bluuebunny/crossref_metadata_2025_split huggingface dataset:
Dectin-1 Interaction with Mycobacterium tuberculosis Leads to Enhanced IL-12p40 Production by Splenic Dendritic Cells
Authors: Rothfuchs Antonio Gigliotti , Bafica Andre , Feng Carl G. , Egen Jackson G. , Williams David L. , Brown Gordon D. , Sher Alan 
Published: April 2014

Abstract
Dectin-1 is a fungal pattern recognition receptor that binds to β-glucans and triggers cytokine production by facilitating interaction with TLR2 or by directly activating spleen tyrosine kinase (Syk). To assess the possible role of Dectin-1 in the innate response to mycobacteria, we used an in vitro system in which IL-12p40 production is measured in splenic dendritic cells (SpDC) following exposure to live Mycobacterium tuberculosis bacilli. Treatment of SpDC with laminarin or glucan phosphate, two molecules known to block Dectin-1-dependent activity, led to a reduction in M. tuberculosis-induced IL-12p40 as well as IL-12p70 production. Moreover, SpDC from Dectin-1−/− chimeric mice displayed reduced IL-12p40 production in response to mycobacteria when compared with Dectin-sufficient DC. Laminarin treatment also inhibited mycobacterial-induced IL-12p40 production in DC from TLR2−/− mice, arguing that Dectin-1 functions independently of TLR2 signaling in this system. Importantly, a Dectin-1 fusion protein was found to directly bind to live mycobacteria in a laminarin-inhibitable manner indicating the presence of ligands for the receptor in the bacterium and laminarin pretreatment resulted in reduced association of mycobacteria to SpDC. In additional experiments, mycobacterial stimulation was shown to be associated with increased phosphorylation of Syk and this response was inhibited by laminarin. Furthermore, pharmacologic inhibition of Syk reduced the M. tuberculosis-induced IL-12p40 response. Together, these findings support a role for Dectin-1 in promoting M. tuberculosis-induced IL-12p40 production by DC in which the receptor augments bacterial-host cell interaction and enhances the subsequent cytokine response through an unknown mechanism involving Syk signaling.
Impaired Induction of CD27 and CD28 Predicts Naive CD4 T Cell Proliferation Defects in HIV Disease
Authors: Luciano Angel A. , Lederman Michael M. , Valentin-Torres Alice , Bazdar Douglas A. , Sieg Scott F. 
Published: April 2014

Abstract
Many immunological defects have been described in HIV disease, including a diminished capacity of naive CD4+ T cells to expand after TCR stimulation. The mechanisms underlying impaired naive CD4+ T cell expansion in HIV disease are not well described. Using a rigorous phenotypic definition of naive T cells, we found that cell cycle entry after TCR engagement was restricted to cells that increased surface expression of costimulatory molecules CD27 and CD28. Induction of these receptors, however, was not sufficient to result in cell cycle entry among the CD4+CD31− naive T cell subset. Analyses of cells from HIV-infected persons indicated that naive CD4+CD31+ T cells from these subjects were impaired in their ability to enter the cell cycle after stimulation and this impairment was predicted by the relatively poor induction of costimulatory molecules on these cells. Thus, failure to increase surface expression of costimulatory molecules may contribute to the naive T cell expansion failure that characterizes HIV infection.
IL-21 Induces Apoptosis of Antigen-Specific CD8+ T Lymphocytes
Authors: Barker Brianne R. , Parvani Jenny G. , Meyer Debra , Hey Adam S. , Skak Kresten , Letvin Norman L. 
Published: April 2014

