bluuebunny/crossref_metadata_2025_split huggingface dataset:
NK Cells Use NKG2D to Recognize a Mouse Renal Cancer (Renca), yet Require Intercellular Adhesion Molecule-1 Expression on the Tumor Cells for Optimal Perforin-Dependent Effector Function
Authors: Abdool Karen , Cretney Erika , Brooks Alan D. , Kelly Janice M. , Swann Jeremy , Shanker Anil , Bere Earl W. , Yokoyama Wayne M. , Ortaldo John R. , Smyth Mark J. , Sayers Thomas J. 
Published: April 2014

AbstractThe NKG2D receptor on NK cells can recognize a variety of ligands on the tumor cell surface. Using a mouse renal cancer (Renca), we show that NKG2D recognition by NK cells was crucial for their ability to limit tumor metastases in vivo in both liver and lungs using perforin-dependent effector mechanisms. However, for the R331 cell line established from Renca, NKG2D recognition and perforin-dependent lysis played no role in controlling liver metastases. R331 cells were also more resistant to perforin-dependent lysis by NK cells in vitro. We therefore used these phenotypic differences between Renca and R331 to further investigate the crucial receptor:ligand interactions required for triggering lytic effector functions of NK cells. Reconstitution of R331 cells with ICAM-1, but not Rae-1γ, restored NKG2D-mediated, perforin-dependent lysis. Interestingly, R331 cells were efficiently lysed by NK cells using death ligand-mediated apoptosis. This death ligand-mediated killing did not depend on NKG2D recognition of its ligands on tumor cells. This result suggests that the intracellular signaling in NK cells required for perforin and death ligand-mediated lysis of tumor target cell are quite distinct, and activation of both of these antitumor lytic effector functions of NK cells could improve therapeutic benefits for certain tumors.
Lipoic Acid Affects Cellular Migration into the Central Nervous System and Stabilizes Blood-Brain Barrier Integrity
Authors: Schreibelt Gerty , Musters René J. P. , Reijerkerk Arie , de Groot Lody R. , van der Pol Susanne M. A. , Hendrikx Esther M. L. , Döpp Ed D. , Dijkstra Christine D. , Drukarch Benjamin , de Vries Helga E. 
Published: April 2014

AbstractReactive oxygen species (ROS) play an important role in various events underlying multiple sclerosis (MS) pathology. In the initial phase of lesion formation, ROS are known to mediate the transendothelial migration of monocytes and induce a dysfunction of the blood-brain barrier (BBB). In this study, we describe the beneficial effect of the antioxidant α-lipoic acid (LA) on these phenomena. In vivo, LA dose-dependently prevented the development of clinical signs in a rat model for MS, acute experimental allergic encephalomyelitis (EAE). Clinical improvement was coupled to a decrease in leukocyte infiltration into the CNS, in particular monocytes. Monocytes isolated from the circulation of LA-treated rats revealed a reduced migratory capacity to cross a monolayer of rat brain endothelial cells in vitro compared with monocytes isolated from untreated EAE controls. Using live cell imaging techniques, we visualized and quantitatively assessed that ROS are produced within minutes upon the interaction of monocytes with brain endothelium. Monocyte adhesion to an in vitro model of the BBB subsequently induced enhanced permeability, which could be inhibited by LA. Moreover, administration of exogenous ROS to brain endothelial cells induced cytoskeletal rearrangements, which was inhibited by LA. In conclusion, we show that LA has a protective effect on EAE development not only by affecting the migratory capacity of monocytes, but also by stabilization of the BBB, making LA an attractive therapeutic agent for the treatment of MS.
Human Mast Cell-Derived Gelatinase B (Matrix Metalloproteinase-9) Is Regulated by Inflammatory Cytokines: Role in Cell Migration
Authors: Di Girolamo Nick , Indoh Ikuko , Jackson Nicole , Wakefield Denis , McNeil H. Patrick , Yan Weixing , Geczy Carolyn , Arm Jonathan P. , Tedla Nicodemus 
Published: April 2014

