bluuebunny/crossref_metadata_2025_split huggingface dataset:
PD-1 Regulates Self-Reactive CD8+ T Cell Responses to Antigen in Lymph Nodes and Tissues
Authors: Keir Mary E. , Freeman Gordon J. , Sharpe Arlene H. 
Published: April 2014

Abstract
PD-1, an inhibitory receptor expressed on activated lymphocytes, regulates tolerance and autoimmunity. We tested the role of PD-1:PD-1 ligand (PD-L) interactions in cross-presentation and the generation and control of CD8+ responses against self-Ag. Ag-naive PD-1−/− OVA-specific OT-I CD8+ T cells exhibited exacerbated responses to cross-presented Ag in mice expressing soluble OVA under the control of the rat insulin promoter (RIP-ovahigh). Following adoptive transfer into RIP-ovahigh recipients, PD-1−/− OT-I T cells expanded in the pancreatic lymph node. In contrast to wild-type OT-I cells, PD-1−/− OT-I T cells secreted IFN-γ and migrated into the pancreas, ultimately causing diabetes. Loss of PD-1 affected CD8+ cells intrinsically, and did not significantly alter the responses of wild-type OT-I T cells adoptively transferred into the same RIP-ovahigh recipient mouse. PD-1:PD-L interactions also limited CD8+ effector cells, and PD-L1 expression on parenchymal tissues protected against effector OT-I T cell attack. Finally, we found that the loss of PD-1 on effector OT-I cells lowers the threshold for Ag recognition in peripheral tissues. These findings indicate two checkpoints where PD-1 attenuates self-reactive T cell responses: presentation of self-Ag to naive self-reactive T cells by dendritic cells in the draining lymph node and reactivation of pathogenic self-reactive T cells in the target organ.
Modulation of miR-155 and miR-125b Levels following Lipopolysaccharide/TNF-α Stimulation and Their Possible Roles in Regulating the Response to Endotoxin Shock
Authors: Tili Esmerina , Michaille Jean-Jacques , Cimino Amelia , Costinean Stefan , Dumitru Calin Dan , Adair Brett , Fabbri Muller , Alder Hannes , Liu Chang Gong , Calin George Adrian , Croce Carlo Maria 
Published: April 2014

Abstract
We report here that miR-155 and miR-125b play a role in innate immune response. LPS stimulation of mouse Raw 264.7 macrophages resulted in the up-regulation of miR-155 and down-regulation of miR-125b levels. The same changes also occurred when C57BL/6 mice were i.p. injected with LPS. Furthermore, the levels of miR-155 and miR-125b in Raw 264.7 cells displayed oscillatory changes in response to TNF-α. These changes were impaired by pretreating the cells with the proteasome inhibitor MG-132, suggesting that these two microRNAs (miRNAs) may be at least transiently under the direct control of NF-κB transcriptional activity. We show that miR-155 most probably directly targets transcript coding for several proteins involved in LPS signaling such as the Fas-associated death domain protein (FADD), IκB kinase ε (IKKε), and the receptor (TNFR superfamily)-interacting serine-threonine kinase 1 (Ripk1) while enhancing TNF-α translation. In contrast, miR-125b targets the 3′-untranslated region of TNF-α transcripts; therefore, its down-regulation in response to LPS may be required for proper TNF-α production. Finally, Eμ-miR-155 transgenic mice produced higher levels of TNF-α when exposed to LPS and were hypersensitive to LPS/d-galactosamine-induced septic shock. Altogether, our data suggest that the LPS/TNF-α-dependent regulation of miR-155 and miR-125b may be implicated in the response to endotoxin shock, thus offering new targets for drug design.
Role of CXCR5 and CCR7 in Follicular Th Cell Positioning and Appearance of a Programmed Cell Death Gene-1High Germinal Center-Associated Subpopulation
Authors: Haynes Nicole M. , Allen Christopher D. C. , Lesley Robin , Ansel K. Mark , Killeen Nigel , Cyster Jason G. 
Published: April 2014