Abstract
IL-21, a member of the common γ-chain family of cytokines, has pleiotropic effects on T, B, and NK cells. We found that IL-21 and the prototype common γ-chain cytokine IL-2 can stimulate proliferation and cytokine secretion by Ag-specific rhesus monkey CD8+ T cells. However, unique among the members of this family of cytokines, we found that IL-21 drives these cells to apoptosis by down-regulation of Bcl-2. These findings suggest that IL-21 may play an important role in the contraction of CD8+ T cell responses.
A Key Role for TGF-β Signaling to T Cells in the Long-Term Acceptance of Allografts
Authors: Daley Stephen R. , Ma Jianbo , Adams Elizabeth , Cobbold Stephen P. , Waldmann Herman 
Published: April 2014

Abstract
TGF-β is a key immunoregulatory cytokine which supports self-tolerance by signaling to T cells. In this report, we show a crucial role for TGF-β signaling to T cells in enabling the long-term acceptance of allografts, whether natural or induced therapeutically by coreceptor and costimulation blockade. The requirement for TGF-β appears most pronounced during the initial exposure to alloantigens. We demonstrate the ability of TGF-β to direct the development in vitro of regulatory cells that suppress graft rejection in vivo. Such suppression was not affected by anti-TGF-β treatment of the recipient mice. Despite this, TGF-β may still have a role in CD4+ cell-mediated suppression of antiallograft responses in vivo, since its neutralization can, in some cases, abrogate suppression. These results show that TGF-β signaling to T cells is dispensable for mounting destructive responses against skin allografts while appearing to be an essential intermediary in establishing long-term tolerance.
Intracellular Cysteine Residues in the Tail of MHC Class I Proteins Are Crucial for Extracellular Recognition by Leukocyte Ig-Like Receptor 1
Authors: Gruda Raizy , Achdout Hagit , Stern-Ginossar Noam , Gazit Roi , Betser-Cohen Gili , Manaster Irit , Katz Gil , Gonen-Gross Tsufit , Tirosh Boaz , Mandelboim Ofer 
Published: April 2014

Abstract
The activity of NK cells is regulated by activating receptors that recognize mainly stress-induced ligands and by inhibitory receptors that recognize mostly MHC class I proteins on target cells. Comparing the cytoplasmic tail sequences of various MHC class I proteins revealed the presence of unique cysteine residues in some of the MHC class I molecules which are absent in others. To study the role of these unique cysteines, we performed site specific mutagenesis, generating MHC class I molecules lacking these cysteines, and demonstrated that their expression on the cell surface was impaired. Surprisingly, we demonstrated that these cysteines are crucial for the surface binding of the leukocyte Ig-like receptor 1 inhibitory receptor to the MHC class I proteins, but not for the binding of the KIR2DL1 inhibitory receptor. In addition, we demonstrated that the cysteine residues in the cytoplasmic tail of MHC class I proteins are crucial for their egress from the endoplasmic reticulum and for their palmitoylation, thus probably affecting their expression on the cell surface. Finally, we show that the cysteine residues are important for proper extracellular conformation. Thus, although the interaction between leukocyte Ig-like receptor 1 and MHC class I proteins is formed between two extracellular surfaces, the intracellular components of MHC class I proteins play a crucial role in this recognition.
A Biochemical Signature for Rapid Recall of Memory CD4 T Cells
Authors: Chandok Meena R. , Okoye Francesca I. , Ndejembi Modesta P. , Farber Donna L. 
Published: April 2014