AbstractMast cells are key effectors in the pathogenesis of inflammatory and tissue destructive diseases such as rheumatoid arthritis (RA). These cells contain specialized secretory granules loaded with bioactive molecules including cytokines, growth factors, and proteases that are released upon activation. This study investigated the regulation of matrix metalloproteinase MMP-9 (gelatinase B) in human mast cells by cytokines that are known to be involved in the pathogenesis of RA. Immunohistochemical staining of synovial tissue showed abundant expression of MMP-9 by synovial tissue mast cells in patients with RA but not in normal controls. The expression, activity, and production of MMP-9 in mast cells was confirmed by RT-PCR, zymography, and Western blotting using cord blood-derived human mast cells (CB-HMC). Treatment of CB-HMC with TNF-α significantly increased the expression of MMP-9 mRNA and up-regulated the activity of MMP-9 in a time- and dose-dependent manner. By contrast, IFN-γ inhibited MMP-9 mRNA and protein expression. The cytokine-mediated regulation of MMP-9 was also apparent in the human mast cell line (HMC-1) and in mouse bone marrow-derived mast cells. Furthermore, TNF-α significantly increased the invasiveness of CB-HMC across Matrigel-coated membranes while the addition of IFN-γ, rTIMP-1, or pharmacological MMP inhibitors significantly reduced this process. These observations suggest that MMP-9 is not a stored product in mast cells but these cells are capable of producing this enzyme under inflammatory conditions that may facilitate the migration of mast cell progenitors to sites of inflammation and may also contribute to local tissue damage.
Monocyte-Derived Human Macrophages Mediate Anergy in Allogeneic T Cells and Induce Regulatory T Cells
Authors: Hoves Sabine , Krause Stefan W. , Schütz Christian , Halbritter Dagmar , Schölmerich Jürgen , Herfarth Hans , Fleck Martin 
Published: April 2014

AbstractActivation of alloreactive T cells by APCs such as dendritic cells (DC) has been implicated as crucial step in transplant rejection. In contrast, it has been proposed that macrophages (Mφ) maintain tolerance toward alloantigens. It was therefore the aim of this study to further analyze the T cell-stimulatory capacity of mature DC and Mφ in vitro using the model of allogeneic MLR. There was a strong proliferative response in T cells cocultured with DC, which was further increased upon restimulation in a secondary MLR. In contrast, T cells did not proliferate in cocultures with Mφ despite costimulation with anti-CD28 and IL-2. Cytokine analysis revealed considerable levels of IL-10 in cocultures of T cells with Mφ, whereas high amounts of IL-2 and IFN-γ were present in cocultures with DC. There was only minimal T cell proliferation in a secondary MLR when T cells were rescued from primary MLR with Mφ and restimulated with DC of the same donor, or DC of an unrelated donor (third party), whereas a strong primary proliferative response was observed in resting T cells, demonstrating induction of T cell anergy by Mφ. Functional analysis of T cells rescued from cocultures with Mφ demonstrated that anergy was at least partly mediated by IL-10-producing regulatory T cells induced by Mφ. These results demonstrate that Mφ drive the differentiation of regulatory T cells and mediate anergy in allogeneic T cells, supporting the concept that Mφ maintain peripheral tolerance in vivo.
The Antineoplastic Agent Bryostatin-1 Differentially Regulates IFN-γ Receptor Subunits in Monocytic Cells: Transcriptional and Posttranscriptional Control of IFN-γR2
Authors: Garcia Carmen S. , Curiel Rafael E. , Mwatibo James M. , Pestka Sidney , Li Huifen , Espinoza-Delgado Igor 
Published: April 2014

