bluuebunny/crossref_metadata_2025_split huggingface dataset:
Cooperative Induction of a Tolerogenic Dendritic Cell Phenotype by Cytokines Secreted by Pancreatic Carcinoma Cells
Authors: Bellone Graziella , Carbone Anna , Smirne Carlo , Scirelli Tiziana , Buffolino Alessandra , Novarino Anna , Stacchini Alessandra , Bertetto Oscar , Palestro Giorgio , Sorio Claudio , Scarpa Aldo , Emanuelli Giorgio , Rodeck Ulrich 
Published: April 2014

AbstractAg presentation by dendritic cells (DC) is essential to effective antitumor T cell responses in cancer patients. Depending on their origin, maturation state, and the ambient cytokine milieu, DC can differentiate into distinct subpopulations, which preferentially either induce Th1 cell activation (CD11c+,CD123− myeloid DC (MDC)) or immunosuppressive T cell development (CD11c−,CD123+ plasmacytoid DC (PDC)). The present study was undertaken to characterize the effects of pancreatic carcinoma cell-derived cytokines on immature monocyte-derived DC (iMo-DC) in vitro and in vivo. Medium conditioned by human pancreatic carcinoma cells inhibited iMo-DC proliferation, expression of costimulatory molecules (CD80 and CD40) and of HLA-DR, and functional activity as assessed by MLR and IL-12p70 production. iMo-DC generated from pancreatic carcinoma patients in advanced stages of the disease similarly showed decreased levels of HLA-DR expression and reduced ability to stimulate MLR in response to CD40L and IFN-γ. Moreover, in tumor-patient peripheral blood, the ratio of MDC to PDC cells was lower than in healthy controls due to reduced numbers of MDC CD11c+ cells. Importantly, rather than a single cytokine, a combination of tumor-derived cytokines was responsible for these effects; these were primarily TGF-β, IL-10, and IL-6, but not vascular endothelial growth factor. In summary, we have identified an array of pancreatic carcinoma-derived cytokines that cooperatively affect iMo-DC activation in a manner consistent with ineffective antitumor immune responses.
Nucleotide-Binding Oligomerization Domain-Like Receptors: Intracellular Pattern Recognition Molecules for Pathogen Detection and Host Defense
Authors: Franchi Luigi , McDonald Christine , Kanneganti Thirumala-Devi , Amer Amal , Núñez Gabriel 
Published: April 2014

Abstract
The nucleotide binding oligomerization domain-like receptor (NLR) family of pattern recognition molecules is involved in a diverse array of processes required for host immune responses against invading pathogens. Unlike TLRs that mediate extracellular recognition of microbes, several NLRs sense pathogens in the cytosol and upon activation induce host defense signaling pathways. Although TLRs and NLRs differ in their mode of pathogen recognition and function, they share similar domains for microbial sensing and cooperate to elicit immune responses against the pathogen. Genetic variation in several NLR genes is associated with the development of inflammatory disorders or increased susceptibility to microbial infection. Further understanding of NLRs should provide critical insight into the mechanisms of host defense and the pathogenesis of inflammatory diseases.
Thrombospondin/CD47 Interaction: A Pathway to Generate Regulatory T Cells from Human CD4+CD25− T Cells in Response to Inflammation
Authors: Grimbert Philippe , Bouguermouh Salim , Baba Nobuyasu , Nakajima Toshiharu , Allakhverdi Zoulfia , Braun Deborah , Saito Hirohisa , Rubio Manuel , Delespesse Guy , Sarfati Marika 
Published: April 2014

Abstract
Thymus-derived CD4+ CD25+ T regulatory cells (Tregs) are essential for the maintenance of self-tolerance. What critical factors and conditions are required for the extra-thymic development of Tregs remains an important question. In this study, we show that the anti-inflammatory extracellular matrix protein, thrombospondin-1, promoted the generation of human peripheral regulatory T cells through the ligation of one of its receptor, CD47. CD47 stimulation by mAb or a thrombospondin-1 peptide induced naive or memory CD4+CD25− T cells to become suppressive. The latter expressed increased amounts of CTLA-4, OX40, GITR, and Foxp3 and inhibited autologous Th0, Th1, and Th2 cells. Their regulatory activity was contact dependent, TGF-β independent, and partially circumvented by IL-2. This previously unknown mechanism to induce human peripheral Tregs in response to inflammation may participate to the limitation of collateral damage induced by exacerbated responses to self or foreign Ags and thus be relevant for therapeutic intervention in autoimmune diseases and transplantation.
CD94/NKG2A Inhibits NK Cell Activation by Disrupting the Actin Network at the Immunological Synapse
Authors: Masilamani Madhan , Nguyen Connie , Kabat Juraj , Borrego Francisco , Coligan John E. 
Published: April 2014

