bluuebunny/crossref_metadata_2025_split huggingface dataset:
B7-DC/PD-L2 Cross-Linking Induces NF-κB-Dependent Protection of Dendritic Cells from Cell Death
Authors: Radhakrishnan Suresh , Nguyen Loc T. , Ciric Bogoljub , Van Keulen Virginia P. , Pease Larry R. 
Published: April 2014

Abstract
Cross-linking cell surface molecules with IgM Abs is a specific approach for activating cells in vitro or in vivo. Dendritic cells (DC) activated with a human B7-DC (PD-L2)-specific IgM Ab can induce strong antitumor responses and block inflammatory airway disease in experimental models, yet the Ab-mediated molecular events promoting these responses remain unclear. Analysis of human or mouse DC treated with the B7-DC cross-linking Ab revealed PI3K-dependent phosphorylation of AKT accompanied by mobilization of NF-κB. Ab-activated DC up-regulated expression of cytokine and chemokine genes in an NF-κB-dependent manner. Importantly, PI3K→AKT→NF-κB activation was found to be indispensable for B7-DC cross-linking Ab-mediated protection of DC from cell death caused by cytokine withdrawal. Although other DC activators similarly protect DC from cell death, a synergy between cross-linking B7-DC and ligating RANK was observed. The parallel signaling events induced in human and mouse DC demonstrate that activation of cells using IgM Ab results in a response governed by a common mechanism and support the hypothesis that B7-DC cross-linking using this Ab may provide beneficial therapeutic immune modulation in human patients similar to those seen in animal models.
Naturally Occurring Lung CD4+CD25+ T Cell Regulation of Airway Allergic Responses Depends on IL-10 Induction of TGF-β
Authors: Joetham Anthony , Takada Katsuyuki , Taube Christian , Miyahara Nobuaki , Matsubara Satoko , Koya Toshiyuki , Rha Yeong-Ho , Dakhama Azzeddine , Gelfand Erwin W. 
Published: April 2014

Abstract
Peripheral tolerance to allergens is mediated in large part by the naturally occurring lung CD4+CD25+ T cells, but their effects on allergen-induced airway responsiveness have not been well defined. Intratracheal, but not i.v., administration of naive lung CD4+CD25+ T cells before allergen challenge of sensitized mice, similar to the administration of the combination of rIL-10 and rTGF-β, resulted in reduced airway hyperresponsiveness (AHR) and inflammation, lower levels of Th2 cytokines, higher levels of IL-10 and TGF-β, and less severe lung histopathology. Significantly, CD4+CD25+ T cells isolated from IL-10−/− mice had no effect on AHR and inflammation, but when incubated with rIL-10 before transfer, suppressed AHR, and inflammation, and was associated with elevated levels of bronchoalveolar lavage TGF-β levels. By analogy, anti-TGF-β treatment reduced regulatory T cell activity. These data identify naturally occurring lung CD4+CD25+ T cells as capable of regulating lung allergic responses in an IL-10- and TGF-β-dependent manner.
Targeting of CD25 and Glucocorticoid-Induced TNF Receptor Family-Related Gene-Expressing T Cells Differentially Modulates Asthma Risk in Offspring of Asthmatic and Normal Mother Mice
Authors: Hubeau Cedric , Apostolou Irina , Kobzik Lester 
Published: April 2014

Abstract
Immunological mechanisms leading to increased asthma susceptibility in early life remain obscure. In this study, we examined the effects of neonatal Ab treatments targeting T cell populations on the development of an asthma syndrome. We used a model of increased asthma susceptibility where offspring of asthmatic BALB/c mother mice are more prone (than normal pups) to develop the disease. Neonatal pretreatment of naive pups with mAb directed against the IL-2Rα chain (CD25), the costimulatory molecule glucocorticoid-induced TNFR family related gene, and the inhibitory molecule CTLA-4 elicited contrasting effects in offspring depending on the mother’s asthma status. Specifically, neonatal CD25high T cell depletion stimulated asthma susceptibility in normal offspring whereas it ameliorated the condition of pups born of asthmatic mothers. Conversely, glucocorticoid-induced TNFR family related gene ligation as a primary signal reduced the spleen cellularity and largely abrogated asthma susceptibility in asthma-prone offspring, without inducing disease in normal pups. Striking changes in Th1/Th2 cytokine levels, especially IL-4, followed mAb pretreatment and were consistent with the impact on asthma susceptibility. These results point to major differences in neonatal T cell population and responsiveness related to maternal asthma history. Interventions that temporarily remove and/or inactivate specific T cell subsets may therefore prove useful to attenuate early life asthma susceptibility and prevent the development of Th2-driven allergic airway disease.
BTNL2, a Butyrophilin/B7-Like Molecule, Is a Negative Costimulatory Molecule Modulated in Intestinal Inflammation
Authors: Arnett Heather A. , Escobar Sabine S. , Gonzalez-Suarez Eva , Budelsky Alison L. , Steffen Lori A. , Boiani Norman , Zhang Ming , Siu Gerald , Brewer Avery W. , Viney Joanne L. 
Published: April 2014