AbstractMechanisms for the rapid recall response mediated by memory T cells remain unknown. In this study, we present a novel, multiparameter analysis of TCR-coupled signaling and function in resting and activated naive and memory CD4 T cells, revealing a biochemical basis for immunological recall. We identify a striking elevation in expression of the proximal tyrosine kinase Zap70 in resting Ag-specific and polyclonal mouse memory vs naive CD4 T cells that is stably maintained independent of protein synthesis. Elevated Zap70 protein levels control effector function as IFN-γ production occurs exclusively from the Zap70high fraction of activated T cells in vitro and in vivo, and specific down-modulation of Zap70 expression in memory CD4 T cells by small interfering RNA or protein inhibition significantly reduces rapid IFN-γ production. Downstream of Zap70, we show quantitative differences in distal phosphorylation associated with effector function in naive and memory subsets, with low accumulation of phosphorylation in memory T cells producing IFN-γ at early time points, contrasting extensive phosphorylation associated with IFN-γ production following sustained activation of naive T cells. Our results reveal a novel biochemical signature imparted to memory CD4 T cells enabling efficacious responses through increased Zap70 expression and reduced accumulation of downstream signaling events.
T Cell Lineage Determination Precedes the Initiation of TCRβ Gene Rearrangement
Authors: Masuda Kyoko , Kakugawa Kiyokazu , Nakayama Toshinori , Minato Nagahiro , Katsura Yoshimoto , Kawamoto Hiroshi 
Published: April 2014

Abstract
Loss of dendritic cell potential is one of the major events in intrathymic T cell development, during which the progenitors become determined to the T cell lineage. However, it remains unclear whether this event occurs in synchrony with another important event, TCRβ chain gene rearrangement, which has been considered the definitive sign of irreversible T cell lineage commitment. To address this issue, we used transgenic mice in which GFP expression is controlled by the lck proximal promoter. We found that the double-negative (DN) 2 stage can be subdivided into GFP− and GFP+ populations, representing functionally different developmental stages in that the GFP−DN2, but not GFP+DN2, cells retain dendritic cell potential. The GFP+DN2 cells were found to undergo several rounds of proliferation before the initiation of TCRβ rearrangement as evidenced by the diversity of D-Jβ rearrangements seen in T cells derived from a single GFP+DN2 progenitor. These results indicated that the determination step of progenitors to the T cell lineage is a separable event from TCRβ rearrangement.
IFN-α Is Not Sufficient to Drive Th1 Development Due to Lack of Stable T-bet Expression
Authors: Ramos Hilario J. , Davis Ann M. , George Thaddeus C. , Farrar J. David 
Published: April 2014

Abstract
During inflammatory immune responses, the innate cytokine IL-12 promotes CD4+ Th-1 development through the activation of the second messenger STAT4 and the subsequent expression of T-bet. In addition, type I IFN (IFN-αβ), secreted primarily during viral and intracellular bacterial infections, can promote STAT4 activation in human CD4+ T cells. However, the role of IFN-αβ in regulating Th1 development is controversial, and previous studies have suggested a species-specific pathway leading to Th1 development in human but not mouse CD4+ T cells. In this study, we found that although both IFN-α and IL-12 can promote STAT4 activation, IFN-α failed to promote Th1 commitment in human CD4+ T cells. The difference between these innate signaling pathways lies with the ability of IL-12 to promote sustained STAT4 tyrosine phosphorylation, which correlated with stable T-bet expression in committed Th1 cells. IFN-α did not promote Th1 development in human CD4+ T cells because of attenuated STAT4 phosphorylation, which was insufficient to induce stable expression of T-bet. Further, the defect in IFN-α-driven Th1 development was corrected by ectopic expression of T-bet within primary naive human CD4+ T cells. These results indicate that IL-12 remains unique in its ability to drive Th1 development in human CD4+ T cells and that IFN-α lacks this activity due to its inability to promote sustained T-bet expression.
Bruton’s Tyrosine Kinase Mediates NF-κB Activation and B Cell Survival by B Cell-Activating Factor Receptor of the TNF-R Family
Authors: Shinners Nicholas P. , Carlesso Gianluca , Castro Iris , Hoek Kristen L. , Corn Radiah A. , Woodland Robert L. , Scott Martin L. , Wang Demin , Khan Wasif N. 
Published: April 2014