Abstract
An adequate immune response is the result of the fine balance between activation and inhibitory signals. The exact means by which inhibitory signals obviate activation signals in immune cells are not totally elucidated. Human CD94/NKG2A is an ITIM-containing inhibitory receptor expressed by NK cells and some CD8+ T cells that recognize HLA-E. We show that the engagement of this receptor prevents NK cell activation by disruption of the actin network and exclusion of lipid rafts at the point of contact with its ligand (inhibitory NK cell immunological synapse, iNKIS). CD94/NKG2A engagement leads to recruitment and activation of src homology 2 domain-bearing tyrosine phosphatase 1. This likely explains the observed dephosphorylation of guanine nucleotide exchange factor and regulator of actin, Vav1, as well as ezrin-radixin-moesin proteins that connect actin filaments to membrane structures. In contrast, NK cell activation by NKG2D induced Vav1 and ezrin-radixin-moesin phosphorylation. Thus, CD94/NKG2A prevents actin-dependent recruitment of raft-associated activation receptors complexes to the activating synapse. This was further substantiated by showing that inhibition of actin polymerization abolished lipid rafts exclusion at the iNKIS, whereas cholesterol depletion had no effect on actin disruption at the iNKIS. These data indicate that the lipid rafts exclusion at the iNKIS is an active process which requires an intact cytoskeleton to maintain lipid rafts outside the inhibitory synapse. The net effect is to maintain an inhibitory state in the proximity of the iNKIS, while allowing the formation of activation synapse at distal points within the same NK cell.
Different Neurotropic Pathogens Elicit Neurotoxic CCR9- or Neurosupportive CXCR3-Expressing Microglia
Authors: Li He , Gang Zhou , Yuling He , Luokun Xie , Jie Xiong , Hao Lei , Li Wei , Chunsong Hu , Junyan Liu , Mingshen Jiang , Youxin Jin , Feili Gong , Boquan Jin , Jinquan Tan 
Published: April 2014

AbstractWhat mechanism that determines microglia accomplishing destructive or constructive role in CNS remains nebulous. We report here that intracranial priming and rechallenging with Toxoplasma gondii in mice elicit neurotoxic CCR9+Irg1+ (immunoresponsive gene 1) microglia, which render resistance to apoptosis and produce a high level of TNF-α; priming and rechallenging with lymphocytic choriomeningitis virus elicit neurosupportive CXCR3+Irg1− microglia, which are sensitive to apoptosis and produce a high level of IL-10 and TGF-β. Administration of CCR9 and/or Irg1 small interfering RNA alters the frequency and functional profiles of neurotoxic CCR9+Irg1+ and neurosupportive CXCR3+Irg1− microglia in vivo. Moreover, by using a series of different neurotropic pathogens, including intracellular parasites, chronic virus, bacteria, toxic substances, and CNS injury to intracranially prime and subsequent rechallenge mice, the bi-directional elicitation of microglia has been confirmed as neurotoxic CCR9+Irg1+ and neurosupportive CXCR3+Irg1− cells in these mouse models. These data suggest that there exist two different types of microglia, providing with a novel insight into microglial involvement in neurodegenerative and neuroinflammatory pathogenesis such as Alzheimer’s disease and AIDS dementia.
Mechanisms Regulating the Proliferative Potential of Human CD8+ T Lymphocytes Overexpressing Telomerase
Authors: Menzel Olivier , Migliaccio Marco , Goldstein Darlene R. , Dahoun Sophie , Delorenzi Mauro , Rufer Nathalie 
Published: April 2014