Abstract
Butyrophilin-like 2 (BTNL2) is a butyrophilin family member with homology to the B7 costimulatory molecules, polymorphisms of which have been recently associated through genetic analyses to sporadic inclusion body myositis and sarcoidosis. We have characterized the full structure, expression, and function of BTNL2. Structural analysis of BTNL2 shows a molecule with an extracellular region containing two sets of two Ig domains, a transmembrane region, and a previously unreported cytoplasmic tail. Unlike most other butyrophilin members, BTNL2 lacks the prototypical B30.2 ring domain. TaqMan and Northern blot analysis indicate BTNL2 is predominantly expressed in digestive tract tissues, in particular small intestine and Peyer’s patches. Immunohistochemistry with BTNL2-specific Abs further localizes BTNL2 to epithelial and dendritic cells within these tissues. Despite its homology to the B7 family, BTNL2 does not bind any of the known B7 family receptors such as CD28, CTLA-4, PD-1, ICOS, or B and T lymphocyte attenuator. Because of its localization in the gut and potential role in the immune system, BTNL2 expression was analyzed in a mouse model of inflammatory bowel disease. BTNL2 is overexpressed during both the asymptomatic and symptomatic phase of the Mdr1a knockout model of spontaneous colitis. In functional assays, soluble BTNL2-Fc protein inhibits the proliferation of murine CD4+ T cells from the spleen, mesenteric lymph node, and Peyer’s patch. In addition, BTNL2-Fc reduces proliferation and cytokine production from T cells activated by anti-CD3 and B7-related protein 1. These data suggest a role for BTNL2 as a negative costimulatory molecule with implications for inflammatory disease.
Secretory Antibody Formation: Conserved Binding Interactions between J Chain and Polymeric Ig Receptor from Humans and Amphibians
Authors: Braathen Ranveig , Hohman Valerie S. , Brandtzaeg Per , Johansen Finn-Eirik 
Published: April 2014

Abstract
Abs of the secretory Ig (SIg) system reinforce numerous innate defense mechanisms to protect the mucosal surfaces against microbial penetration. SIgs are generated by a unique cooperation between two distinct cell types: plasma cells that produce polymers of IgA or IgM (collectively called pIgs) and polymeric Ig receptor (pIgR)-expressing secretory epithelial cells that mediate export of the pIgs to the lumen. Apical delivery of SIgs occurs by cleavage of the pIgR to release its extracellular part as a pIg-bound secretory component, whereas free secretory components are derived from an unoccupied receptor. The joining chain (J chain) is crucial in pIg/SIg formation because it serves to polymerize Igs and endows them with a binding site for the pIgR. In this study, we show that the J chain from divergent tetrapods including mammals, birds, and amphibians efficiently induced polymerization of human IgA, whereas the J chain from nurse shark (a lower vertebrate) did not. Correctly assembled polymers showed high affinity to human pIgR. Sequence analysis of the J chain identified two regions, conserved only in tetrapods, which by mutational analysis were found essential for pIgA-pIgR complexing. Furthermore, we isolated and characterized pIgR from the amphibian Xenopus laevis and demonstrated that its pIg binding domain showed high affinity to human pIgA. These results showed that the functional site of interaction between pIgR, J chain and Ig H chains is conserved in these species and suggests that SIgs originated in an ancestor common to tetrapods.
Suppression of Early IL-4 Production Underlies the Failure of CD4 T Cells Activated by TLR-Stimulated Dendritic Cells to Differentiate into Th2 Cells
Authors: Sun Jie , Pearce Edward J. 
Published: April 2014

