bluuebunny/crossref_metadata_2025_split huggingface dataset:
Cutting Edge: Lectin-Like Transcript-1 Is a Ligand for the Inhibitory Human NKR-P1A Receptor
Authors: Rosen David B. , Bettadapura Jayaram , Alsharifi Mohammed , Mathew Porunelloor A. , Warren Hilary S. , Lanier Lewis L. 
Published: April 2014

Abstract
Increasingly, roles are emerging for C-type lectin receptors in immune regulation. One receptor whose function has remained largely enigmatic is human NKR-P1A (CD161), present on NK cells and subsets of T cells. In this study, we demonstrate that the lectin-like transcript-1 (LLT1) is a physiologic ligand for NKR-P1A. LLT1-containing liposomes bind to NKR-P1A+ cells, and binding is inhibited by anti-NKR-P1A mAb. Additionally, LLT1 activates NFAT-GFP reporter cells expressing a CD3ζ-NKR-P1A chimeric receptor; reciprocally, reporter cells with a CD3ζ-LLT1 chimeric receptor are stimulated by NKR-P1A. Moreover, LLT1 on target cells can inhibit NK cytotoxicity via interactions with NKR-P1A.
CD18 Is Required for Optimal Development and Function of CD4+CD25+ T Regulatory Cells
Authors: Marski Marissa , Kandula Sravanthi , Turner Jerrold R. , Abraham Clara 
Published: April 2014

AbstractCD4+CD25+ T regulatory (Treg) cells inhibit immunopathology and autoimmune disease in vivo. CD4+CD25+ Treg cells’ capacity to inhibit conventional T cells in vitro is dependent upon cell-cell contact; however, the cell surface molecules mediating this cell:cell contact have not yet been identified. LFA-1 (CD11a/CD18) is an adhesion molecule that plays an established role in T cell-mediated cell contact and in T cell activation. Although expressed at high levels on murine CD4+CD25+ Treg cells, the role of LFA-1 in these cells has not been defined previously. We hypothesized that LFA-1 may play a role in murine CD4+CD25+ Treg function. To evaluate this, we analyzed LFA-1-deficient (CD18−/−) CD4+CD25+ T cells. We show that CD18−/− mice demonstrate a propensity to autoimmunity. Absence of CD18 led to diminished CD4+CD25+ T cell numbers and affected both thymic and peripheral development of these cells. LFA-1-deficient CD4+ CD25+ T cells were deficient in mediating suppression in vitro and in mediating protection from colitis induced by the transfer of CD4+CD25− T cells into lymphopenic hosts. Therefore, we define a crucial role for CD18 in optimal CD4+CD25+ Treg development and function.
Identification of Specific Proteins and Peptides in Mycobacterium leprae Suitable for the Selective Diagnosis of Leprosy
Authors: Spencer John S. , Dockrell Hazel M. , Kim Hee Jin , Marques Maria A. M. , Williams Diana L. , Martins Marcia V. S. B. , Martins Marcio L. F. , Lima Monica C. B. S. , Sarno Euzenir N. , Pereira Geraldo M. B. , Matos Haroldo , Fonseca Leila S. , Sampaio Elisabeth P. , Ottenhoff Thomas H. M. , Geluk Annemieke , Cho Sang-Nae , Stoker Neil G. , Cole Stewart T. , Brennan Patrick J. , Pessolani Maria C. V. 
Published: April 2014

Abstract
Diagnosis of leprosy is a major obstacle to disease control and has been compromised in the past due to the lack of specific reagents. We have used comparative genome analysis to identify genes that are specific to Mycobacterium leprae and tested both recombinant proteins and synthetic peptides from a subset of these for immunological reactivity. Four unique recombinant proteins (ML0008, ML0126, ML1057, and ML2567) and a panel of 58 peptides (15 and 9 mer) were tested for IFN-γ responses in PBMC from leprosy patients and contacts, tuberculosis patients, and endemic and nonendemic controls. The responses to the four recombinant proteins gave higher levels of IFN-γ production, but less specificity, than the peptides. Thirty-five peptides showed IFN-γ responses only in the paucibacillary leprosy and household contact groups, with no responses in the tuberculosis or endemic control groups. High frequencies of IFN-γ-producing CD4+ and CD8+ T cells specific for the 15- and 9-mer peptides were observed in the blood of a paucibacillary leprosy patient. 9-mer peptides preferentially activated CD8+ T cells, while the 15-mer peptides were efficient in inducing responses in both the CD4+ and CD8+ T cell subsets. Four of the six 9-mer peptides tested showed promising specificity, indicating that CD8+ T cell epitopes may also have diagnostic potential. Those peptides that provide specific responses in leprosy patients from an endemic setting could potentially be developed into a rapid diagnostic test for the early detection of M. leprae infection and epidemiological surveys of the incidence of leprosy, of which little is known.
Long-Term MHC Class II Presentation of the EBV Lytic Protein BHRF1 by EBV Latently Infected B Cells following Capture of BHRF1 Antigen
Authors: Landais Elise , Saulquin Xavier , Bonneville Marc , Houssaint Elisabeth 
Published: April 2014

