bluuebunny/crossref_metadata_2025_split huggingface dataset:
Dendritic Cell Modulation by Mast Cells Controls the Th1/Th2 Balance in Responding T Cells
Authors: Mazzoni Alessandra , Siraganian Reuben P. , Leifer Cynthia A. , Segal David M. 
Published: April 2014

Abstract
The cytokines secreted by pathogen-activated human dendritic cells (DC) are strongly regulated in vitro by histamine, a major component of mast cell granules, ultimately modulating the capacity of the DC to polarize naive T cells. Because DC and mast cells are located in close proximity in peripheral compartments, we hypothesized that mast cell products would influence the maturation of DC and hence the Th balance of an immune response in vivo. In this study, we show that specific mast cell degranulation stimuli, given s.c. in mice with Ag and adjuvant, produce effector T cells that proliferate to Ag but secrete dramatically reduced levels of IFN-γ and increased amounts of IL-4 compared with control T cells primed in the absence of a mast cell stimulus. Immunization with Ag and adjuvant in the presence of a degranulation stimulus also resulted in the accumulation of DC in the draining lymph nodes that had reduced capacity to induce Ag-specific Th1 cells, in comparison with DC from mice lacking a degranulation stimulus. Therefore, by acting upon DC at sites of inflammation, mast cells play a critical role in determining the polarity of Ag-specific T cell responses in vivo.
T Cell-Dependent Activation of Dendritic Cells Requires IL-12 and IFN-γ Signaling in T Cells
Authors: Miro Francesc , Nobile Cinzia , Blanchard Nicolas , Lind Marianne , Filipe-Santos Orchidée , Fieschi Claire , Chapgier Ariane , Vogt Guillaume , de Beaucoudrey Ludovic , Kumararatne Dinakantha S. , Le Deist Françoise , Casanova Jean-Laurent , Amigorena Sebastian , Hivroz Claire 
Published: April 2014

Abstract
Patients presenting with genetic deficiencies in IFNGR1, IFNGR2, IL-12B, and IL-12RB1 display increased susceptibility to mycobacterial infections. We analyzed in this group of patients the cross-talk between human CD4+ T lymphocytes and dendritic cells (DCs) that leads to maturation of DC into producers of bioactive IL-12 and to activation of T cells into IFN-γ producers. We found that this cross-talk is defective in all patients from this group. Unraveling the mechanisms underlying this deficiency, we showed that IL-12 signaling in T cells is required to induce expression of costimulatory molecules and secretion of IL-12 by DCs and that IFNGR expression is required on both DCs and CD4+ T cells to induce IL-12 secretion by DCs. These data suggest that CD4+ T cell-mediated activation of DCs plays a critical role in the defense against mycobacterial infections in humans.
Hydrodynamic-Based Delivery of an Interleukin-22-Ig Fusion Gene Ameliorates Experimental Autoimmune Myocarditis in Rats
Authors: Chang He , Hanawa Haruo , Liu Hui , Yoshida Tsuyoshi , Hayashi Manabu , Watanabe Ritsuo , Abe Satoru , Toba Ken , Yoshida Kaori , Elnaggar Raafat , Minagawa Shiro , Okura Yuji , Kato Kiminori , Kodama Makoto , Maruyama Hiroki , Miyazaki Junichi , Aizawa Yoshifusa 
Published: April 2014

