bluuebunny/crossref_metadata_2025_split huggingface dataset:
Tumor-Associated Embryonic Antigen-Expressing Vaccines that Target CCR6 Elicit Potent CD8+ T Cell-Mediated Protective and Therapeutic Antitumor Immunity
Authors: Biragyn Arya , Schiavo Roberta , Olkhanud Purevdorj , Sumitomo Kenya , King Alan , McCain Megan , Indig Fred E. , Almanzar Giovanni , Baatar Dolgor 
Published: April 2014

Abstract
Despite its potency, the wider use of immunotherapy for B cell malignancies is hampered by the lack of well-defined tumor-specific Ags. In this study, we demonstrate that an evolutionarily conserved 37-kDa immature laminin receptor protein (OFA-iLRP), a nonimmunogenic embryonic Ag expressed by a variety of tumors, is rendered immunogenic if targeted to the APCs using the CCR6 ligands MIP3α/CCL20 and mDF2β. The CCR6 targeting facilitated efficient Ag cross-presentation and induction of tumor-neutralizing CTLs. Although the Ag targeting alone, without activation of dendritic cells (DCs), is proposed to induce tolerance, and MIP3α does not directly activate DCs, the MIP3α-based vaccine efficiently induced protective and therapeutic antitumor responses. The responses were as strong as those elicited by the OFA-iLRP fusions with moieties that activated DCs and Th1-type cytokine responses, mDF2β, or mycobacterial Hsp70 Ag. Although the same cDNA encodes the dimerized high-affinity mature 67-kDa mLRP that is expressed in normal tissues to stabilize the binding of laminin to cell surface integrins, the vaccines expressing OFA-iLRP elicited long-term protective CD8+ T cell-mediated memory responses against syngeneic B cell lymphoma, indicating the potential application of these simple vaccines as preventive and therapeutic formulations for human use.
Cutting Edge: Transgenic Expression of Human MUC1 in IL-10−/− Mice Accelerates Inflammatory Bowel Disease and Progression to Colon Cancer
Authors: Beatty Pamela L. , Plevy Scott E. , Sepulveda Antonia R. , Finn Olivera J. 
Published: April 2014

Abstract
Epithelial cell MUC1 is aberrantly expressed on human epithelial adenocarcinomas where it functions as a regulator of immune responses and an oncogene. Normally expressed at low levels in healthy colonic epithelium, MUC1 was reported to be overexpressed in human inflammatory bowel disease (IBD) and thus may be expected to play an important role in regulating chronic inflammation and its progression to colitis-associated colon cancer. Studies in the immunobiology and pathology of IBD and colitis-associated colon cancer have been done in various mouse models but none could properly address the role of MUC1 due to low homology between the mouse and the human molecule. We report that IL-10−/− mice, a widely accepted mouse model of IBD, crossed to human MUC1-transgenic mice, develop MUC1+ IBD characterized by an earlier age of onset, higher inflammation scores, and a much higher incidence and number of colon cancers compared with IL-10−/− mice.
Cutting Edge: Genetic Variation Influences FcεRI-Induced Mast Cell Activation and Allergic Responses
Authors: Yamashita Yumi , Charles Nicolas , Furumoto Yasuko , Odom Sandra , Yamashita Toshiyuki , Gilfillan Alasdair M. , Constant Stephanie , Bower Molly A. , Ryan John J. , Rivera Juan 
Published: April 2014