Abstract
In human somatic cells, including T lymphocytes, telomeres progressively shorten with each cell division, eventually leading to a state of cellular senescence. Ectopic expression of telomerase results in the extension of their replicative life spans without inducing changes associated with transformation. However, it is yet unknown whether somatic cells that overexpress telomerase are physiologically indistinguishable from normal cells. Using CD8+ T lymphocyte clones overexpressing telomerase, we investigated the molecular mechanisms that regulate T cell proliferation. In this study, we show that early passage T cell clones transduced or not with human telomerase reverse transcriptase displayed identical growth rates upon mitogenic stimulation and no marked global changes in gene expression. Surprisingly, reduced proliferative responses were observed in human telomerase reverse transcriptase-transduced cells with extended life spans. These cells, despite maintaining high expression levels of genes involved in the cell cycle progression, also showed increased expression in several genes found in common with normal aging T lymphocytes. Strikingly, late passage T cells overexpressing telomerase accumulated the cyclin-dependent inhibitors p16Ink4a and p21Cip1 that have largely been associated with in vitro growth arrest. We conclude that alternative growth arrest mechanisms such as those mediated by p16Ink4a and p21Cip1 still remained intact and regulated the growth potential of cells independently of their telomere status.
The Major Glycoprotein Allergen from Arachis hypogaea, Ara h 1, Is a Ligand of Dendritic Cell-Specific ICAM-Grabbing Nonintegrin and Acts as a Th2 Adjuvant In Vitro
Authors: Shreffler Wayne G. , Castro Russell R. , Kucuk Z. Yesim , Charlop-Powers Zachary , Grishina Galina , Yoo Steven , Burks A. Wesley , Sampson Hugh A. 
Published: April 2014

Abstract
Nonmammalian glycan structures from helminths act as Th2 adjuvants. Some of these structures are also common on plant glycoproteins. We hypothesized that glycan structures present on peanut glycoallergens act as Th2 adjuvants. Peanut Ag (PNAg), but not deglycosylated PNAg, activated monocyte-derived dendritic cells (MDDCs) as measured by MHC/costimulatory molecule up-regulation, and by their ability to drive T cell proliferation. Furthermore, PNAg-activated MDDCs induced 2- to 3-fold more IL-4- and IL-13-secreting Th2 cells than immature or TNF/IL-1-activated MDDCs when cultured with naive CD4+ T cells. Human MDDCs rapidly internalized Ag in a calcium- and glycan-dependent manner consistent with recognition by C-type lectin. Dendritic cell (DC)-specific ICAM-grabbing nonintegrin (DC-SIGN) (CD209) was shown to recognize PNAg by enhanced uptake in transfected cell lines. To identify the DC-SIGN ligand from unfractionated PNAg, we expressed the extracellular portion of DC-SIGN as an Fc-fusion protein and used it to immunoprecipitate PNAg. A single glycoprotein was pulled down in a calcium-dependent manner, and its identity as Ara h 1 was proven by immunolabeling and mass spectrometry. Purified Ara h 1 was found to be sufficient for the induction of MDDCs that prime Th2-skewed T cell responses. Both PNAg and purified Ara h 1 induced Erk 1/2 phosphorylation of MDDCs, consistent with previous reports on the effect of Th2 adjuvants on DCs.
A Role for Intercellular Antigen Transfer in the Recognition of EBV-Transformed B Cell Lines by EBV Nuclear Antigen-Specific CD4+ T Cells
Authors: Taylor Graham S. , Long Heather M. , Haigh Tracey A. , Larsen Martin , Brooks Jill , Rickinson Alan B. 
Published: April 2014

Abstract
The CD4+ T cell response to EBV may have an important role in controlling virus-driven B lymphoproliferation because CD4+ T cell clones to a subset of EBV nuclear Ag (EBNA) epitopes can directly recognize virus-transformed lymphoblastoid cell lines (LCLs) in vitro and inhibit their growth. In this study, we used a panel of EBNA1, 2, 3A, and 3C-specific CD4+ T cell clones to study the route whereby endogenously expressed EBNAs access the HLA class II-presentation pathway. Two sets of results spoke against a direct route of intracellular access. First, none of the clones recognized cognate Ag overexpressed in cells from vaccinia vectors but did recognize Ag fused to an endo/lysosomal targeting sequence. Second, focusing on clones with the strongest LCL recognition that were specific for EBNA2- and EBNA3C-derived epitopes LCL recognition was unaffected by inhibiting autophagy, a postulated route for intracellular Ag delivery into the HLA class II pathway in LCL cells. Subsequently, using these same epitope-specific clones, we found that Ag-negative cells with the appropriate HLA-restricting allele could be efficiently sensitized to CD4+ T cell recognition by cocultivation with Ag-positive donor lines or by exposure to donor line-conditioned culture medium. Sensitization was mediated by a high m.w. antigenic species and required active Ag processing by recipient cells. We infer that intercellular Ag transfer plays a major role in the presentation of EBNA-derived CD4 epitopes by latently infected target cells.
Monocyte 15-Lipoxygenase Expression Is Regulated by a Novel Cytosolic Signaling Complex with Protein Kinase C δ and Tyrosine-Phosphorylated Stat3
Authors: Bhattacharjee Ashish , Xu Bo , Frank David A. , Feldman Gerald M. , Cathcart Martha K. 
Published: April 2014