Abstract
IL-22 is one of several cytokines with limited homology to IL-10. However, the biological activities of IL-22 are mostly unknown. The purpose of this study was to evaluate the effect of IL-22 on rat experimental autoimmune myocarditis (EAM) and elucidate an aspect of the biological activities of IL-22. Rats were immunized on day 0; IL-22-Ig-treated rats were injected with pCAGGS-IL-22-Ig and control rats with pCAGGS-Ig using hydrodynamics-based gene delivery on day 1 or day 6. IL-22-Ig gene therapy administered on day 1 or day 6 after immunization was effective in controlling EAM as monitored by the heart weight to body weight ratio, and the myocarditis area in rats was sacrificed on day 17. Examination of the expression of IL-22-related genes in purified cells from EAM hearts suggested that IL-22-Ig acting target cells were noncardiomyocytic (NC) noninflammatory cells such as fibroblasts, smooth muscle cells, and endothelial cells. Therefore, we examined the effect of rIL-22 or serum containing IL-22-Ig on the expression of immune-relevant genes in IL-1-stimulated NC cells cultured from EAM hearts. Results showed that the expression of immunologic molecules (PGE synthase, cyclooxygenase-2, MIP-2, MCP-1, IL-6, and cytokine-induced neutrophil chemoattractant-2) in IL-1-stimulated NC cells was significantly decreased by rIL-22 or serum containing IL-22-Ig. EAM was suppressed by hydrodynamics-based delivery of plasmid DNA encoding IL-22-Ig, and the reason for this effectiveness may be that IL-22 suppressed gene expression of PG synthases, IL-6, and chemokines in activated NC noninflammatory cells.
Invariant NKT Cells Rapidly Activated via Immunization with Diverse Contact Antigens Collaborate In Vitro with B-1 Cells to Initiate Contact Sensitivity
Authors: Campos Regis A. , Szczepanik Marian , Lisbonne Mariette , Itakura Atsuko , Leite-de-Moraes Maria , Askenase Philip W. 
Published: April 2014

Abstract
In cutaneous contact sensitivity there is an early elicited innate cascade of complement, mast cells, and platelets activated via IgM Abs. This response is required to initiate the elicitation of acquired classical contact sensitivity by leading to local recruitment of effector T cells. We recently performed in vivo experiments showing that collaboration is required between innate-like invariant Vα14+ NKT cells (iNKT) and the innate-like B-1 B cell subset to induce this initiation process. Contact sensitization triggers iNKT cells to produce IL-4 to coactivate the B-1 cells along with specific Ag for production of the initiating IgM Abs. We now describe in vitro collaboration of iNKT and B-1 cells. Normal peritoneal B-1 cells, incubated in vitro with soluble Ag, and with 1-h in vivo immune iNKT cells producing IL-4, are activated to mediate the contact sensitivity-initiation cascade. The three components of this process can be activated by different Ag. Thus, 1-h iNKT cell activation, B-1 cell stimulation, and generation of immune effector T cells can be induced by sensitization with three different Ag to respectively generate IL-4 and Ag-specific IgM Abs, to recruit the Ag-specific effector T cells. These findings have relevance to allergic and autoimmune diseases in which infections can trigger exacerbation of T cell responses to allergens or to autoantigens.
Peroxisome Proliferator-Activated Receptor γ Promotes Lymphocyte Survival through Its Actions on Cellular Metabolic Activities
Authors: Jo Seung-Hee , Yang Chunyan , Miao Qi , Marzec Michal , Wasik Mariusz A. , Lu Pin , Wang Y. Lynn 
Published: April 2014