AbstractBryostatin-1 (Bryo-1) is a potent ligand and modulator of protein kinase C that exerts antineoplastic and immunomodulatory activities both in vitro and in vivo. We have previously reported that Bryo-1 synergized with IFN-γ to induce NO synthase and NO by macrophages. To determine whether this effect was associated with changes in levels of IFN-γR, we investigated the effects of Bryo-1 on the expression and regulation of IFN-γR chains in monocytic cells. Northern blot analysis revealed that Bryo-1 treatment of the human monocytic cell lines MonoMac6 and THP-1 and human monocytes enhanced the expression of IFN-γR2 mRNA but did not affect IFN-γR1 mRNA expression. Bryo-1 increased IFN-γR2 mRNA in a dose-dependent manner as early as 3 h posttreatment. Bryo-1-induced up-regulation of IFN-γR2 mRNA levels is not dependent on de novo protein synthesis as shown by cell treatment with the protein-synthesis inhibitor cycloheximide. Bryo-1 treatment increased the IFN-γR2 mRNA half-life by 2 h. EMSA analysis from Bryo-1-treated MonoMac6 cells showed an increased nuclear protein binding to the NF-κB motif present in the 5′ flanking region of the human IFN-γR2 promoter that was markedly decreased by pretreatment with the NF-κB inhibitor SN50. These results show for the first time that Bryo-1 up-regulates IFN-γR2 expression in monocytic cells. Given the pivotal role that IFN-γ exerts on monocyte activation and in the initiation and outcome of the immune response, the induction of IFN-γR2 by Bryo-1 has significant implications in immunomodulation and could overcome some of the immune defects observed in cancer patients.
Cutting Edge: Decreased Accumulation and Regulatory Function of CD4+CD25high T Cells in Human STAT5b Deficiency
Authors: Cohen Aileen C. , Nadeau Kari C. , Tu Wenwei , Hwa Vivian , Dionis Kira , Bezrodnik Liliana , Teper Alejandro , Gaillard Maria , Heinrich Juan , Krensky Alan M. , Rosenfeld Ron G. , Lewis David B. 
Published: April 2014

Abstract
We show that STAT5b is important for the in vivo accumulation of CD4+CD25high T cells with regulatory cell function. A patient homozygous for a missense A630P STAT5b mutation displayed immune dysregulation and decreased numbers of CD4+CD25high T cells. STAT5bA630P/A630P CD4+CD25high T cells had low expression of forkhead box P3 and an impaired ability to suppress the proliferation of or to kill CD4+CD25− T cells. Expression of CD25, a component of the high-affinity IL-2R, was also reduced in response to IL-2 or after in vitro propagation. The impact of the STAT5b mutation was selective in that IL-2-mediated up-regulation of the common γ-chain cytokine receptor and perforin, and activation-induced expressions of CD154 and IFN-γ were normal. These results indicate that STAT5b propagates an important IL-2-mediated signal for the in vivo accumulation of functional regulatory T cells.
Molecular and Functional Characterization of CD300b, a New Activating Immunoglobulin Receptor Able to Transduce Signals through Two Different Pathways
Authors: Martínez-Barriocanal Águeda , Sayós Joan 
Published: April 2014

AbstractIn this study, we describe the characterization of human CD300b, a novel member of the CMRF-35/immune receptor expressed by myeloid cell (IREM) multigene family of immune receptors. Immune receptor expressed by myeloid cell-3 cDNA was cloned from a PHA-activated PBMC library and RT-PCR revealed the gene to be expressed preferentially in cells of myeloid origin. The CD300b cDNA open reading frame encodes a 201-aa type I protein composed of a single extracellular Ig V-type domain followed by a transmembrane region containing a positively charged residue (lysine) which is a common feature among receptors that associate with activating adaptor proteins. Indeed, CD300b was able to associate with DNAX-activating protein of 12 kDa (DAP-12) and deliver different activating signals through this ITAM-based adaptor. Unusually for an activating receptor, the 29-aa cytoplasmic tail of CD300b contains a tyrosine-based motif that, upon c-Fyn phosphorylation, became a docking site for the intracellular signaling mediator growth factor receptor-bound protein 2. Moreover, in the absence of DAP-12, CD300b was able to activate NFAT/AP-1-dependent transcriptional activity in RBL-2H3 cells. This activity could be abolished only by mutating both the cytoplasmic tyrosine and the transmembrane lysine. Our data suggest the existence of an unidentified molecule capable of interacting with CD300b through a charged residue of the transmembrane region and allowing receptor signaling independent of DAP-12. Therefore, CD300b defines a nonclassical Ig receptor able to trigger signals by coupling distinct mediators and thus initiating different signaling pathways.
P2X7 Receptor-Dependent Cell Death Is Modulated during Murine T Cell Maturation and Mediated by Dual Signaling Pathways
Authors: Tsukimoto Mitsutoshi , Maehata Machiko , Harada Hitoshi , Ikari Akira , Takagi Kuniaki , Degawa Masakuni 
Published: April 2014