Abstract
Th cell access to primary B cell follicles is dependent on CXCR5. However, whether CXCR5 induction on T cells is sufficient in determining their follicular positioning has been unclear. In this study, we find that transgenic CXCR5 overexpression is not sufficient to promote follicular entry of naive T cells unless the counterbalancing influence of CCR7 ligands is removed. In contrast, the positioning of Ag-engaged T cells at the B/T boundary could occur in the absence of CXCR5. The germinal center (GC) response was 2-fold reduced when T cells lacked CXCR5, although these T cells were able to access the GC. Finally, CXCR5highCCR7low T cells were found to have elevated IL-4 transcript and programmed cell death gene-1 (PD-1) expression, and PD-1high cells were reduced in the absence of T cell CXCR5 or in mice compromised in GC formation. Overall, these findings provide further understanding of how the changes in CXCR5 and CCR7 expression regulate Th cell positioning during Ab responses, and they suggest that development and/or maintenance of a PD-1high follicular Th cell subset is dependent on appropriate interaction with GC B cells.
Mycobacterium bovis Bacillus Calmette-Guérin Secreting Active Cathepsin S Stimulates Expression of Mature MHC Class II Molecules and Antigen Presentation in Human Macrophages
Authors: Soualhine Hafid , Deghmane Ala-Eddine , Sun Jim , Mak Karen , Talal Amina , Av-Gay Yossef , Hmama Zakaria 
Published: April 2014

Abstract
A successful Th cell response to bacterial infections is induced by mature MHC class II molecules presenting specific Ag peptides on the surface of macrophages. In recent studies, we demonstrated that infection with the conventional vaccine Mycobacterium bovis bacillus Calmette-Guérin (BCG) specifically blocks the surface export of mature class II molecules in human macrophages by a mechanism dependent on inhibition of cathepsin S (Cat S) expression. The present study examined class II expression in macrophages infected with a rBCG strain engineered to express and secrete biologically active human Cat S (rBCG-hcs). Cat S activity was completely restored in cells ingesting rBCG-hcs, which secreted substantial levels of Cat S intracellularly. Thus, infection with rBCG-hcs, but not parental BCG, restored surface expression of mature MHC class II molecules in response to IFN-γ, presumably as result of MHC class II invariant chain degradation dependent on active Cat S secreted by the bacterium. These events correlated with increased class II-directed presentation of mycobacterial Ag85B to a specific CD4+ T cell hybridoma by rBCG-hcs-infected macrophages. Consistent with these findings, rBCG-hcs was found to accelerate the fusion of its phagosome with lysosomes, a process that optimizes Ag processing in infected macrophages. These data demonstrated that intracellular restoration of Cat S activity improves the capacity of BCG-infected macrophages to stimulate CD4+ Th cells. Given that Th cells play a major role in protection against tuberculosis, rBCG-hcs would be a valuable tuberculosis vaccine candidate.
Inhibition of T Cell Activation by Cyclic Adenosine 5′-Monophosphate Requires Lipid Raft Targeting of Protein Kinase A Type I by the A-Kinase Anchoring Protein Ezrin
Authors: Ruppelt Anja , Mosenden Randi , Grönholm Mikaela , Aandahl Einar M. , Tobin Derek , Carlson Cathrine R. , Abrahamsen Hilde , Herberg Friedrich W. , Carpén Olli , Taskén Kjetil 
Published: April 2014

Abstract
cAMP negatively regulates T cell immune responses by activation of type I protein kinase A (PKA), which in turn phosphorylates and activates C-terminal Src kinase (Csk) in T cell lipid rafts. Using yeast two-hybrid screening, far-Western blot, immunoprecipitation and immunofluorescense analyses, and small interfering RNA-mediated knockdown, we identified Ezrin as the A-kinase anchoring protein that targets PKA type I to lipid rafts. Furthermore, Ezrin brings PKA in proximity to its downstream substrate Csk in lipid rafts by forming a multiprotein complex consisting of PKA/Ezrin/Ezrin-binding protein 50, Csk, and Csk-binding protein/phosphoprotein associated with glycosphingolipid-enriched microdomains. The complex is initially present in immunological synapses when T cells contact APCs and subsequently exits to the distal pole. Introduction of an anchoring disruptor peptide (Ht31) into T cells competes with Ezrin binding to PKA and thereby releases the cAMP/PKA type I-mediated inhibition of T cell proliferation. Finally, small interfering RNA-mediated knockdown of Ezrin abrogates cAMP regulation of IL-2. We propose that Ezrin is essential in the assembly of the cAMP-mediated regulatory pathway that modulates T cell immune responses.
Silent Development of Memory Progenitor B Cells
Authors: Aviszus Katja , Zhang Xianghua , Wysocki Lawrence J. 
Published: April 2014