Abstract
Peroxisome proliferator-activated receptor γ (PPARγ) is a metabolic regulator that plays an important role in sensitizing tissues to the action of insulin and in normalizing serum glucose and free fatty acids in type 2 diabetic patients. The receptor has also been implicated in the modulation of inflammatory responses, and ligands of PPARγ have been found to induce apoptosis in lymphocytes. However, apoptosis induction may not depend on the receptor, because high doses of PPARγ agonists are required for this process. Using cells containing or lacking PPARγ, we reported previously that PPARγ attenuates apoptosis induced by cytokine withdrawal in a murine lymphocytic cell line via a receptor-dependent mechanism. PPARγ exerts this effect by enhancing the ability of cells to maintain their mitochondrial membrane potential during cytokine deprivation. In this report, we demonstrate that activation of PPARγ also protects cells from serum starvation-induced apoptosis in human T lymphoma cell lines. Furthermore, we show that the survival effect of PPARγ is mediated through its actions on cellular metabolic activities. In cytokine-deprived cells, PPARγ attenuates the decline in ATP level and suppresses accumulation of reactive oxygen species (ROS). Moreover, PPARγ regulates ROS through its coordinated transcriptional control of proteins and enzymes involved in ROS scavenging, including uncoupling protein 2, catalase, and copper zinc superoxide dismutase. Our studies identify cell survival promotion as a novel activity of PPARγ and suggest that PPARγ may modulate cytokine withdrawal-induced activated T cell death.
Immature Dendritic Cells Suppress Collagen-Induced Arthritis by In Vivo Expansion of CD49b+ Regulatory T Cells
Authors: Charbonnier Louis-Marie , van Duivenvoorde Leonie M. , Apparailly Florence , Cantos Céline , Han Wanda G. H. , Noël Danièle , Duperray Christophe , Huizinga Tom W. J. , Toes René E. M. , Jorgensen Christian , Louis-Plence Pascale 
Published: April 2014

Abstract
Dendritic cells (DCs) are specialized APCs with an important role in the initiation and regulation of immune responses. Immature DCs (iDCs) reportedly mediate tolerance in the absence of maturation/inflammatory stimuli, presumably by the induction of regulatory T cells. In this study, we show for the first time that repetitive iDC injections trigger the expansion of a novel regulatory population with high immunomodulatory properties, able to protect mice from collagen-induced arthritis. These regulatory T cells are characterized by the expression of the CD49b molecule and correspond to a CD4+ α-galactosylceramide/CD1d-nonrestricted T cell population producing IL-10. Adoptive transfer of &lt;105 TCRβ+CD49b+ cells isolated from the liver of iDCs-vaccinated mice, conferred a complete protection against arthritis. This protection was associated with an attenuation of the B and T cell response associated with a local secretion of IL-10. Thus, together these data demonstrate that iDCs can expand and activate a novel regulatory population of CD49b+ T cells, with high immunosuppressive potential able to mediate protection against a systemic autoimmune disease.
Impaired Memory CD8 T Cell Development in the Absence of Methyl-CpG-Binding Domain Protein 2
Authors: Kersh Ellen N. 
Published: April 2014

Abstract
Intracellular differentiation events that determine which cells develop into memory CD8 T cells are currently incompletely understood. Methyl-CpG-binding domain protein 2 (MBD2) is a transcriptional repressor that binds to methylated DNA and mediates the biological consequences of epigenetic gene methylation. The role of MBD2 during the differentiation of naive CD8 T cells into effector and memory cells was determined following acute infection of MBD2-deficient mice with lymphocytic choriomeningitis virus. Despite rapid viral clearance and an efficient primary effector CD8 T cell response, reduced numbers of Ag-specific memory CD8 T cells were observed. Importantly, the appearance of precursor memory cells (IL-7Rαhigh) was delayed. The remaining MBD2−/− memory cells were not fully protective during rechallenge, and memory cell characteristics were altered with regard to surface markers (IL-7Rα, KLRG-1, CD27, and others) and cytokine production. The defect was CD8 T cell intrinsic, because memory cell development was also delayed when MBD2−/− CD8 T cells were adoptively transferred into SCID mice. These data demonstrate that MBD2 is a previously unrecognized intracellular factor required for the efficient generation of protective memory CD8 T cells.
Constitutive Expression of Murine Decay-Accelerating Factor 1 Is Controlled by the Transcription Factor Sp1
Authors: Cauvi David M. , Cauvi Gabrielle , Pollard K. Michael 
Published: April 2014