Abstract
Although T lymphocytes are considered essential for the control of EBV infection, it remains uncertain how this control occurs. We previously reported unexpected killing of EBV-transformed B-lymphoblastoid cells (LCLs) that did not express BHRF1 by CD4+ T cells specific for BHRF1, an EBV lytic cycle protein. Using LCLs transformed with an EBV mutant, in which the BHRF1 gene was deleted, we showed that killing of latently infected cells through the recognition of a protein produced during the lytic cycle is due to transfer of BHRF1 from lytically infected to latently infected cells, which occurs in culture. Accordingly, LCLs efficiently presented exogenous BHRF1 protein. Furthermore, we present evidence for persistence of captured BHRF1 Ag for several days. Due to this long-term persistence, repeated loading of suboptimal amounts of BHRF1 led to accumulation of BHRF1 Ags in LCLs and, ultimately, to their optimal recognition by BHRF1-specific CD4+ T cells. These results unveil an MHC class II-dependent pathway that could be important for the control of EBV latent infection through recognition of lytic cycle Ags.
Protein Tyrosine Phosphatase α Regulates Fyn Activity and Cbp/PAG Phosphorylation in Thymocyte Lipid Rafts
Authors: Maksumova Lola , Le Hoa T. , Muratkhodjaev Farkhad , Davidson Dominique , Veillette André , Pallen Catherine J. 
Published: April 2014

Abstract
A role for the receptor protein tyrosine phosphatase α (PTPα) in immune cell function and regulation of Src family kinases was investigated using thymocytes from PTPα-deficient mice. PTPα-null thymocytes develop normally, but unstimulated PTPα−/− cells exhibit increased tyrosine phosphorylation of specific proteins, increased Fyn activity, and hyperphosphorylation of Cbp/PAG that promotes its association with C-terminal Src kinase. Elevated Fyn activity in the absence of PTPα is due to enhanced phosphorylation of Fyn tyrosines 528 and 417. Some PTPα is localized in lipid rafts of thymocytes, and raft-associated Fyn is specifically activated in PTPα−/− cells. PTPα is not a Cbp/PAG phosphatase, because it is not required for Cbp/PAG dephosphorylation in unstimulated or anti-CD3-stimulated thymocytes. Together, our results indicate that PTPα, likely located in lipid rafts, regulates the activity of raft Fyn. In the absence of PTPα this population of Fyn is activated and phosphorylates Cbp/PAG to enhance association with C-terminal Src kinase. Although TCR-mediated tyrosine phosphorylation was apparently unaffected by the absence of PTPα, the long-term proliferative response of PTPα−/− thymocytes was reduced. These findings indicate that PTPα is a component of the complex Src family tyrosine kinase regulatory network in thymocytes and is required to suppress Fyn activity in unstimulated cells in a manner that is not compensated for by the major T cell PTP and SFK regulator, CD45.
The Sphingosine 1-Phosphate Receptor Agonist FTY720 Differentially Affects the Sequestration of CD4+/CD25+ T-Regulatory Cells and Enhances Their Functional Activity
Authors: Sawicka Elzbieta , Dubois Gerald , Jarai Gabor , Edwards Matthew , Thomas Matthew , Nicholls Andy , Albert Rainer , Newson Catherine , Brinkmann Volker , Walker Christoph 
Published: April 2014