Abstract
Dendritic cells (DCs) activated through TLRs provide a potent negative signal for Th2 cell development that is independent of positive signals for Th1 cell development such as IL-12 and IFN-γ. In this study we demonstrate that the ability of TLR-activated DCs to suppress Th2 cell development is Ag dose-independent and unique to DCs that have been activated through TLRs vs by cytokines. We show that TLR-activated DCs inhibit early IL-4 production by CD4 T cells and thus inhibit their ability to subsequently increase GATA-3 expression and commit to the Th2 lineage. This occurs independently of expression of the GATA-3 antagonist T-bet. Although CD4 T cells activated by TLR-activated DCs make IL-2, they are not capable of phosphorylating STAT5 in response to this cytokine. This inhibition of responsiveness to IL-2 appears to underlie the failure to make early IL-4. Our findings suggest that DCs provide instructional signals for T cell differentiation before cytokine-mediated Th cell selection and outgrowth.
Fiber-Modified Adenovirus Vectors Decrease Liver Toxicity through Reduced IL-6 Production
Authors: Koizumi Naoya , Yamaguchi Tomoko , Kawabata Kenji , Sakurai Fuminori , Sasaki Tomomi , Watanabe Yoshiteru , Hayakawa Takao , Mizuguchi Hiroyuki 
Published: April 2014

Abstract
Adenovirus (Ad) vectors are one of the most commonly used viral vectors in gene therapy clinical trials. However, they elicit a robust innate immune response and inflammatory responses. Improvement of the therapeutic index of Ad vector gene therapy requires elucidation of the mechanism of Ad vector-induced inflammation and cytokine/chemokine production as well as development of the safer vector. In the present study, we found that the fiber-modified Ad vector containing poly-lysine peptides in the fiber knob showed much lower serum IL-6 and aspartate aminotransferase levels (as a maker of liver toxicity) than the conventional Ad vector after i.v. administration, although the modified Ad vector showed higher transgene production in the liver than the conventional Ad vector. RT-PCR analysis showed that spleen, not liver, is the major site of cytokine, chemokine, and IFN expression. Splenic CD11c+ cells were found to secret cytokines. The tissue distribution of Ad vector DNA showed that spleen distribution was much reduced in this modified Ad vector, reflecting reduced IL-6 levels in serum. Liver toxicity by the conventional Ad vector was reduced by anti-IL-6R Ab, suggesting that IL-6 signaling is involved in liver toxicity and that decreased liver toxicity of the modified Ad vector was due in part to the reduced IL-6 production. This study contributes to an understanding of the biological mechanism in innate immune host responses and liver toxicity toward systemically administered Ad vectors and will help in designing safer gene therapy methods that can reduce robust innate immunity and inflammatory responses.
C3a Is Required for the Production of CXC Chemokines by Tubular Epithelial Cells after Renal Ishemia/Reperfusion
Authors: Thurman Joshua M. , Lenderink Amanda M. , Royer Pamela A. , Coleman Kathrin E. , Zhou Jian , Lambris John D. , Nemenoff Raphael A. , Quigg Richard J. , Holers V. Michael 
Published: April 2014

Abstract
The complement system is one of the major ways by which the body detects injury to self cells, and the alternative pathway of complement is rapidly activated within the tubulointerstitium after renal ischemia/reperfusion (I/R). In the current study, we investigate the hypothesis that recognition of tubular injury by the complement system is a major mechanism by which the systemic inflammatory response is initiated. Gene array analysis of mouse kidney following I/R initially identified MIP-2 (CXCL2) and keratinocyte-derived chemokine (KC or CXCL1) as factors that are produced in a complement-dependent fashion. Using in situ hybridization, we next demonstrated that these factors are expressed in tubular epithelial cells of postischemic kidneys. Mouse proximal tubular epithelial cells (PTECs) in culture were then exposed to an intact alternative pathway and were found to rapidly produce both chemokines. Selective antagonism of the C3a receptor significantly attenuated production of MIP-2 and KC by PTECs, whereas C5a receptor antagonism and prevention of membrane attack complex (MAC) formation did not have a significant effect. Treatment of PTECs with an NF-κB inhibitor also prevented full expression of these factors in response to an intact alternative pathway. In summary, alternative pathway activation after renal I/R induces production of MIP-2 and KC by PTECs. This innate immune system thereby recognizes hypoxic injury and triggers a systemic inflammatory response through the generation of C3a and subsequent activation of the NF-κB system.
High Concentration of Antioxidants N-Acetylcysteine and Mitoquinone-Q Induces Intercellular Adhesion Molecule 1 and Oxidative Stress by Increasing Intracellular Glutathione
Authors: Mukherjee Tapan K. , Mishra Anurag K. , Mukhopadhyay Srirupa , Hoidal John R. 
Published: April 2014