AbstractThe complement regulatory protein decay-accelerating factor (DAF or CD55) protects host tissue from complement-mediated injury by inhibiting the classical and alternative complement pathways. Besides its role in complement regulation, DAF has also been shown to be a key player in T cell immunity. Modulation of DAF expression could therefore represent a critical regulatory mechanism in both innate and adaptive immune responses. To identify and characterize key transcriptional regulatory elements controlling mouse Daf1 expression, a 2.5-kb fragment corresponding to the 5′ flanking region of the mouse Daf1 gene was cloned. Sequence analysis showed that the mouse Daf1 promoter lacks conventional TATA and CCAAT boxes and displays a high guanine and cytosine content. RACE was used to identify one major and two minor transcription start sites 47, 20, and 17 bp upstream of the translational codon. Positive and negative regulatory regions were identified by transiently transfecting sequential 5′deletion constructs of the 5′flanking region into NIH/3T3, M12.4, and RAW264.7 cells. Mutational analyses of the promoter region combined with Sp1-specific ELISA showed that the transcription factor Sp1 is required for basal transcription and LPS-induced expression of the Daf1 gene. These findings provide new information on the regulation of the mouse Daf1 promoter and will facilitate further studies on the expression of Daf1 during immune responses.
Mapping the Binding Site on CD8β for MHC Class I Reveals Mutants with Enhanced Binding
Authors: Devine Lesley , Thakral Deepshi , Nag Shanta , Dobbins Jessica , Hodsdon Michael E. , Kavathas Paula B. 
Published: April 2014

AbstractIn an effective immune response, CD8+ T cell recognition of virally derived Ag, bound to MHC class I, results in killing of infected cells. The CD8αβ heterodimer acts as a coreceptor with the TCR, to enhance sensitivity of the T cells to peptide/MHC class I, and is two orders of magnitude more efficient as a coreceptor than the CD8αα. To understand the important interaction between CD8αβ and MHC class I, we created a panel of CD8β mutants and identified mutations in the CDR1, CDR2, and CDR3 loops that decreased binding to MHC class I tetramers as well as mutations that enhanced binding. We tested the coreceptor function of a subset of reducing and enhancing mutants using a T cell hybridoma and found similar reducing and enhancing effects. CD8β-enhancing mutants could be useful for immunotherapy by transduction into T cells to enhance T cell responses against weak Ags such as those expressed by tumors. We also addressed the question of the orientation of CD8αβ with MHC class I using CD8α mutants expressed as a heterodimer with wild-type CD8α or CD8β. The partial rescuing of binding with wild-type CD8β compared with wild-type CD8α is consistent with models in which either the topology of CD8αα and CD8αβ binding to MHC class I is different or CD8αβ is capable of binding in both the T cell membrane proximal and distal positions.
Aspergillus fumigatus Induces Innate Immune Responses in Alveolar Macrophages through the MAPK Pathway Independently of TLR2 and TLR4
Authors: Dubourdeau Marc , Athman Rafika , Balloy Viviane , Huerre Michel , Chignard Michel , Philpott Dana J. , Latgé Jean-Paul , Ibrahim-Granet Oumaïma 
Published: April 2014

Abstract
Aspergillus fumigatus causes invasive aspergillosis in immunosuppressed patients. In the immunocompetent host, inhaled conidia are cleared by alveolar macrophages. The signaling pathways of the alveolar macrophage involved in the clearance of A. fumigatus are poorly understood. Therefore, we investigated the role of TLRs in the immune response against A. fumigatus and their contribution to the signaling events triggered in murine alveolar macrophages upon infection with A. fumigatus conidia. Specifically, we examined the MAPKs and NF-κB activation and cytokine signaling. Our investigations revealed that immunocompetent TLR2, TLR4, and MyD88 knockout mice were not more susceptible to invasive aspergillosis as compared with wild-type mice and that the in vitro phosphorylation of the MAPKs ERK and p38 was not affected in TLR2, TLR4, or MyD88 knockout mice following stimulation with conidia. In vivo experiments suggest that ERK was an essential MAPK in the defense against A. fumigatus, whereas the activation of NF-κB appeared to play only a secondary role. In conclusion, our findings demonstrate that TLR2/4 recognition and MyD88 signaling are dispensable for the clearance of A. fumigatus under immunocompetent situations. Furthermore, our data stress the important role of ERK activation in innate immunity to A. fumigatus.
Listeriolysin O-Deficient Listeria monocytogenes as a Vaccine Delivery Vehicle: Antigen-Specific CD8 T Cell Priming and Protective Immunity
Authors: Hamilton Sara E. , Badovinac Vladimir P. , Khanolkar Aaruni , Harty John T. 
Published: April 2014