Abstract
Mast cell responses are influenced by a diverse array of environmental factors, but little is known about the effect of genetic background. In this study, we report that 129/Sv mice had high levels of circulating IgE, increased expression of the high-affinity receptor for IgE (FcεRI), and greater sensitivity to anaphylaxis when compared with C57BL/6 mice. Bone marrow-derived mast cells (BMMCs) from 129/Sv mice showed more robust degranulation upon the engagement of FcεRI. Deficiency of the Src family kinase Lyn enhanced degranulation in 129/Sv BMMCs but inhibited this response in C57BL/6 cells. C57BL/6 lyn−/− BMMCs had reduced expression of the Src family kinase Fyn, and increasing its expression markedly enhanced degranulation. In human mast cells the silencing of Lyn or Fyn expression resulted in hyperdegranulation or hypodegranulation, respectively. The findings demonstrate a genetic influence on the extent of a mast cell’s response and identify Fyn kinase as a contributory determinant.
Cutting Edge: High Molecular Weight Hyaluronan Promotes the Suppressive Effects of CD4+CD25+ Regulatory T Cells
Authors: Bollyky Paul L. , Lord James D. , Masewicz Susan A. , Evanko Stephen P. , Buckner Jane H. , Wight Thomas N. , Nepom Gerald T. 
Published: April 2014

Abstract
Hyaluronan is a glycosaminoglycan present in the extracellular matrix. When hyaluronan is degraded during infection and injury, low m.w. forms are generated whose interactions influence inflammation and angiogenesis. Intact high m.w. hyaluronan, conversely, conveys anti-inflammatory signals. We demonstrate that high m.w. hyaluronan enhances human CD4+CD25+ regulatory T cell functional suppression of responder cell proliferation, whereas low m.w. hyaluronan does not. High m.w. hyaluronan also up-regulates the transcription factor FOXP3 on CD4+CD25+ regulatory T cells. These effects are only seen with activated CD4+CD25+ regulatory T cells and are associated with the expression of CD44 isomers that more highly bind high m.w. hyaluronan. At higher concentrations, high m.w. hyaluronan also has direct suppressive effects on T cells. We propose that the state of HA in the matrix environment provides contextual cues to CD4+CD25+ regulatory T cells and T cells, thereby providing a link between the innate inflammatory network and the regulation of adaptive immune responses.
Cutting Edge: CD8+ T Cell Clones Possess the Potential to Differentiate into both High- and Low-Avidity Effector Cells
Authors: Kroger Charles J. , Alexander-Miller Martha A. 
Published: April 2014

Abstract
The property of functional avidity is recognized to be of critical importance in determining pathogen clearance. An unresolved question with regard to this property is whether distinct naive subsets exist that display inherent differences in their peptide sensitivity requirements for activation, i.e., functional avidity, or whether differences in peptide sensitivity are induced following peptide encounter. In this study, we demonstrate that naive populations that can give rise to both high- and low-avidity cells do not contain subsets that exhibit differences in the amount of peptide required for activation. Furthermore, we show that an individual T cell clone can generate both high- and low-avidity effectors. The work presented here provides the first formal demonstration that an individual cell can give rise to both high- and low-avidity progeny, suggesting that avidity modulation at the level of an individual cell may play an important role in the CD8+ T cell response generated in vivo.
Oral Administration of High Molecular Mass Poly-γ-Glutamate Induces NK Cell-Mediated Antitumor Immunity
Authors: Kim Tae Woo , Lee Tae Young , Bae Hyun Cheol , Hahm Jeong Ho , Kim Yang Hyun , Park Chung , Kang Tae Heung , Kim Chul Joong , Sung Moon Hee , Poo Haryoung 
Published: April 2014

