules, similar to pDC in blood. Surprisingly, both DC subsets were depleted from peripheral and mesenteric lymph nodes and spleens in monkeys with AIDS, although the activation status of the remaining DC subsets was similar to that of DC in health. In peripheral and mesenteric lymph nodes from animals with AIDS there was an accumulation of Lin−HLA-DRmoderateCD11c−CD123− cells that resembled monocytoid cells but failed to acquire a DC phenotype upon culture, suggesting they were not DC precursors. mDC and pDC from the lymphoid tissues of monkeys with AIDS were prone to spontaneous death in culture, indicating that apoptosis may be a mechanism for their loss in disease. These findings demonstrate that DC are lost from rather than recruited to lymphoid tissue in advanced SIV infection, suggesting that systemic DC depletion plays a direct role in the pathophysiology of AIDS.