Abstract
Our previous studies demonstrated that the IL-13-induced 15-lipoxygenase expression in primary human monocytes is regulated by the activation of both Stat1 and Stat3 and by protein kinase C (PKC)δ. IL-13 stimulated the phosphorylation of Stat3 on both Tyr705 and Ser727. In this study we show that IL-13 induces the association of PKCδ with Stat3, not with Stat1, and is required for Stat3 Ser727 phosphorylation. We found a novel IL-13-dependent cytosolic signaling complex of PKCδ and tyrosine-phosphorylated Stat3. A tyrosine kinase inhibitor blocked PKCδ association with Stat3 as well as Stat3 Ser727 phosphorylation. We therefore hypothesized that tyrosine phosphorylation was required for Stat3 interaction with PKCδ and subsequent PKCδ-dependent phosphorylation of Stat3 Ser727. We developed an efficient transfection protocol for human monocytes. Expression of Stat3 containing a mutation in Tyr705 inhibited the association of PKCδ with Stat3 and blocked Stat3 Ser727 phosphorylation, whereas transfection with wild-type Stat3 did not. Furthermore, by transfecting monocytes with Stat3 containing mutations in Tyr705 or Ser727 or with wild-type Stat3, we demonstrated that both Stat3 tyrosine and serine phosphorylations are required for optimal binding of Stat3 with DNA and maximal expression of 15-lipoxygenase, an important regulator of inflammation and apoptosis.
Epigenetic Regulation during B Cell Differentiation Controls CIITA Promoter Accessibility
Authors: Green Myesha R. , Yoon Hyesuk , Boss Jeremy M. 
Published: April 2014

Abstract
B cell to plasma cell maturation is marked by the loss of MHC class II expression. This loss is due to the silencing of the MHC class II transcriptional coactivator CIITA. In this study, experiments to identify the molecular mechanism responsible for CIITA silencing were conducted. CIITA is expressed from four promoters in humans, of which promoter III (pIII) controls the majority of B cell-mediated expression. Chromatin immunoprecipitation assays were used to establish the histone code for pIII and determine the differences between B cells and plasma cells. Specific histone modifications associated with accessible promoters and transcriptionally active genes were observed at pIII in B cells but not in plasma cells. A reciprocal exchange of histone H3 lysine 9 acetylation to methylation was also observed between B cells and plasma cells. The lack of histone acetylation correlated with an absence of transcription factor binding to pIII, particularly that of Sp1, PU.1, CREB, and E47. Intriguingly, changes in chromatin architecture of the 13-kb region encompassing all CIITA promoters showed a remarkable deficit in histone H3 and H4 acetylation in plasma cells, suggesting that the mechanism of silencing is global. When primary B cells were differentiated ex vivo, most of the histone marks associated with pIII activation and expression were lost within 24 h. The results demonstrate that CIITA silencing occurs by controlling chromatin accessibility through a multistep mechanism that includes the loss of histone acetylation and transcription factor binding, and the acquisition of repressive histone methylation marks.
Strong TCR Conservation and Altered T Cell Cross-Reactivity Characterize a B*57-Restricted Immune Response in HIV-1 Infection
Authors: Gillespie Geraldine M. A. , Stewart-Jones Guillaume , Rengasamy Jaya , Beattie Tara , Bwayo Job. J. , Plummer Francis A. , Kaul Rupert , McMichael Andrew J. , Easterbrook Philippa , Dong Tao , Jones E. Yvonne , Rowland-Jones Sarah L. 
Published: April 2014