Abstract
We analyzed the in vivo tumor regression activity of high molecular mass poly-γ-glutamate (γ-PGA) from Bacillus subtilis sups. chungkookjang. C57BL/6 mice were orally administered 10-, 100-, or 2000-kDa γ-PGA or β-glucan (positive control), and antitumor immunity was examined. Our results revealed higher levels of NK cell-mediated cytotoxicity and IFN-γ secretion in mice treated with higher molecular mass γ-PGA (2000 kDa) vs those treated with lower molecular mass γ-PGA (10 or 100 kDa) or β-glucan. We then examined the effect of oral administration of 10- or 2000-kDa γ-PGA on protection against B16 tumor challenge in C57BL/6 mice. Mice receiving high molecular mass γ-PGA (2000 kDa) showed significantly smaller tumor sizes following challenge with the MHC class I-down-regulated tumor cell lines, B16 and TC-1 P3 (A15), but not with TC-1 cells, which have normal MHC class I expression. Lastly, we found that γ-PGA-induced antitumor effect was decreased by in vivo depletion of NK cells using mAb PK136 or anti-asialo GM1 Ab, and that was completely blocked in NK cell-deficient B6 beige mice or IFN-γ knockout mice. Taken together, we demonstrated that oral administration of high molecular mass γ-PGA (2000 kDa) generated significant NK cell-mediated antitumor activity in mice bearing MHC class I-deficient tumors.
The CD16−/CD56bright Subset of NK Cells Is Resistant to Oxidant-Induced Cell Death
Authors: Thorén Fredrik B. , Romero Ana I. , Hermodsson Svante , Hellstrand Kristoffer 
Published: April 2014

Abstract
Phagocyte-derived reactive oxygen species (“oxygen radicals”) have been ascribed a suppressive role in immunoregulation by inducing dysfunction and apoptotic cell death in lymphocytes. Earlier studies show that human NK cells are exceptionally sensitive to oxygen radical-induced apoptosis and functional inhibition. Two subsets of human CD56+ NK cells have been identified: the highly cytotoxic CD56dim cells which constitute &gt;90% of NK cells in peripheral blood, and the less cytotoxic but efficiently cytokine-producing CD56bright cells. In this study, we demonstrate that the CD56bright subset of NK cells, in contrast to CD56dim cells, remains viable and functionally intact after exposure to phagocyte-derived or exogenously added oxygen radicals. The resistance of CD56bright cells to oxidative stress was accompanied by a high capacity of neutralizing exogenous hydrogen peroxide, and by a high cell-surface expression of antioxidative thiols. Our results imply that CD56bright NK cells are endowed with an efficient antioxidative defense system that protects them from oxygen radical-induced inactivation.
Apoptosis-Inducing Factor Regulates Death in Peripheral T Cells
Authors: Srivastava Smita , Banerjee Hridesh , Chaudhry Ashutosh , Khare Anupriya , Sarin Apurva , George Anna , Bal Vineeta , Durdik Jeannine M. , Rath Satyajit 
Published: April 2014

Abstract
Apoptosis-inducing factor (Aif) is a mitochondrial flavoprotein with multiple roles in apoptosis as well as in cellular respiration and redox regulation. The harlequin (Hq) mouse strain carries an aif locus modification causing reduced Aif expression. We demonstrate that activated CD4+ and CD8+ peripheral T cells from Hq mice show resistance to neglect-induced death (NID) triggered by growth factor withdrawal, but not to death induced by multiple agents that trigger DNA damage. Aif translocates to the nucleus in cells undergoing NID, and, in Hq T cell blasts, resistance to NID is associated with reduced cytosolic release of mitochondrial cytochrome c, implicating Aif in this event. In contrast, Hq T cell blasts express higher levels of CD95L, demonstrating increased susceptibility to activation-induced cell death (AICD) and apoptosis triggered by hydrogen peroxide. Superoxide scavenging protects from AICD in wild-type, but not Hq, T cell blasts, suggesting that Aif plays a crucial superoxide-scavenging role to regulate T cell AICD. Finally, the altered pattern of death susceptibility is reproduced by siRNA-mediated reduction of Aif expression in normal T cells. Thus, Aif serves nonredundant roles, both proapoptotic and antiapoptotic, in activated peripheral T cells.
Distinct Activities of Stromal Cells Involved in the Organogenesis of Lymph Nodes and Peyer’s Patches
Authors: Okuda Masato , Togawa Atsushi , Wada Hiromi , Nishikawa Shin-ichi 
Published: April 2014