AbstractExtracellular ATP causes apoptosis and/or necrosis of the hemopoietic lineage through the activation of P2X7 receptors. In this study, we investigated P2X7 receptor-mediated cell death during murine T cell maturation. The expression level and activity of P2X7 receptors, as measured by induction of cell death and pore formation, were higher in splenocytes than thymocytes. Flow cytometric analysis revealed that cell shrinkage was induced by activation of the P2X7 receptor in murine lymphocytes and the responding cells were T cells. Splenic T cells were more responsive than their thymic counterpart. These observations indicate that the system of P2X7 receptor-mediated cell death in T cells could be modulated during T cell maturation. Furthermore, decreased extracellular Cl− suppressed ATP-induced cell shrinkage in splenocytes without inhibiting ERK1/2 phosphorylation, which is reported to mediate necrotic cell death. Treatment with U0126 (a MEK inhibitor) suppressed ATP-induced ERK1/2 phosphorylation without inhibiting cell shrinkage. Moreover, decreased extracellular Cl− and treatment with U0126 suppressed ATP-induced cell death. These observations indicate that the activation of P2X7 receptor leads to T cell death by two independent pathways, one of which is cell shrinkage dependent and the other of which involves the phosphorylation of ERK1/2. In conclusion, we demonstrate increasing P2X7 receptor activity during T cell maturation and the existence of two essential pathways in P2X7 receptor-mediated T cell death. Our findings suggest that ATP-induced cell death of peripheral T lymphocytes is important in P2X7 receptor-regulated immune responses.
T Helper Lymphocytes Rescue CTL from Activation-Induced Cell Death
Authors: Kennedy Richard , Celis Esteban 
Published: April 2014

Abstract
T cell activation is characterized by a vast expansion of Ag-specific T cells followed by an equally extensive reduction in T cell numbers. This decline is due, in part, to activation-induced apoptosis of the responding T cells during repeated encounter with Ag. In the current study, we used solid-phase MHC class I/peptide monomers to cause activation-induced cell death (AICD) of previously activated CD8 T cells in an Ag-specific manner. AICD occurred rapidly and was mediated primarily by Fas–FasL interactions. Most interestingly, we observed that Th cells could provide survival signals to CTL significantly reducing the level of AICD. Both Th1 and Th2 subsets were capable of protecting CTL from AICD, and a major role for soluble factors in this protection was ruled out, as cell-to-cell contact was an essential component of this Th-mediated protection. Upon encounter with Ag-expressing tumor cells, CTL underwent significant apoptosis. However, in the presence of Th cells, the CTL not only were protected against death, but also had significantly greater lytic ability. In vivo tumor protection studies using peptide immunization showed that the activation of Ag-specific Th cells was crucial for optimal protection, but did not affect the magnitude of the CTL response in the lymphoid tissues. In this study, we examine the type of help that CD4 T cells may provide and propose a model of Th cell–CTL interaction that reduces CTL death. Our results show a novel role for Th cells in the maintenance of CTL responses.
Primitive Lymphoid Progenitors in Bone Marrow with T Lineage Reconstituting Potential
Authors: Perry S. Scott , Welner Robert S. , Kouro Taku , Kincade Paul W. , Sun Xiao-Hong 
Published: April 2014