Abstract
T cell-dependent immune responses generate long-lived plasma cells and memory B cells, both of which express hypermutated Ab genes. The relationship between these cell types is not entirely understood. Both appear to emanate from the germinal center reaction, but it is unclear whether memory cells evolve while obligatorily generating plasma cells by siblings under all circumstances. In the experiments we report, plasma cell development was functionally segregated from memory cell development by a series of closely spaced injections of Ag delivered during the period of germinal center development. The injection series elevated serum Ab of low affinity, supporting the idea that a strong Ag signal drives plasma cell development. At the same time, the injection series produced a distinct population of affinity/specificity matured memory B cells that were functionally silent, as manifested by an absence of corresponding serum Ab. These cells could be driven by a final booster injection to develop into Ab-forming cells. This recall response required that a rest period precede the final booster injection, but a pause of only 4 days was sufficient. Our results support a model of memory B cell development in which extensive affinity/specificity maturation can take place within a B cell clone under some circumstances in which a concomitant generation of Ab-forming cells by siblings does not take place.
High Susceptibility of Human Dendritic Cells to Avian Influenza H5N1 Virus Infection and Protection by IFN-α and TLR Ligands
Authors: Thitithanyanont Arunee , Engering Anneke , Ekchariyawat Peeraya , Wiboon-ut Suwimon , Limsalakpetch Amporn , Yongvanitchit Kosol , Kum-Arb Utaiwan , Kanchongkittiphon Watcharoot , Utaisincharoen Pongsak , Sirisinha Stitaya , Puthavathana Pilaipan , Fukuda Mark M. , Pichyangkul Sathit 
Published: April 2014

Abstract
There is worldwide concern that the avian influenza H5N1 virus, with a mortality rate of &gt;50%, might cause the next influenza pandemic. Unlike most other influenza infections, H5N1 infection causes a systemic disease. The underlying mechanisms for this effect are still unclear. In this study, we investigate the interplay between avian influenza H5N1 and human dendritic cells (DC). We showed that H5N1 virus can infect and replicate in monocyte-derived and blood myeloid DC, leading to cell death. These results suggest that H5N1 escapes viral-specific immunity, and could disseminate via DC. In contrast, blood pDC were resistant to infection and produced high amounts of IFN-α. Addition of this cytokine to monocyte-derived DC or pretreatment with TLR ligands protected against infection and the cytopathic effects of H5N1 virus.
Induction of Indoleamine 2,3-Dioxygenase in Vascular Smooth Muscle Cells by Interferon-γ Contributes to Medial Immunoprivilege
Authors: Cuffy Madison C. , Silverio Amanda M. , Qin Lingfeng , Wang Yinong , Eid Raymond , Brandacher Gerald , Lakkis Fadi G. , Fuchs Dietmar , Pober Jordan S. , Tellides George 
Published: April 2014

Abstract
Atherosclerosis and graft arteriosclerosis are characterized by leukocytic infiltration of the vessel wall that spares the media. The mechanism(s) for medial immunoprivilege is unknown. In a chimeric humanized mouse model of allograft rejection, medial immunoprivilege was associated with expression of IDO by vascular smooth muscle cells (VSMCs) of rejecting human coronary artery grafts. Inhibition of IDO by 1-methyl-tryptophan (1-MT) increased medial infiltration by allogeneic T cells and increased VSMC loss. IFN-γ-induced IDO expression and activity in cultured human VSMCs was considerably greater than in endothelial cells (ECs) or T cells. IFN-γ-treated VSMCs, but not untreated VSMCs nor ECs with or without IFN-γ pretreatment, inhibited memory Th cell alloresponses across a semipermeable membrane in vitro. This effect was reversed by 1-MT treatment or tryptophan supplementation and replicated by the absence of tryptophan, but not by addition of tryptophan metabolites. However, IFN-γ-treated VSMCs did not activate allogeneic memory Th cells, even after addition of 1-MT or tryptophan. Our work extends the concept of medial immunoprivilege to include immune regulation, establishes the compartmentalization of immune responses within the vessel wall due to distinct microenvironments, and demonstrates a duality of stimulatory EC signals versus inhibitory VSMC signals to artery-infiltrating T cells that may contribute to the chronicity of arteriosclerotic diseases.
Role of Activation-Induced Deaminase Protein Kinase A Phosphorylation Sites in Ig Gene Conversion and Somatic Hypermutation
Authors: Chatterji Monalisa , Unniraman Shyam , McBride Kevin M. , Schatz David G. 
Published: April 2014