Abstract
Strains of Listeria monocytogenes (LM) that are deficient in the virulence factor listeriolysin O (LLO) are highly attenuated and are thought not to elicit protective immunity. This failure has been attributed to the inability of the bacterium to enter the host cell cytosol and access MHC class I Ag processing machinery. We reexamined this issue using recombinant strains of LM that are deficient in LLO but express an additional CD8 T cell epitope derived from lymphocytic choriomeningitis virus. After infection with LLO-deficient strains, we find sizable priming of epitope-specific CD8 T cells and the development of a functional memory cell population. Mice primed with the LLO-deficient LM strain are equally resistant against high-dose challenge with virulent LM as mice primed with wild-type virulent bacteria and also resist heterologous challenge with lymphocytic choriomeningitis virus. Interestingly, priming with a low dose of LLO-deficient LM, which occurred in environment of reduced inflammation (IFN-γ), allowed rapid amplification of Ag-specific CD8 T cells by booster immunization, despite an undetectable primary response. We conclude that the generation of protective immunity by LLO-deficient strains of LM does in fact occur and that this highly attenuated LM strain may be a useful platform for vaccine delivery.
First Identification of a Chemotactic Receptor in an Invertebrate Species: Structural and Functional Characterization of Ciona intestinalis C3a Receptor
Authors: Melillo Daniela , Sfyroera Georgia , De Santis Rosaria , Graziano Rita , Marino Rita , Lambris John D. , Pinto Maria Rosaria 
Published: April 2014

Abstract
In mammals, the bioactive fragment C3a, released from C3 during complement activation, is a potent mediator of inflammatory reactions and exerts its functional activity through the specific binding to cell surface G protein-coupled seven-transmembrane receptors. Recently, we demonstrated a Ciona intestinalis C3a (CiC3a)-mediated chemotaxis of hemocytes in the deuterostome invertebrate Ciona intestinalis and suggested an important role for this molecule in inflammatory processes. In the present work, we have cloned and characterized the receptor molecule involved in the CiC3a-mediated chemotaxis and studied its expression profile. The sequence, encoding a 95,394 Da seven-transmembrane domain protein, shows the highest sequence homology with mammalian C3aRs. Northern blot analysis revealed that the CiC3aR is expressed abundantly in the heart and neural complex and to a lesser extent in the ovaries, hemocytes, and larvae. Three polyclonal Abs raised in rabbits against peptides corresponding to CiC3aR regions of the first and second extracellular loop and of the third intracellular loop react specifically in Western blotting with a single band of 98–102 kDa in hemocyte protein extracts. Immunostaining performed on circulating hemocytes with the three specific Abs revealed that CiC3aR is constitutively expressed only in hyaline and granular amoebocytes. In chemotaxis experiments, the Abs against the first and second extracellular loop inhibited directional migration of hemocytes toward the synthetic peptide reproducing the CiC3a C-terminal sequence, thus providing the compelling evidence that C. intestinalis expresses a functional C3aR homologous to the mammalian receptor. These findings further elucidate the evolutionary origin of the vertebrate complement-mediated proinflammatory process.
DNA Immunization against Tissue-Restricted Antigens Enhances Tumor Immunity after Allogeneic Hemopoietic Stem Cell Transplantation
Authors: Perales Miguel-Angel , Diab Adi , Cohen Adam D. , Huggins Deonka W. , Guevara-Patiño José A. , Hubbard Vanessa M. , Engelhorn Manuel E. , Kochman Adam A. , Eng Jeffrey M. , Mortazavi Fariborz , Alpdogan Onder , Terwey Theis H. , Heller Glenn , Wolchok Jedd D. , Houghton Alan N. , van den Brink Marcel R. M. 
Published: April 2014