Abstract
Multiple subsets of the bone marrow contain T cell precursors, but it remains unclear which is most likely to replenish the adult thymus. Therefore, RAG-1+ early lymphoid progenitors (RAG-1+ ELP), and CD62L/L-selectin+ progenitors (LSP), as well as common lymphoid progenitors from C57BL6-Thy1.1-RAG-1/GFP mouse bone marrow were directly compared in transplantation assays. The two c-Kithigh populations vigorously regenerated the thymus and were superior to common lymphoid progenitors in magnitude and frequency of thymic reconstitution. Regeneration was much faster than the 22 days described for transplanted stem cells, and RAG-1+ ELP produced small numbers of lymphocytes within 13 days. As previously reported, LSP were biased to a T cell fate, but this was not the case for RAG-1+ ELP. Although RAG-1+ ELP and LSP had reduced myeloid potential, they were both effective progenitors for T lymphocytes and NK cells. The LSP subset overlapped with and included most RAG-1+ ELP and many RAG-1−TdT+ ELP. LSP and RAG-1+ ELP were both present in the peripheral circulation, but RAG-1+ ELP had no exact counterpart among immature thymocytes. The most primitive of thymocytes were similar to Lin−c-KithighL-selectin+TdT+RAG-1− progenitors present in the marrow, suggesting that this population is normally important for sustaining the adult thymus.
Addition of a Prominent Epitope Affects Influenza A Virus-Specific CD8+ T Cell Immunodominance Hierarchies When Antigen Is Limiting
Authors: Jenkins Misty Rayna , Webby Richard , Doherty Peter C. , Turner Stephen J. 
Published: April 2014

AbstractA reverse genetics strategy was used to insert the OVA peptide (amino acid sequence SIINFEKL; OVA257–264) into the neuraminidase stalk of both the A/PR8 (H1N1) and A/HK×31 (H3N2) influenza A viruses. Initial characterization determined that KbOVA257 is presented on targets infected with PR8-OVA and HK-OVA without significantly altering Db nucleoprotein (NP)366 presentation. There were similar levels of KbOVA257- and DbNP366-specific CTL expansion following both primary and secondary intranasal challenge. Interestingly, while variable, the presence of the immunodominant KbOVA257-specific response resulted in diminished Db acidic polymerase224- and Kb basic polymerase subunit 1703-, but not DbNP366-specific responses and didn’t alter endogenous influenza A virus-specific immunodominance hierarchies. However, challenging PR8-OVA-primed mice with HK-OVA via the i.p. route, and thereby limiting Ag dose, led to a reduction in the magnitude of all the influenza A virus-specific responses measured. A similar reduction in CTL response to native epitopes was also seen following primary respiratory HK-OVA infection of mice that received substantial numbers of KbOVA257-specific TCR transgenic T cells. Thus, during the course of infection, the generation of individual virus-specific CTL responses is independently regulated. However, in cases in which Ag is limiting, or high precursor frequency, the presence of immunodominant CTL responses can impact on the magnitude of other specific populations. Therefore, depending on both the size of the T cell precursor pool and the mode of Ag presentation, the addition of a major epitope can diminish the size of endogenous, influenza-specific CD8+ T cell responses, although never to the point that these are totally compromised.
CD38 Is Required for the Peripheral Survival of Immunotolerogenic CD4+ Invariant NK T Cells in Nonobese Diabetic Mice
Authors: Chen Yi-Guang , Chen Jing , Osborne Melissa A. , Chapman Harold D. , Besra Gurdyal S. , Porcelli Steven A. , Leiter Edward H. , Wilson S. Brian , Serreze David V. 
Published: April 2014