AbstractLoss of Bruton’s tyrosine kinase (Btk) function results in mouse Xid disease characterized by a reduction in mature B cells and impaired humoral immune responses. These defects have been mainly attributed to impaired BCR signaling including reduced activation of the classical NF-κB pathway. In this study we show that Btk also couples the receptor for B cell-activating factor (BAFF) of the TNF family (BAFF-R) to the NF-κB pathway. Loss of Btk results in defective BAFF-mediated activation of both classical and alternative NF-κB pathways. Btk appears to regulate directly the classical pathway in response to BAFF such that Btk-deficient B cells exhibit reduced kinase activity of IκB kinase γ-containing complexes and defective IκBα degradation. In addition, Btk-deficient B cells produce reduced levels of NF-κB2 (p100) basally and in response to stimulation via the BCR or BAFF-R, resulting in impaired activation of the alternative NF-κB pathway by BAFF. These results suggest that Btk regulates B cell survival by directly regulating the classical NF-κB pathway under both BCR and BAFF-R, as well as by inducing the expression of the components of alternative pathway for sustained NF-κB activation in response BAFF. Thus, impaired BCR- and BAFF-induced signaling to NF-κB may contribute to the observed defects in B cell survival and humoral immune responses in Btk-deficient mice.
CD8+ T Cell Protective Immunity against Chlamydia pneumoniae Includes an H2-M3-Restricted Response That Is Largely CD4+ T Cell-Independent
Authors: Tvinnereim Amy , Wizel Benjamin 
Published: April 2014

Abstract
CD8+ T cells are important for immunity to the intracellular bacterial pathogen Chlamydia pneumoniae (Cpn). Recently, we reported that type 1 CD8+ (Tc1) from Cpn-infected B6 mice recognize peptides from multiple Cpn Ags in a classical MHC class Ia-restricted fashion. In this study, we show that Cpn infection also induces nonclassical MHC class Ib-(H2-M3)-restricted CD8+ T cell responses. H2-M3-binding peptides representing the N-terminal formylated sequences from five Cpn Ags sensitized target cells for lysis by cytolytic effectors from the spleens of infected B6 mice. Of these, only peptides fMFFAPL (P1) and fMLYWFL (P4) stimulated IFN-γ production by infection-primed splenic and pulmonary CD8+ T cells. Studies with Cpn-infected Kb−/−/Db−/− mice confirmed the Tc1 cytokine profile of P1- and P4-specific CD8+ T cells and revealed the capacity of these effectors to exert in vitro H2-M3-restricted lysis of Cpn-infected macrophages and in vivo pulmonary killing of P1- and P4-coated splenocytes. Furthermore, adoptive transfer of P1- and P4-specific CD8+ T cells into naive Kb−/−/Db−/− mice reduced lung Cpn loads following challenge. Finally, we show that in the absence of MHC class Ia-restricted CD8+ T cell responses, CD4+ T cells are largely expendable for the control of Cpn growth, and for the generation, memory maintenance, and secondary expansion of P1- and P4-specific CD8+ T cells. These results suggest that H2-M3-restricted CD8+ T cells contribute to protective immunity against Cpn, and that chlamydial Ags presented by MHC class Ib molecules may represent novel targets for inclusion in anti-Cpn vaccines.
Critical Negative Regulation of Type 1 T Cell Immunity and Immunopathology by Signaling Adaptor DAP12 during Intracellular Infection
Authors: Divangahi Maziar , Yang Tony , Kugathasan Kapilan , McCormick Sarah , Takenaka Shunsuke , Gaschler Gordon , Ashkar Ali , Stampfli Martin , Gauldie Jack , Bramson Jonathan , Takai Toshiyuki , Brown Earl , Yokoyama Wayne M. , Aoki Naoko , Xing Zhou 
Published: April 2014