Abstract
It is now well established that the interaction between “inducer” cells of hemopoietic origin and “organizer” cells of mesenchymal lineage is involved in the organogenesis of lymph node (LN) and Peyer’s patch (PP). Organizer cells are defined by the expression of VCAM-1 and ICAM-1 and the production of homeostatic chemokines. However, several studies suggested the presence of a diversity among these cells from different lymphoid tissues. Thus, we attempted to define the difference of organizer cells of LN and PP in terms of gene expression profile. Microarray analyses of organizer cells revealed that these cells isolated from embryonic mesenteric LN expressed higher levels of genes that are related to inflammation, tissue remodeling, and development of mesenchymal lineage compared with those from PP. Several transcription factors related to epithelial-mesenchymal interactions were also up-regulated in organizer cells from LN. These results indicate that organizer cells in LN and PP are indeed distinct and suggest that the organizer cells in LN are at a more activated stage than those in PP.
Dendritic Cells Trigger Tumor Cell Death by a Nitric Oxide-Dependent Mechanism
Authors: Nicolas Alexandra , Cathelin Dominique , Larmonier Nicolas , Fraszczak Jennifer , Puig Pierre-Emmanuel , Bouchot André , Bateman Andrew , Solary Eric , Bonnotte Bernard 
Published: April 2014

Abstract
Dendritic cells (DCs) are well known for their capacity to induce adaptive antitumor immune response through Ag presentation and tumor-specific T cell activation. Recent findings reveal that besides this role, DCs may display additional antitumor effects. In this study, we provide evidence that LPS- or IFN-γ-activated rat bone marrow-derived dendritic cells (BMDCs) display killing properties against tumor cells. These cytotoxic BMDCs exhibit a mature DC phenotype, produce high amounts of IL-12, IL-6, and TNF-α, and retain their phagocytic properties. BMDC-mediated tumor cell killing requires cell-cell contact and depends on NO production, but not on perforin/granzyme or on death receptors. Furthermore, dead tumor cells do not exhibit characteristics of apoptosis. Thus, intratumoral LPS injections induce an increase of inducible NO synthase expression in tumor-infiltrating DCs associated with a significant arrest of tumor growth. Altogether, these results suggest that LPS-activated BMDCs represent powerful tumoricidal cells which enforce their potential as anticancer cellular vaccines.
CTLs Target Th Cells That Acquire Bystander MHC Class I-Peptide Complex from APCs
Authors: Cox Jennifer H. , McMichael Andrew J. , Screaton Gavin R. , Xu Xiao-Ning 
Published: April 2014

Abstract
CTLs can acquire MHC class I-peptide complexes from their target cells, whereas CD4+ T cells obtain MHC class II-peptide complexes from APCs in a TCR-specific manner. As a consequence, Ag-specific CTL can kill each other (fratricide) or CD4+ T cells become APCs themselves. The purpose of the acquisition is not fully understood and may be either inhibition or prolongation of an immunological response. In this study, we demonstrate that human CD4+ Th cells are able to capture membrane fragments from APC during the process of immunological synapse formation. The fragments contain not only MHC class II-peptide complexes but also MHC class I-peptide complexes, rendering these cells susceptible to CTL killing in an Ag-specific manner. The control of CD4+ Th cells by Ag-specific CTL, therefore, maybe another mechanism to regulate CD4+ T cell expansion in normal immune responses or cause immunopathoglogy during the course of viral infections such as HIV.
Brain Microenvironment Promotes the Final Functional Maturation of Tumor-Specific Effector CD8+ T Cells
Authors: Masson Frédérick , Calzascia Thomas , Di Berardino-Besson Wilma , de Tribolet Nicolas , Dietrich Pierre-Yves , Walker Paul R. 
Published: April 2014