Abstract
The sphingosine 1-phosphate (S1P) receptor agonist FTY720 is well known for its immunomodulatory activity, sequestering lymphocytes from blood and spleen into secondary lymphoid organs and thereby preventing their migration to sites of inflammation. Because inflammation is critically dependent on a balance between Ag-specific Th/effector cells and T-regulatory cells, we investigated the effect of FTY720 on T-regulatory cell trafficking and functional activity. An increased number of CD4+/CD25+ T cells was found in blood and spleens of FTY720-treated mice, and transfer of these cells resulted in a significantly more pronounced accumulation in spleens but not lymph nodes after treatment, suggesting that this compound differentially affects the homing properties of T-regulatory cells compared with other T cell subsets. Indeed, CD4+/CD25+ T cells express lower levels of S1P1 and S1P4 receptors and demonstrate a reduced chemotactic response to S1P. Moreover, analysis of the functional response of FTY720-treated CD4+/CD25+ T cells revealed an increased suppressive activity in an in vitro Ag-specific proliferation assay. This correlated with enhanced function in vivo, with T-regulatory cells obtained from FTY720-treated mice being able to suppress OVA-induced airway inflammation. Thus, FTY720 differentially affects the sequestration of T-regulatory cells and importantly, increases the functional activity of T-regulatory cells, suggesting that it may have disease-modifying potential in inflammatory disorders.
IL-2 Regulates Perforin and Granzyme Gene Expression in CD8+ T Cells Independently of Its Effects on Survival and Proliferation
Authors: Janas Michelle L. , Groves Penny , Kienzle Norbert , Kelso Anne 
Published: April 2014

Abstract
Perforin and the serine protease granzymes are key effectors of CD8+ T cell granule-mediated cytotoxicity, but the requirements for their expression remain largely undefined. We show in this study that IL-2 increased the expression of perforin and granzyme A, B, and C mRNA; intracellular granzyme B protein levels; and cytolytic function in a dose-dependent manner during primary activation of murine CD8+ T cells in vitro. Two approaches showed that these responses were not a consequence of the effects of IL-2 on cell survival and proliferation. First, IL-2 enhancement of perforin and granzyme expression was equivalent in CD8+ T cells from wild-type and bcl-2 transgenic mice, although only the latter cells survived in low concentrations or the absence of added IL-2. This property of bcl-2 transgenic T cells also allowed the demonstration that induction of granzyme A, B, and C mRNA and granzyme B protein required exogenous IL-2, whereas induction of perforin and IFN-γ expression did not. Second, analysis of perforin and granzyme mRNA levels in cells separated according to division number using the dye CFSE showed that the effects of IL-2 were unrelated to division number. Together, these findings indicate that IL-2 can directly regulate perforin and granzyme gene expression in CD8+ T cells independently of its effects on cell survival and proliferation.
Sequence Transfers between Variable Regions in a Mouse Antibody Transgene Can Occur by Gene Conversion
Authors: D’Avirro Nicole , Truong David , Xu Bo , Selsing Erik 
Published: April 2014

Abstract
Different vertebrate species show widely differing usage of somatic hyperconversion (SHC) as a mechanism for diversifying expressed Ab V genes. The basis for the differing levels of SHC in different species is not known. Although no clear evidence for SHC has been found in normal mouse B cells, transgenic mice carrying high-copy numbers of a gene construct designed to optimize detection of SHC have previously been shown to exhibit sequence transfers that resemble gene conversion events. However, these transgene sequence transfers could reflect multistep or reciprocal DNA recombination events rather than gene conversions. We now find in low-copy number transgenic mice that transgene sequence transfers can exhibit the unidirectional sequence information movement that is a hallmark of gene conversion. This indicates that gene conversion between V region sequences can occur in mouse B cells; we propose that the lack of efficient SHC contributions to Ab diversification in normal mice may be due, at least in part, to the particular pattern of V gene recombinational accessibility that occurs in differentiating mouse B cells.
Intergenic Transcription Is Not Required in Th2 Cells to Maintain Histone Acetylation and Transcriptional Permissiveness at the Il4-Il13 Locus
Authors: Baguet Aurelie , Sun Xizhang , Arroll Thomas , Krumm Anton , Bix Mark 
Published: April 2014

Abstract
Noncoding RNA transcripts mapping to intergenic regions of the Il4-Il13 locus have been detected in Th2 cells harboring transcriptionally permissive Il4 and Il13 genes but not in Th1 cells where these genes are repressed. This correlation has given rise to the idea that intergenic transcription may be involved in maintaining the “open” chromatin structure of the Il4-Il13 locus in Th2 cells. We present evidence from real-time RT-PCR, nuclear run on, chromatin immunoprecipitation and 5,6-dichlorobenzimidazole 1-β-d-ribofuranoside-mediated transcriptional inhibition analyses that argue against this hypothesis. Instead, our results are consistent with an alternative role for intergenic transcription in the maintenance of transcriptional silence in Th1-primed cells.
Defective Microarchitecture of the Spleen Marginal Zone and Impaired Response to a Thymus-Independent Type 2 Antigen in Mice Lacking Scavenger Receptors MARCO and SR-A
Authors: Chen Yunying , Pikkarainen Timo , Elomaa Outi , Soininen Raija , Kodama Tatsuhiko , Kraal Georg , Tryggvason Karl 
Published: April 2014