Abstract
Malignant relapse remains a major problem for recipients of allogeneic hemopoietic stem cell transplantation (HSCT). We hypothesized that immunization of allogeneic HSCT recipients against tissue-restricted Ags using DNA vaccines would decrease the risk of relapse without enhancing graft-vs-host disease (GVHD). Using the mouse B16 melanoma model, we found that post-HSCT DNA immunization against a single tumor Ag induces tumor rejection that is significantly greater than HSCT alone in a T cell-depleted MHC-matched minor Ag-mismatched allogeneic HSCT model (LP → B6). In treatment models, post-HSCT DNA immunization provides significantly greater overall survival than the vaccine alone. Donor leukocyte infusion further enhances tumor-free survival, including in treatment models. There was no GVHD in HSCT recipients treated with DNA vaccination and donor leukocyte infusion. Further analysis demonstrated that these effects are dependent on CD8+ T cells of donor origin that recognize multiple epitopes. These results demonstrate that DNA immunization against tissue-restricted Ags after allogeneic T cell-depleted HSCT can induce potent antitumor effects without causing GVHD.
Antibody Targeting to a Class I MHC-Peptide Epitope Promotes Tumor Cell Death
Authors: Wittman Vaughan P. , Woodburn David , Nguyen Tiffany , Neethling Francisca A. , Wright Stephen , Weidanz Jon A. 
Published: April 2014

Abstract
Therapeutic mAbs that target tumor-associated Ags on the surface of malignant cells have proven to be an effective and specific option for the treatment of certain cancers. However, many of these protein markers of carcinogenesis are not expressed on the cells’ surface. Instead these tumor-associated Ags are processed into peptides that are presented at the cell surface, in the context of MHC class I molecules, where they become targets for T cells. To tap this vast source of tumor Ags, we generated a murine IgG2a mAb, 3.2G1, endowed with TCR-like binding specificity for peptide-HLA-A*0201 (HLA-A2) complex and designated this class of Ab as TCR mimics (TCRm). The 3.2G1 TCRm recognizes the GVL peptide (GVLPALPQV) from human chorionic gonadotropin β presented by the peptide-HLA-A*0201 complex. When used in immunofluorescent staining reactions using GVL peptide-loaded T2 cells, the 3.2G1 TCRm specifically stained the cells in a peptide and Ab concentration-dependent manner. Staining intensity correlated with the extent of cell lysis by complement-dependent cytotoxicity (CDC), and a peptide concentration-dependent threshold level existed for the CDC reaction. Staining of human tumor lines demonstrated that 3.2G1 TCRm was able to recognize endogenously processed peptide and that the breast cancer cell line MDA-MB-231 highly expressed the target epitope. The 3.2G1 TCRm-mediated CDC and Ab-dependent cellular cytotoxicity of a human breast carcinoma line in vitro and inhibited in vivo tumor implantation and growth in nude mice. These results provide validation for the development of novel TCRm therapeutic reagents that specifically target and kill tumors via recognition and binding to MHC-peptide epitopes.
The Inflammatory Caspases: Key Players in the Host Response to Pathogenic Invasion and Sepsis
Authors: Nadiri Amal , Wolinski Melissa K. , Saleh Maya 
Published: April 2014

Abstract
Caspases are cysteinyl-aspartate-specific proteinases known for their role in apoptosis (cell death or apoptotic caspases) and proinflammatory cytokine maturation (inflammatory caspases). The inflammatory caspases were among the first to be discovered, but only recently have the mechanisms leading to their activation and inhibition begun to be elucidated. In this review, we examine the biochemistry, substrates, and function of this unique family of inflammatory proteases, highlight the most recent findings regarding their regulatory mechanisms, and discuss what remains to be understood about their roles in health and disease.