AbstractDuring the priming phase of an antitumor immune response, CD8+ T cells undergo a program of differentiation driven by professional APCs in secondary lymphoid organs. This leads to clonal expansion and acquisition both of effector functions and a specific adhesion molecule pattern. Whether this program can be reshaped during the effector phase to adapt to the effector site microenvironment is unknown. We investigated this in murine brain tumor models using adoptive transfer of tumor-specific CD8+ T cells, and in spontaneous immune responses of patients with malignant glioma. Our data show proliferation of Ag-experienced tumor-specific T cells within the brain parenchyma. Moreover, CD8+ T cells further differentiated in the brain, exhibiting enhanced IFN-γ and granzyme B expression and induction of αE(CD103)β7 integrin. This unexpected integrin expression identified a subpopulation of CD8+ T cells conditioned by the brain microenvironment and also had functional consequences: αE(CD103)β7-expressing CD8+ T cells had enhanced retention in the brain. These findings were further investigated for CD8+ T cells infiltrating human malignant glioma; CD8+ T cells expressed αE(CD103)β7 integrin and granzyme B as in the murine models. Overall, our data indicate that the effector site plays an active role in shaping the effector phase of tumor immunity. The potential for local expansion and functional reprogramming should be considered when optimizing future immunotherapies for regional tumor control.
KIR2DS1-Positive NK Cells Mediate Alloresponse against the C2 HLA-KIR Ligand Group In Vitro
Authors: Chewning Joseph H. , Gudme Charlotte N. , Hsu Katharine C. , Selvakumar Annamalai , Dupont Bo 
Published: April 2014

AbstractThe inhibitory 2DL1 and activating 2DS1 killer Ig-like receptors (KIR) both have shared ligand specificity for codon sequences in the C2 group HLA-Cw Ags. In this study, we have investigated NK cell activation by allogeneic target cells expressing different combinations of the HLA-KIR ligand groups C1, C2, and Bw4. We demonstrate that fresh NK cells as well as IL-2-propagated NK cells from 2DS1-positive donors that are homozygous for the C1 ligand group are activated in vitro by B lymphoblastoid cell lines expressing the C2 group. This response is, in part, due to the absence of C1 group recognition mediated by the inhibitory receptor 2DL2/3. This “missing self” alloresponse to C2, however, is rarely observed in NK cells from donors lacking 2DS1. Even in presence of 2DS1, the NK alloresponse is dramatically reduced in donors that have C2 group as “self.” Analysis of selected NK clones that express 2DS1 mRNA and lack mRNA for 2DL1 demonstrates that activation by the C2 ligand and mAb cross-linking of 2DS1 in these clones induces IFN-γ. Furthermore, this C2 group-induced activation is inhibited by Abs to both HLA class I and the receptor. Collectively, these studies demonstrate that NK cells from 2DS1-positive donors are activated by target cells that express the C2 group as an alloantigen. This leads to increased IFN-γ-positive fresh NK cells and induces NK allocytotoxicity in IL2-propagated polyclonal NK cells and NK clones. This study also provides support for the concept that incompatibility for the HLA-KIR ligand groups C1, C2, and Bw4 dominates NK alloactivation in vitro.
Resistance to Experimental Autoimmune Encephalomyelitis and Impaired T Cell Priming by Dendritic Cells in Src Homology 2 Domain-Containing Protein Tyrosine Phosphatase Substrate-1 Mutant Mice
Authors: Tomizawa Takeshi , Kaneko Yuka , Kaneko Yoriaki , Saito Yasuyuki , Ohnishi Hiroshi , Okajo Jun , Okuzawa Chie , Ishikawa-Sekigami Tomomi , Murata Yoji , Okazawa Hideki , Okamoto Koichi , Nojima Yoshihisa , Matozaki Takashi 
Published: April 2014