Abstract
The macrophage scavenger receptor macrophage receptor with a collagenous structure (MARCO) is expressed in mice by the marginal zone macrophages of the spleen and by macrophages of the medullary cords of lymph nodes, as well as the peritoneal macrophages. MARCO is a relative of scavenger receptor A (SR-A), the more widely expressed prototypic member of the scavenger receptor family. In the present study, we found that genetic ablation of MARCO leads to changes in the organization of the splenic marginal zone, and causes a significant reduction in the size of the resident peritoneal macrophage population, possibly due to changes in adhesion and migration capacity. In mice lacking both MARCO and SR-A these effects are even more apparent. During ontogeny, the appearance and organization of the MARCO-expressing cells in the spleen precedes the appearance of other receptors on macrophages in the marginal zone, such as SIGNR1 and Siglec-1. In the absence of MARCO, a clear delay in the organization of the marginal zone was observed. Similar findings were seen when the reappearance of the various subsets from precursors was studied after depleting macrophages from the adult spleen by a liposome treatment. When challenged with a pneumococcal polysaccharide vaccine, a T-independent type 2 Ag for which an intact marginal zone is crucial, the knockout mice exhibited a clearly impaired response. These findings suggest that both MARCO and SR-A, in addition to being important scavenger receptors, could be involved in the positioning and differentiation of macrophages, possibly through interaction with endogenous ligands.
Yersinia Outer Protein P Suppresses TGF-β-Activated Kinase-1 Activity to Impair Innate Immune Signaling in Yersinia enterocolitica-Infected Cells
Authors: Haase Rudolf , Richter Kathleen , Pfaffinger Gudrun , Courtois Gilles , Ruckdeschel Klaus 
Published: April 2014

Abstract
Pathogenic Yersinia spp. use a panel of virulence proteins that antagonize signal transduction processes in infected cells to undermine host defense mechanisms. One of these proteins, Yersinia enterocolitica outer protein P (YopP), down-regulates the NF-κB and MAPK signaling pathways, which suppresses the proinflammatory host immune response. In this study, we explored the mechanism by which YopP succeeds to simultaneously disrupt several of these key signaling pathways of innate immunity. Our data show that YopP operates upstream of its characterized eukaryotic binding partner IκB kinase-β to shut down the NF-κB signaling cascade. Accordingly, YopP efficiently impaired the activities of TGF-β-activated kinase-1 (TAK1) in infected cells. TAK1 is an important activator of the IκB kinase complex in the TLR signaling cascade. The repression of TAK1 activities correlated with reduced activation of NF-κB- as well as AP-1-dependent reporter gene expression in Yersinia-infected murine macrophages. This suggests that the impairment of the TAK1 enzymatic activities by Yersinia critically contributes to down-regulate activation of NF-κB and of MAPK members in infected host cells. The inhibition of TAK1 potentially results from the blockade of signaling events that control TAK1 induction. This process could involve the attenuation of ubiquitination of the upstream signal transmitter TNFR-associated factor-6. Together, these results indicate that, by silencing the TAK1 signaling complex, Yersinia counteracts the induction of several conserved signaling pathways of innate immunity, which aids the bacterium in subverting the host immune response.
Pure Lipopolysaccharide or Synthetic Lipid A Induces Activation of p21Ras in Primary Macrophages through a Pathway Dependent on Src Family Kinases and PI3K
Authors: David Muriel D. , Cochrane Chris L. , Duncan Sherie K. , Schrader John W. 
Published: April 2014