Abstract
Activation-induced deaminase (AID) is thought to initiate somatic hypermutation (SHM), gene conversion (GCV), and class switch recombination (CSR) by the transcription-coupled deamination of cytosine residues in Ig genes. Phosphorylation of AID by protein kinase A (PKA) and subsequent interaction of AID with replication protein A (RPA) have been proposed to play important roles in allowing AID to deaminate DNA during transcription. Serine 38 (S38) of mouse AID is phosphorylated in vivo and lies in a consensus target site for PKA, and mutation of this residue interferes with CSR and SHM. In this study, we demonstrate that S38 in mouse and chicken AID is phosphorylated in chicken DT40 cells and is required for efficient GCV and SHM in these cells. Paradoxically, zebra fish AID, which lacks a serine at the position corresponding to S38, has previously been shown to be active for CSR and we demonstrate that it is active for GCV/SHM. Aspartate 44 (D44) of zebra fish AID has been proposed to compensate for the absence of the S38 phosphorylation site but we demonstrate that mutation of D44 has no effect on GCV/SHM. Some features of zebra fish AID other than D44 might compensate for the absence of S38. Alternatively, the zebra fish protein might function in a manner that is independent of PKA and RPA in DT40 cells, raising the possibility that, under some circumstances, AID mediates efficient Ig gene diversification without the assistance of RPA.
A Role for EZH2 in Silencing of IFN-γ Inducible MHC2TA Transcription in Uveal Melanoma
Authors: Holling Tjadine M. , Bergevoet Marloes W. T. , Wilson Louis , Van Eggermond Marja C. J. A. , Schooten Erik , Steenbergen Renske D. M. , Snijders Peter J. F. , Jager Martine J. , Van den Elsen Peter J. 
Published: April 2014

Abstract
We investigated the contribution of epigenetic mechanisms in MHC2TA transcriptional silencing in uveal melanoma. Although no correlation was observed between impaired CIITA transcript levels after IFN-γ induction and DNA methylation of MHC2TA promoter IV (CIITA-PIV), an association was found with high levels of trimethylated histone H3-lysine 27 (3Me-K27-H3) in CIITA-PIV chromatin. The 3Me-K27-H3 modification correlated with a strong reduction in RNA polymerase II-recruitment to CIITA-PIV. Interestingly, we observed that none of these epigenetic modifications affected recruitment of activating transcription factors to this promoter. Subsequently, we demonstrated the presence of the histone methyltransferase EZH2 in CIITA-PIV chromatin, which is known to be a component of the Polycomb repressive complex 2 and able to triple methylate histone H3-lysine 27. RNA interference-mediated down-regulation of EZH2 expression resulted in an increase in CIITA transcript levels after IFN-γ induction. Our data therefore reveal that EZH2 contributes to silencing of IFN-γ-inducible transcription of MHC2TA in uveal melanoma cells.
Expression Profiling of Immature Thymocytes Revealed a Novel Homeobox Gene That Regulates Double-Negative Thymocyte Development
Authors: Kawazu Masahito , Yamamoto Go , Yoshimi Mayumi , Yamamoto Kazuki , Asai Takashi , Ichikawa Motoshi , Seo Sachiko , Nakagawa Masahiro , Chiba Shigeru , Kurokawa Mineo , Ogawa Seishi 
Published: April 2014

Abstract
Intrathymic development of CD4/CD8 double-negative (DN) thymocytes can be tracked by well-defined chronological subsets of thymocytes, and is an ideal target of gene expression profiling analysis to clarify the genetic basis of mature T cell production, by which differentiation of immature thymocytes is investigated in terms of gene expression profiles. In this study, we show that development of murine DN thymocytes is predominantly regulated by largely repressive rather than inductive activities of transcriptions, where lineage-promiscuous gene expression in immature thymocytes is down-regulated during their differentiation. Functional mapping of genes showing common temporal expression profiles implicates previously uncharacterized gene regulations that may be relevant to early thymocytes development. A small minority of genes is transiently expressed in the CD44lowCD25+ subset of DN thymocytes, from which we identified a novel homeobox gene, Duxl, whose expression is up-regulated by Runx1. Duxl promotes the transition from CD44highCD25+ to CD44lowCD25+ in DN thymocytes, while constitutive expression of Duxl inhibits expression of TCR β-chains and leads to impaired β selection and greatly reduced production of CD4/CD8 double-positive thymocytes, indicating its critical roles in DN thymocyte development.
Regulation of Tumor Cell Sensitivity to TRAIL-Induced Apoptosis by the Metastatic Suppressor Raf Kinase Inhibitor Protein via Yin Yang 1 Inhibition and Death Receptor 5 Up-Regulation
Authors: Baritaki Stavroula , Katsman Alina , Chatterjee Devasis , Yeung Kam C. , Spandidos Demetrios A. , Bonavida Benjamin 
Published: April 2014