Abstract
T cell-mediated autoimmune type-1 diabetes (T1D) in NOD mice partly results from this strain’s numerical and functional defects in invariant NK T (iNKT) cells. T1D is inhibited in NOD mice treated with the iNKT cell superagonist α-galactosylceramide through a process involving enhanced accumulation of immunotolerogenic dendritic cells in pancreatic lymph nodes. Conversely, T1D is accelerated in NOD mice lacking CD38 molecules that play a role in dendritic cell migration to inflamed tissues. Unlike in standard NOD mice, α-galactosylceramide pretreatment did not protect the CD38-deficient stock from T1D induced by an adoptively transferred pancreatic β cell-autoreactive CD8 T cell clone (AI4). We found that in the absence of CD38, ADP-ribosyltransferase 2 preferentially activates apoptotic deletion of peripheral iNKT cells, especially the CD4+ subset. Therefore, this study documents a previously unrecognized role for CD38 in maintaining survival of an iNKT cell subset that preferentially contributes to the maintenance of immunological tolerance.
CD8+ Cytotoxic T-APC Stimulate Central Memory CD8+ T Cell Responses via Acquired Peptide-MHC Class I Complexes and CD80 Costimulation, and IL-2 Secretion
Authors: Xia Dajing , Hao Siguo , Xiang Jim 
Published: April 2014

Abstract
We previously showed that naive CD4+ Th cells acquire peptide-MHC class I (pMHC I) and costimulatory molecules from OVA-pulsed dendritic cells (DCOVA), and act as Th-APCs in stimulation of CD8+CTL responses. In this study, we further demonstrated that naive CD8+ cytotoxic T (Tc) cells also acquire pMHC I and costimulatory CD54 and CD80 molecules by DCOVA stimulation, and act as Tc-APC. These Tc-APC can play both negative and positive modulations in antitumor immune responses by eliminating DCOVA and neighboring Tc-APC, and stimulating OVA-specific CD8+ central memory T responses and antitumor immunity. Interestingly, the stimulatory effect of Tc-APC is mediated via its IL-2 secretion and acquired CD80 costimulation, and is specifically targeted to OVA-specific CD8+ T cells in vivo via its acquired pMHC I complexes. These principles could be applied to not only antitumor immunity, but also other immune disorders (e.g., autoimmunity).
G12/G13 Family G Proteins Regulate Marginal Zone B Cell Maturation, Migration, and Polarization
Authors: Rieken Stefan , Sassmann Antonia , Herroeder Susanne , Wallenwein Barbara , Moers Alexandra , Offermanns Stefan , Wettschureck Nina 
Published: April 2014

Abstract
G protein-coupled receptors play an important role in the regulation of lymphocyte functions such as migration, adhesion, proliferation, and differentiation. Although the role of Gi family G proteins has been intensively studied, no in vivo data exist with respect to G12/G13 family G proteins. We show in this study that mice that lack the G protein α-subunits Gα12 and Gα13 selectively in B cells show significantly reduced numbers of splenic marginal zone B (MZB) cells, resulting in a delay of Ab production in response to thymus-independent Ags. Basal and chemokine-induced adhesion to ICAM-1 and VCAM-1, two adhesion molecules critically involved in MZB localization, is normal in mutant B cells, and the same is true for chemokine-induced migration. However, migration in response to serum and sphingosine 1-phosphate is strongly increased in mutant MZB cells, but not in mutant follicular B cells. Live-cell imaging studies revealed that Gα12/Gα13-deficient MZB cells assumed more frequently an ameboid form than wild-type cells, and pseudopod formation was enhanced. In addition to their regulatory role in serum- and sphingosine 1-phosphate-induced migration, G12/G13 family G proteins seem to be involved in peripheral MZB cell maturation, because also splenic MZB cell precursors are reduced in mutant mice, although less prominently than mature MZB cells. These data suggest that G12/G13 family G proteins contribute to the formation of the mature MZB cell compartment both by controlling MZB cell migration and by regulating MZB cell precursor maturation.