Abstract
Recognition of bacterial LPS by macrophages plays a critical role in host defense against infection by Gram-negative bacteria. However, when not tightly regulated, the macrophage’s response to LPS can induce severe disease and septic shock. Although LPS triggers the activation of multiple signaling pathways in macrophages, it was unclear whether these include activation of the p21Ras GTPases. We report that p21Ras is rapidly and transiently activated in murine primary macrophages stimulated with an ultra-pure preparation of LPS or with synthetic lipid A. The molecular basis of this activation was investigated using a pharmacological approach. LPS-induced activation of p21Ras was inhibited in the presence of PP2, LY294002, or wortmannin, suggesting that it depends on the activity of one or more members of the Src kinase family and the subsequent activation of PI3K. In that pharmacological inhibitors of PI3K inhibited LPS-induced activation of p21Ras, but not activation of ERK, we concluded that LPS-induced activation of ERK occurs through a pathway that is not dependent on the activation of p21Ras.
Differential Regulation of Osteoblast Activity by Th Cell Subsets Mediated by Parathyroid Hormone and IFN-γ
Authors: Young Nathan , Mikhalkevich Natallia , Yan Ying , Chen Di , Zheng Wei-ping 
Published: April 2014

AbstractBone loss is a typical pathological feature of chronic inflammatory bone diseases including rheumatoid arthritis, in which CD4 effector T cells play critical roles. We found that activated mouse Th2 and not Th1 cells produced the parathyroid hormone (PTH). Unlike in the parathyroid cells, PTH expression in Th2 cells was not regulated by the fluctuation of calcium level, but rather it required the full activation of the T cells. Although PTH was expressed in immature Th2 cells, and its receptor was transiently expressed during Th1 and Th2 cell differentiation, PTH did not significantly affect the outcome of the differentiation. In primary osteoblasts cultured in Th2 cell condition medium, the alkaline phosphatase (ALP) activity was maintained at a basal level. However, antagonizing PTH in the condition medium resulted in a significant reduction of the ALP activity. These results demonstrated an important role of the Th2 cell-derived PTH in maintaining the bone-forming activity of the osteoblasts under inflammatory conditions. In osteoblasts cultured in the Th1 cell condition medium, the ALP activity was significantly suppressed. Neutralizing IFN-γ alleviated the suppression. Conversely, treatment of osteoblasts with IFN-γ suppressed the ALP activity. Unlike ALP, expression of the major bone matrix proteins by the osteoblasts was only minimally affected by either Th1 or Th2 cytokine environment. In addition, the Th2 cytokine environment also regulated to expression of receptor activator of NF-κB ligand and osteoprotegerin through both PTH-dependent and -independent mechanisms. Our study therefore identified new regulatory events in bone remodeling under inflammatory conditions.
Human Dendritic Cells: Potent Antigen-Presenting Cells at the Crossroads of Innate and Adaptive Immunity
Authors: Rossi Marco , Young James W. 
Published: April 2014

Abstract
Dendritic cells (DCs) are specialized, bone marrow-derived leukocytes that are critical to the development of immunity. Investigators have emphasized the role of DCs in initiating adaptive or acquired MHC-restricted, Ag-specific T cell responses. More recent evidence supports important roles for DCs in the onset of innate immunity and peripheral tolerance. Progress in the generation of DCs from defined hemopoietic precursors in vitro has revealed the heterogeneity of these APCs and their attendant divisions of labor. This review will address these developments in an attempt to integrate the activities of different DCs in coordinating innate and adaptive immunity.
Cutting Edge: HLA-E Binds a Peptide Derived from the ATP-Binding Cassette Transporter Multidrug Resistance-Associated Protein 7 aSnd Inhibits NK Cell-Mediated Lysis
Authors: Wooden Stacey L. , Kalb Suzanne R. , Cotter Robert J. , Soloski Mark J. 
Published: April 2014

AbstractHLA-E is an MHC class Ib molecule that binds nonamer peptides derived from the leader sequence of MHC class 1a molecules and is the major ligand for CD94/NKG2 receptors found on NK and T cells. Using the MHC class Ia-null cell line 721.221, we find that surface HLA-E increases following heat shock at 42°C and NK cell-mediated lysis is inhibited using heat-stressed 721.221 targets. We have used mass spectrometry to identify and sequence a novel peptide from HLA-E following heat shock, ALALVRMLI, derived from the transmembrane domain of the human ATP-binding cassette protein, multidrug resistance-associated protein, MRP7. Pulsing 721.221 targets with synthetic MRP7 peptide results in strong inhibition of NK cell-mediated lysis that is reversible using anti-CD94 and anti-class I mAbs. This report is the first to identify a non-MHC leader inhibitory peptide bound to HLA-E and provides insight into the immunoregulatory role of HLA-E during cell stress.