Abstract
In endothelial cells, the intracellular level of glutathione is depleted during offering protection against proinflammatory cytokine TNF-α-induced oxidative stress. Administration of anti-inflammatory drugs, i.e., N-acetylcysteine (NAC) or mitoquinone-Q (mito-Q) in low concentrations in the human pulmonary aortic endothelial cells offered protection against depletion of reduced glutathione and oxidative stress mediated by TNF-α. However, this study addressed that administration of NAC or mito-Q in high concentrations resulted in a biphasic response by initiating an enhanced generation of both reduced glutathione and oxidized glutathione and enhanced production of reactive oxygen species, along with carbonylation and glutathionylation of the cellular proteins. This study further addressed that IκB kinase (IKK), a phosphorylation-dependent regulator of NF-κB, plays an important regulatory role in the TNF-α-mediated induction of the inflammatory cell surface molecule ICAM-1. Of the two catalytic subunits of IKK (IKKα and IKKβ), low concentrations of NAC and mito-Q activated IKKα activity, thereby inhibiting the downstream NF-κB and ICAM-1 induction by TNF-α. High concentrations of NAC and mito-Q instead caused glutathionylation of IKKα, thereby inhibiting its activity that in turn enhanced the downstream NF-κB activation and ICAM-1 expression by TNF-α. Thus, establishing IKKα as an anti-inflammatory molecule in endothelial cells is another focus of this study. This is the first report that describes a stressful situation in the endothelial cells created by excess of antioxidative and anti-inflammatory agents NAC and mito-Q, resulting in the generation of reactive oxygen species, carbonylation and glutathionylation of cellular proteins, inhibition of IKKα activity, and up-regulation of ICAM-1expression.
Identification of pH-Regulated Antigen 1 Released from Candida albicans as the Major Ligand for Leukocyte Integrin αMβ2
Authors: Soloviev Dmitry A. , Fonzi William A. , Sentandreu Rafael , Pluskota Elzbieta , Forsyth Christopher B. , Yadav Satya , Plow Edward F. 
Published: April 2014

Abstract
Candida albicans is a common opportunistic fungal pathogen and is the leading cause of invasive fungal disease in immunocompromised individuals. The induction of cell-mediated immunity to C. albicans is of critical importance in host defense and the prime task of cells of the innate immune system. We previously demonstrated that the integrin αMβ2 (CD11b/CD18) is the major leukocyte receptor involved in C. albicans recognition, mediating both adhesive and migratory responses to the fungus. In the present study, we demonstrate that various C. albicans strains release a protease-sensitive activity into their conditioned medium that supports αMβ2-mediated cell adhesion and migration. The isolation and characterization of this protein was undertaken by two independent approaches: 1) immunoaffinity purification on a mAb raised to conditioned medium which blocked αMβ2-dependent adhesion and migration; and 2) affinity chromatography on purified αMβ2. Each approach led to the isolation of the same protein, which was unequivocally identified as pH-regulated Ag 1 (Pra1p), based on mass spectrometry and amino acid sequence analyses. C. albicans mutant strains lacking Pra1p were unable to support leukocyte adhesion or migration. In a neutrophil-mediated fungal killing assay, such mutant strains were resistant to killing and/or phagocytosis. Addition of purified Pra1p or reagents that block αMβ2 function prevented killing of Pra1p-expressing but not Pra1p-deficient strains of C. albicans. Together, these data indicate that Pra1p is a ligand of αMβ2 on C. albicans and that the soluble form of Pra1p may assist the fungus in escaping host surveillance.
Differential CD40/CD40L Expression Results in Counteracting Antitumor Immune Responses
Authors: Murugaiyan Gopal , Agrawal Reena , Mishra Gyan C. , Mitra Debashis , Saha Bhaskar 
Published: April 2014