Abstract
Transmembrane signaling adaptor DAP12 has increasingly been recognized for its important role in innate responses. However, its role in the regulation of antimicrobial T cell responses has remained unknown. In our current study, we have examined host defense, T cell responses, and tissue immunopathology in models of intracellular infection established in wild-type and DAP12-deficient mice. During mycobacterial infection, lack of DAP12 leads to pronounced proinflammatory and Th1 cytokine responses, overactivation of Ag-specific CD4 and CD8 T cells of type 1 phenotype, and heightened immunopathology both in the lung and lymphoid organs. DAP12-deficient airway APC display enhanced NF-κB activation and cytokine responses upon TLR stimulation or mycobacterial infection in vitro. Of importance, adoptive transfer of Ag-loaded DAP12-deficient APC alone could lead to overactivation of transferred transgenic or endogenous wild-type T cells in vivo. We have further found that the immune regulatory role by DAP12 is not restricted only to intracellular bacterial infection, since lack of this molecule also leads to uncontrolled type 1 T cell activation and severe immunopathology and tissue injury during intracellular viral infection. Our study thus identifies DAP12 as an important novel immune regulatory molecule that acts, via APC, to control the level of antimicrobial type 1 T cell activation and immunopathology.
Plasmid-Deficient Chlamydia muridarum Fail to Induce Immune Pathology and Protect against Oviduct Disease
Authors: O’Connell Catherine M. , Ingalls Robin R. , Andrews Charles W. , Scurlock Amy M. , Darville Toni 
Published: April 2014

Abstract
Chlamydia trachomatis is the most prevalent sexually transmitted bacterial infection in the world. In women, genital infection can cause endometritis and pelvic inflammatory disease with the severe sequelae of ectopic pregnancy or infertility. Chlamydia sp. do not damage tissues directly, but induce an injurious host inflammatory response at the infected site. In the murine model of genital disease with Chlamydia muridarum, TLR2 plays a role in both early production of inflammatory mediators and development of chronic oviduct pathology. We report the results of studies with plasmid-cured C. muridarum mutants that retain the ability to infect the murine genital tract, but fail to cause disease in the oviduct. These mutants do not stimulate TLR2-dependent cytokine production in mice, nor in innate immune cells or epithelial cells in vitro. They induce an effective Th1 immune response, with no evidence for Th1-immune-mediated collateral tissue damage. Furthermore, mice previously infected with the plasmid-deficient strains are protected against oviduct disease upon challenge with virulent C. muridarum. If plasmid-cured derivatives of human C. trachomatis biovars exhibit similar phenotypic characteristics, they have the potential to serve as vaccines to prevent human disease.
Chloride Movements in Human Neutrophils during Phagocytosis: Characterization and Relationship to Granule Release
Authors: Busetto Sara , Trevisan Elisa , Decleva Eva , Dri Pietro , Menegazzi Renzo 
Published: April 2014

Abstract
Chloride ion efflux is an early event occurring after exposure of human neutrophils to several soluble agonists. Under these circumstances, a rapid and reversible fall in the high basal intracellular chloride (Cl−i) levels is observed. This event is thought to play a crucial role in the modulation of several critical neutrophil responses including activation and up-regulation of adhesion molecules, cell attachment and spreading, cytoplasmic alkalinization, and activation of the respiratory burst. At present, however, no data are available on chloride ion movements during neutrophil phagocytosis. In this study, we provide evidence that phagocytosis of Candida albicans opsonized with either whole serum, complement-derived opsonins, or purified human IgG elicits an early and long-lasting Cl− efflux accompanied by a marked, irreversible loss of Cl−i. Simultaneous assessment of Cl− efflux and phagocytosis in cytochalasin D-treated neutrophils indicated that Cl− efflux occurs without particle ingestion. These results suggest that engagement of immune receptors is sufficient to promote chloride ion movements. Several structurally unrelated chloride channel blockers inhibited phagocytosis-induced Cl− efflux as well as the release of azurophilic—but not specific—granules. It implicates that different neutrophil secretory compartments display distinct sensitivity to Cl−i modifications. Intriguingly, inhibitors of Cl− exchange inhibited cytosolic Ca2+ elevation, whereas Cl− efflux was not impaired in Ca2+-depleted neutrophils. We also show that FcγR(s)- and CR3/CR1-mediated Cl− efflux appears to be dependent on protein tyrosine phosphorylation but independent of PI3K and phospholipase C activation.
IL-17 Enhances Chemokine Gene Expression through mRNA Stabilization
Authors: Hartupee Justin , Liu Caini , Novotny Michael , Li Xiaoxia , Hamilton Thomas 
Published: April 2014