Abstract
Src homology 2 domain-containing protein tyrosine phosphatase (SHP) substrate-1 (SHPS-1) is a transmembrane protein that binds the protein tyrosine phosphatases SHP-1 and SHP-2 through its cytoplasmic region and is expressed on the surface of CD11c+ dendritic cells (DCs) and macrophages. In this study, we show that mice that express a mutant form of SHPS-1 lacking most of the cytoplasmic region are resistant to experimental autoimmune encephalomyelitis (EAE) in response to immunization with a peptide derived from myelin oligodendrocyte glycoprotein (MOG (35–55)). The MOG (35–55)-induced proliferation of, and production of IFN-γ, IL-2, and IL-17, by T cells from immunized SHPS-1 mutant mice were reduced compared with those apparent for wild-type cells. The abilities of splenic DCs from mutant mice to stimulate an allogenic MLR and to prime Ag-specific T cells were reduced. Both IL-12-stimulated and TLR-dependent cytokine production by DCs of mutant mice were also impaired. Finally, SHPS-1 mutant mice were resistant to induction of EAE by adoptive transfer of MOG (35–55)-specific T cells. These results show that SHPS-1 on DCs is essential for priming of naive T cells and the development of EAE. SHPS-1 is thus a potential therapeutic target in inflammatory disorders of the CNS and other autoimmune diseases.
Reciprocal Regulation of SH3 and SH2 Domain Binding via Tyrosine Phosphorylation of a Common Site in CD3ε
Authors: Kesti Tapio , Ruppelt Anja , Wang Jing-Huan , Liss Michael , Wagner Ralf , Taskén Kjetil , Saksela Kalle 
Published: April 2014

Abstract
Recruitment of cellular signaling proteins by the CD3 polypeptides of the TCR complex mediates T cell activation. We have screened a human Src homology 3 (SH3) domain phage display library for proteins that can bind to the proline-rich region of CD3ε. This screening identified Eps8L1 (epidermal growth factor receptor pathway substrate 8-like 1) together with the N-terminal SH3 domain of Nck1 and Nck2 as its preferred SH3 partners. Studies with recombinant proteins confirmed strong binding of CD3ε to Eps8L1 and Nck SH3 domains. CD3ε bound well also to Eps8 and Eps8L3, and modestly to Eps8L2, but not detectably to other SH3 domains tested. Interestingly, binding of Nck and Eps8L1 SH3 domains was mapped to a PxxDY motif that shared its tyrosine residue (Y166) with the ITAM of CD3ε. Phosphorylation of this residue abolished binding of Eps/Nck SH3 domains in peptide spot filter assays, as well as in cells cotransfected with a dominantly active Lck kinase. TCR ligation-induced binding and phosphorylation-dependent loss of binding were also demonstrated between Eps8L1 and endogenous CD3ε in Jurkat T cells. Thus, phosphorylation of Y166 serves as a molecular switch during T cell activation that determines the capacity of CD3ε to interact with either SH3 or SH2 domain-containing proteins.
Early TCR Expression and Aberrant T Cell Development in Mice with Endogenous Prerearranged T Cell Receptor Genes
Authors: Serwold Thomas , Hochedlinger Konrad , Inlay Matthew A. , Jaenisch Rudolf , Weissman Irving L. 
Published: April 2014

Abstract
The factors that regulate the rate of production of T cells by the thymus remain incompletely defined. To test whether generation of functional T cell receptors limits the rate of thymic T cell export, we made use of a line of mice, LN3αβ, that have endogenously prerearranged TCR genes. The prerearranged TCR genes were expressed abnormally early in hemopoietic development, indicating that RAG-mediated recombination, rather than transcription factor expression, is the key determinant of the initiation of robust TCR transcription. Thymic T cell export rates were similar between wild-type (wt) and LN3αβ mice, indicating that T cell maturation rates in these mice are determined by factors other than TCR gene rearrangement. In competitive bone marrow chimeras, however, LN3αβ thymocytes were out-competed by wt cells and failed to develop beyond the double-negative 4 stage. Furthermore, wt progenitors transplanted intrathymically into LN3αβ mice proliferated excessively, suggesting that increased proliferative signals in the LN3αβ thymus compensate for faulty T cell development driven by early TCR expression.