Abstract
HLA-B*57 is associated with slower disease progression to AIDS, and CD8+ T cell responses to B*57-restricted epitopes are thought to contribute to this protective effect. In this study, we evaluate the B*57-restricted p24 KAFSPEVIPMF (KF11) immune response which is immunodominant during chronic infection. Previously, we observed that the KF11 clade variants KGFNPEVIPMF [A2G,S4N] and KAFNPEIIMPF [S4N,V7I], sharing a position 4 mutation, are differentially recognized by KF11-specific T cells. By combining structural and cellular studies, we now demonstrate that the KF11 and [A2G,S4N] epitopes induce distinct functional responses in [A2G,S4N] and KF11-specific T cells, respectively, despite minimal structural differences between the individual B*57-peptide complexes. Recently, we also elucidated the highly distinct structure of KF11 in complex with B*5703, and have now characterized the CD8+ T cell repertoire recognizing this epitope. We now report striking features of TCR conservation both in terms of TCR Vα and Vβ chain usage, and throughout the hypervariable region. Collectively, our findings highlight unusual features of the B*5701/B*5703-KF11-specific immune responses which could influence disease progression and that might be important to consider when designing future vaccine regimens.
Structural Basis of Inducible Costimulator Ligand Costimulatory Function: Determination of the Cell Surface Oligomeric State and Functional Mapping of the Receptor Binding Site of the Protein
Authors: Chattopadhyay Kausik , Bhatia Sumeena , Fiser Andras , Almo Steven C. , Nathenson Stanley G. 
Published: April 2014

Abstract
Inducible costimulator (ICOS) ligand (ICOSL), a B7-related transmembrane glycoprotein with extracellular IgV and IgC domains, binds to ICOS on activated T cells and delivers a positive costimulatory signal for optimal T cell function. Toward determining the structural features of ICOSL crucial for its costimulatory function, the present study shows that ICOSL displays a marked oligomerization potential, resembling more like B7-1 than B7-2. Use of ICOSL constructs lacking either the IgC or IgV domain demonstrates that receptor binding is mediated solely by the IgV domain but requires the IgC domain for maintaining the structural integrity of the protein. To map further the receptor recognition surface on ICOSL, a homology-based protein structure model of the ICOS:ICOSL complex was constructed. Based on predictions from the model, a series of mutations were generated targeting the potential receptor binding surface on ICOSL, and the mutants were tested for their biological function in terms of ICOS binding and T cell costimulation ability. The results provide experimental validation of the model and show that the receptor binding site on ICOSL is constituted chiefly by aromatic/hydrophobic residues. Critical ICOSL residues essential for ICOS binding map to the GFCC′C″ β-sheet face of the IgV domain and approximately overlap with the B7-1/B7-2 motif(s) that recognize CD28/CTLA-4. Altogether, similar structural features of ICOSL and B7 isoforms suggest a close evolutionary relationship between these costimulatory ligands, yet differences at the same time explain their unique specificity for the cognate binding partners, ICOS and CD28/CTLA-4, respectively.
TNF Is Important for Pathogen Control and Limits Brain Damage in Murine Cerebral Listeriosis
Authors: Virna Simona , Deckert Martina , Lütjen Sonja , Soltek Sabine , Foulds Kathryn E. , Shen Hao , Körner Heinrich , Sedgwick Jonathon D. , Schlüter Dirk 
Published: April 2014

AbstractCerebral listeriosis is a life-threatening disease. However, little is known about the bacterial virulence factors responsible for the severe course of disease and the factors of the immune system contributing to the control of Listeria monocytogenes (LM) or even to the damage of the brain. To analyze the importance of the actA gene of LM, which mediates cell-to-cell spread of intracellular LM, the function of TNF in murine cerebral listeriosis was studied. C57BL/6 mice survived an intracerebral (i.c.) infection with actA-deficient LM, but succumbed to infection with wild-type (WT) LM. Upon infection with actA-deficient LM, macrophages and microglial cells rapidly, and later LM-specific CD4 and CD8 T cells, produced TNF. In contrast to WT mice, TNF-deficient animals succumbed to the infection within 4 days due to failure of control of LM. Histology identified a more severe meningoencephalitis, brain edema, and neuronal damage, but a reduced inducible NO synthase expression in TNF-deficient mice. Reciprocal bone marrow chimeras between WT and TNF-deficient mice revealed that hematogenously derived TNF was essential for survival, whereas TNF produced by brain-resident cells was less important. Death of TNF-deficient mice could be prevented by LM-specific T cells induced by an active immunization before i.c. infection. However, brain pathology and inflammation of immunized TNF-deficient mice were still more severe. In conclusion, these findings identify a crucial role of TNF for the i.c. control of LM and survival of cerebral listeriosis, whereas TNF was not responsible for the destruction of brain tissue.