Abstract
IL-17 plays an important role in host defense and autoimmunity via the induction of proinflammatory gene expression, particularly in combination with TNF-α. The molecular mechanisms by which IL-17 regulates such expression are not well understood. Using the mouse chemokine CXCL1 (KC) gene as a model, we have examined the effects of IL-17 alone or in combination with TNF-α on transcriptional and posttranscriptional events. Although treatment of mouse embryonic fibroblasts with IL-17 alone only modestly increased KC expression, the combination of IL-17 with TNF-α induced a synergistic response. IL-17 treatment exerted a strong posttranscriptional effect by extending the t1/2 of the highly unstable, TNF-α-induced KC mRNA. Using a tetracycline-regulated transgene in HeLa cells, we determined that IL-17 treatment alone promoted stabilization of KC mRNA in the absence of TNF-α. IL-17 treatment exerted little effect on KC transcription or NF-κB activation, suggesting that it primarily acts posttranscriptionally. We identified a number of other mRNAs whose t1/2 are prolonged in response to IL-17, suggesting that this is a common mechanism by which IL-17 promotes enhanced gene expression. Finally, activator of NF-κB1 protein (Act1), an adaptor protein recently implicated in IL-17 signaling, was necessary for IL-17-induced stabilization, and overexpression of Act1 resulted in stabilization of KC mRNA, indicating that events downstream of Act1 are sufficient to initiate this process. Thus, the synergy between TNF-α and IL-17 reflects their independent actions on KC gene expression; TNF-α serves as a stimulus to initiate transcription through activation of NF-κB, whereas IL-17 drives mRNA stabilization through an Act1-dependent pathway.
Hydrogen Sulfide Up-Regulates Substance P in Polymicrobial Sepsis-Associated Lung Injury
Authors: Zhang Huili , Hegde Akhil , Ng Siaw Wei , Adhikari Sharmila , Moochhala Shabbir M. , Bhatia Madhav 
Published: April 2014

Abstract
Hydrogen sulfide (H2S) has been shown to induce the activation of neurogenic inflammation especially in normal airways and urinary bladder. However, whether endogenous H2S would regulate sepsis-associated lung inflammation via substance P (SP) and its receptors remains unknown. Therefore, the aim of the study was to investigate the effect of H2S on the pulmonary level of SP in cecal ligation and puncture (CLP)-induced sepsis and its relevance to lung injury. Male Swiss mice or male preprotachykinin-A gene knockout (PPT-A−/−) mice and their wild-type (PPT-A+/+) mice were subjected to CLP-induced sepsis. DL-propargylglycine (50 mg/kg i.p.), an inhibitor of H2S formation was administered either 1 h before or 1 h after the induction of sepsis, while NaHS, an H2S donor, was given at the same time as CLP. L703606, an inhibitor of the neurokinin-1 receptor was given 30 min before CLP. DL-propargylglycine pretreatment or posttreatment significantly decreased the PPT-A gene expression and the production of SP in lung whereas administration of NaHS resulted in a further rise in the pulmonary level of SP in sepsis. PPT-A gene deletion and pretreatment with L703606 prevented H2S from aggravating lung inflammation. In addition, septic mice genetically deficient in PPT-A gene or pretreated with L703606 did not exhibit further increase in lung permeability after injection of NaHS. The present findings show for the first time that in sepsis, H2S up-regulates the generation of SP, which contributes to lung inflammation and lung injury mainly via activation of the neurokinin-1 receptor.