Abstract
Establishment of host-protective memory T cells against tumors is the objective of an antitumor immunoprophylactic strategy such as reinforcing T cell costimulation via CD40-CD40L interaction. Previous CD40-targeted strategies assumed that T cell costimulation is an all-or-none phenomenon. It was unknown whether different levels of CD40L expression induce quantitatively and qualitatively different effector T cell responses. Using mice expressing different levels of CD40L, we demonstrated that the greater the T cell CD40L expression the less tumor growth occurred; the antitumor T cell response was host-protective. Lower levels of CD40L expression on T cells induced IL-10-mediated suppression of tumor-regressing effector CD8+ T cells and higher productions of IL-4 and IL-10. Using mice expressing different levels of CD40 or by administering different doses of anti-CD40 Ab, similar observations were recorded implying that the induction of protumor or antitumor T cell responses was a function of the extent of CD40 cross-linking. IL-10 neutralization during priming with tumor Ags resulted in a stronger tumor-regressing effector T cell response. Using IL-10−/− DC for priming of mice expressing different levels of CD40L and subsequent transfer of the T cells from the primed mice to nu/nu mice, we demonstrated the protumor role of IL-10 in the induction of tumor-promoting T cells. Our results demonstrate that a dose-dependent cross-linking of a costimulatory molecule dictates the functional phenotype of the elicited effector T cell response. The T cell costimulation is a continuum of a function that induces not only graded T cell responses but also two counteracting responses at two extremes.
Cognate CD4+ Help Elicited by Resting Dendritic Cells Does Not Impair the Induction of Peripheral Tolerance in CD8+ T Cells
Authors: Steptoe Raymond J. , Ritchie Janine M. , Wilson Nicholas S. , Villadangos Jose A. , Lew Andrew M. , Harrison Leonard C. 
Published: April 2014

Abstract
Peripheral tolerance is required to prevent autoimmune tissue destruction by self-reactive T cells that escape negative selection in the thymus. One mechanism of peripheral tolerance in CD8+ T cells is their activation by resting dendritic cells (DC). In contrast, DC can be “licensed” by CD4+ T cells to induce cytotoxic function in CD8+ T cells. The question that then arises, whether CD4+ T cell help could impair peripheral tolerance induction in self-reactive CD8+ T cells, has not been addressed. In this study we show that CD4+ T cell activation by resting DC results in helper function that transiently promotes the expansion and differentiation of cognate CD8+ T cells. However, both the CD4+ and CD8+ T cell populations ultimately undergo partial deletion and acquire Ag unresponsiveness, disabling their ability to destroy OVA-expressing pancreatic β cells and cause diabetes. Thus, effective peripheral tolerance can be induced by resting DC in the presence of CD4+ and CD8+ T cells with specificity for the same Ag.
Natural Regulatory T Cells and De Novo-Induced Regulatory T Cells Contribute Independently to Tumor-Specific Tolerance
Authors: Zhou Gang , Levitsky Hyam I. 
Published: April 2014

Abstract
Thymus-derived, naturally occurring CD4+CD25+Foxp3+ regulatory T cells (nTregs) and Tregs induced in the periphery (iTregs) have both been implicated in regulating immune responses. However, the relationship between these populations in the same host, and their relative contribution to the overall Treg pool, has not been examined. Using a tumor-induced T cell tolerance model, we find that expansion of nTregs and de novo generation of iTregs both contribute to tumor-specific T cell tolerance. In this system in which the number of tumor-specific nTregs can be controlled, the efficiency of nTreg expansion significantly exceeds that of the induction of Tregs from uncommitted progenitors in the tumor-bearing host. However, pre-existing nTregs are neither required for the induction of Tregs nor measurably impact on the extent of their accumulation. Instead, induction of Ag-specific regulatory cells from naive cells is intrinsically influenced by the tumor microenvironment and the presence of tumor Ag.
Insect Baculoviruses Strongly Potentiate Adaptive Immune Responses by Inducing Type I IFN
Authors: Hervas-Stubbs Sandra , Rueda Paloma , Lopez Lissette , Leclerc Claude 
Published: April 2014

Abstract
Baculoviruses (BVs) are dsDNA viruses that are pathogenic for insects. They have been used worldwide as selective bioinsecticides and for producing recombinant proteins in insect cells. Surprisingly, despite their widespread use in research and industry and their dissemination in the environment, the potential effects of these insect viruses on the immune responses of mammals remain totally unknown. We show in this study that BVs have strong adjuvant properties in mice, promoting potent humoral and CD8+ T cell adaptive responses against coadministered Ag. BVs also induce the in vivo maturation of dendritic cells and the production of inflammatory cytokines. We demonstrate that BVs play a major role in the strong immunogenicity of virus-like particles produced in the BV-insect cell expression system. The presence of even small numbers of BVs among the recombinant proteins produced in the BV expression system may therefore strengthen the immunological properties of these proteins. This adjuvant behavior of BVs is mediated primarily by IFN-αβ, although mechanisms independent of type I IFN signaling are also involved. This study demonstrates that nonpathogenic insect viruses may have a strong effect on the mammalian immune system.