Abstract
Raf-1 kinase inhibitor protein (RKIP) has been implicated in the regulation of cell survival pathways and metastases, and is poorly expressed in tumors. We have reported that the NF-κB pathway regulates tumor resistance to apoptosis by the TNF-α family via inactivation of the transcription repressor Yin Yang 1 (YY1). We hypothesized that RKIP overexpression may regulate tumor sensitivity to death ligands via inhibition of YY1 and up-regulation of death receptors (DRs). The TRAIL-resistant prostate carcinoma PC-3 and melanoma M202 cell lines were examined. Transfection with CMV-RKIP, but not with control CMV-EV, sensitized the cells to TRAIL-mediated apoptosis. Treatment with RKIP small interfering RNA (siRNA) inhibited TRAIL-induced apoptosis. RKIP overexpression was paralleled with up-regulation of DR5 transcription and expression; no change in DR4, decoy receptor 1, and decoy receptor 2 expression; and inhibition of YY1 transcription and expression. Inhibition of YY1 by YY1 siRNA sensitized the cells to TRAIL apoptosis concomitantly with DR5 up-regulation. RKIP overexpression inhibited several antiapoptotic gene products such as X-linked inhibitor of apoptosis (XIAP), c-FLIP long, and Bcl-xL that were accompanied with mitochondrial membrane depolarization. RKIP overexpression in combination with TRAIL resulted in the potentiation of these above effects and activation of caspases 8, 9, and 3, resulting in apoptosis. These findings demonstrate that RKIP overexpression regulates tumor cell sensitivity to TRAIL via inhibition of YY1, up-regulation of DR5, and modulation of apoptotic pathways. We suggest that RKIP may serve as an immune surveillance cancer gene, and its low expression or absence in tumors allows the tumor to escape host immune cytotoxic effector cells.
OX40 Controls Functionally Different T Cell Subsets and Their Resistance to Depletion Therapy
Authors: Kroemer Alexander , Xiao Xiang , Vu Minh Diem , Gao Wenda , Minamimura Keisuke , Chen Ming , Maki Takashi , Li Xian Chang 
Published: April 2014

Abstract
T cell depletion is a widely used approach in clinical transplantation. However, not all T cells are equally sensitive to depletion therapies and a significant fraction of T cells persists even after aggressive treatment. The functional attributes of such T cells and the mechanisms responsible for their resistance to depletion are poorly studied. In the present study, we showed that CD4+ T cells that are resistant to polyclonal anti-lymphocyte serum (ALS) mediated depletion exhibit phenotypic features of memory cells and uniformly express OX40 on the cell surface. Studies using the foxp3gfp knockin mice revealed that the remaining CD4+OX40+ cells consist of Foxp3+ Tregs and Foxp3− T effector/memory cells. The ALS-resistant CD4+OX40+ cells failed to mediate skin allograft rejection upon adoptive transferring into congenic Rag−/− mice, but removal of Foxp3+ Tregs from the OX40+ cells resulted in prompt skin allograft rejection. Importantly, OX40 is critical to survival of both Foxp3+ Tregs and T effector/memory cells. However, OX40 exhibits opposing effects on the functional status of Foxp3+ Tregs and T effector/memory cells, as stimulation of OX40 on T effector cells induced amplified cell proliferation but stimulation of OX40 on the Foxp3+ Tregs impaired their suppressor functions. Our study demonstrates that OX40 is a critical molecule in regulating survival and functions of depletion-resistant T cells; and these findings may have important clinical implications.
Cutting Edge: Two Distinct Motifs within the Fas Ligand Tail Regulate Fas Ligand-Mediated Costimulation
Authors: Sun Mingyi , Lee Shinhee , Karray Saoussen , Levi-Strauss Matthieu , Ames Kristina T. , Fink Pamela J. 
Published: April 2014

AbstractThe cytoplasmic domain of Fas ligand is sufficient to costimulate CD8+ T cells by driving Fas ligand recruitment into lipid rafts and association with select Src homology 3-containing proteins, activating PI3K and MAPK pathways, mediating nuclear translocation of the transcription factors NFAT and AP-1, and enhancing IFN-γ production and Ag-specific CD8+ T cell proliferation. We now show that Fas ligand molecules lacking amino acids 45–54 in the proline-rich region of the cytoplasmic domain fail to costimulate but serve as effective death inducers. Death induction and costimulation by Fas ligand are therefore clearly separable functions. Further, upon Fas ligand-mediated costimulation, casein kinase I phosphorylates Fas ligand, in which two conserved casein kinase I binding sites regulate NFAT activation and costimulation. These results help resolve how one molecule can serve as a double-edged immunomodulator by directing discrete biological consequences.