bluuebunny/crossref_metadata_2025_split huggingface dataset:
Exacerbation of Granuloma Formation in IL-1 Receptor Antagonist-Deficient Mice with Impaired Dendritic Cell Maturation Associated with Th2 Cytokine Production
Authors: Iizasa Hisashi , Yoneyama Hiroyuki , Mukaida Naofumi , Katakoka Yuki , Naito Makoto , Yoshida Nobuaki , Nakashima Emi , Matsushima Kouji 
Published: April 2014

AbstractDendritic cell (DC) maturation at the site of inflammation and migration into draining lymph nodes is fundamental to initiate Ag-specific immune responses. Although several proinflammatory cytokines, including IL-1, are known to promote DC maturation in vitro, their contributions to DC activation and migration within peripheral inflamed tissue compartments are not yet fully understood. We show here that endogenous IL-1 receptor antagonist (IL-1ra) controls the activation state of liver-recruited DCs and their migration in a Propionibacterium acnes-induced murine granulomatous liver disease model. After P. acnes treatment, formation of portal tract-associated lymphoid tissue was conversely impaired in IL-1ra-deficient mice. IL-1ra-deficient mice developed hepatic granulomas within 3 days after P. acnes administration and showed a more pronounced granuloma formation than wild-type mice. Although sinusoidal granulomas contained numerous CD11c+ DCs at day 7, expressions of CCR7, IL-12p40 by these DCs were dramatically decreased in IL-1ra-deficient mice, suggesting aberrant DC maturation and sinusoid portal migration in the absence of endogenous IL-1ra. This was accompanied with enhanced intrahepatic Th2 cytokine production and severe hepatocellular damage. Thus, hepatocyte-derived IL-1ra may control optimal activation and migration of inflammatory DCs within the liver and thereby determine the local immune responses in granulomatous liver disease.
Δ-9-Tetrahydrocannabinol Enhances Breast Cancer Growth and Metastasis by Suppression of the Antitumor Immune Response
Authors: McKallip Robert J. , Nagarkatti Mitzi , Nagarkatti Prakash S. 
Published: April 2014

Abstract
In the current study, we tested the central hypothesis that exposure to Δ-9-tetrahydrocannabinol (Δ9-THC), the major psychoactive component in marijuana, can lead to enhanced growth of tumors that express low to undetectable levels of cannabinoid receptors by specifically suppressing the antitumor immune response. We demonstrated that the human breast cancer cell lines MCF-7 and MDA-MB-231 and the mouse mammary carcinoma 4T1 express low to undetectable levels of cannabinoid receptors, CB1 and CB2, and that these cells are resistant to Δ9-THC-induced cytotoxicity. Furthermore, exposure of mice to Δ9-THC led to significantly elevated 4T1 tumor growth and metastasis due to inhibition of the specific antitumor immune response in vivo. The suppression of the antitumor immune response was mediated primarily through CB2 as opposed to CB1. Furthermore, exposure to Δ9-THC led to increased production of IL-4 and IL-10, suggesting that Δ9-THC exposure may specifically suppress the cell-mediated Th1 response by enhancing Th2-associated cytokines. This possibility was further supported by microarray data demonstrating the up-regulation of a number of Th2-related genes and the down-regulation of a number of Th1-related genes following exposure to Δ9-THC. Finally, injection of anti-IL-4 and anti-IL-10 mAbs led to a partial reversal of the Δ9-THC-induced suppression of the immune response to 4T1. Such findings suggest that marijuana exposure either recreationally or medicinally may increase the susceptibility to and/or incidence of breast cancer as well as other cancers that do not express cannabinoid receptors and are resistant to Δ9-THC-induced apoptosis.
CD38 Controls ADP-Ribosyltransferase-2-Catalyzed ADP-Ribosylation of T Cell Surface Proteins
Authors: Krebs Christian , Adriouch Sahil , Braasch Fenja , Koestner Wolfgang , Leiter Edward H. , Seman Michel , Lund Frances E. , Oppenheimer Norman , Haag Friedrich , Koch-Nolte Friedrich 
Published: April 2014

AbstractADP-ribosyltransferase-2 (ART2), a GPI-anchored, toxin-related ADP-ribosylating ectoenzyme, is prominently expressed by murine T cells but not by B cells. Upon exposure of T cells to NAD, the substrate for ADP-ribosylation, ART2 catalyzes ADP-ribosylation of the P2X7 purinoceptor and other functionally important cell surface proteins. This in turn activates P2X7 and induces exposure of phosphatidylserine and shedding of CD62L. CD38, a potent ecto-NAD-glycohydrolase, is strongly expressed by most B cells but only weakly by T cells. Following incubation with NAD, CD38-deficient splenocytes exhibited lower NAD-glycohydrolase activity and stronger ADP-ribosylation of cell surface proteins than their wild-type counterparts. Depletion of CD38high cells from wild-type splenocytes resulted in stronger ADP-ribosylation on the remaining cells. Similarly, treatment of total splenocytes with the CD38 inhibitor nicotinamide 2′-deoxy-2′-fluoroarabinoside adenine dinucleotide increased the level of cell surface ADP-ribosylation. Furthermore, the majority of T cells isolated from CD38-deficient mice “spontaneously” exposed phosphatidylserine and lacked CD62L, most likely reflecting previous encounter with ecto-NAD. Our findings support the notion that ecto-NAD functions as a signaling molecule following its release from cells by lytic or nonlytic mechanisms. ART2 can sense and translate the local concentration of ecto-NAD into corresponding levels of ADP-ribosylated cell surface proteins, whereas CD38 controls the level of cell surface protein ADP-ribosylation by limiting the substrate availability for ART2.
Identification of Stimulating and Inhibitory Epitopes within the Heat Shock Protein 70 Molecule That Modulate Cytokine Production and Maturation of Dendritic Cells
Authors: Wang Yufei , Whittall Trevor , McGowan Edward , Younson Justine , Kelly Charles , Bergmeier Lesley A. , Singh Mahavir , Lehner Thomas 
Published: April 2014

AbstractThe 70-kDa microbial heat shock protein (mHSP70) has a profound effect on the immune system, interacting with the CD40 receptor on DC and monocytes to produce cytokines and chemokines. The mHSP70 also induces maturation of dendritic cells (DC) and thus acts as an alternative ligand to CD40L on T cells. In this investigation, we have identified a cytokine-stimulating epitope (peptide 407–426), by activating DC with overlapping synthetic peptides (20-mers) derived from the sequence of mHSP70. This peptide also significantly enhances maturation of DC stimulated by mHSP70 or CD40L. The epitope is located at the base of the peptide-binding groove of HSP70 and has five critical residues. Furthermore, an inhibitory epitope (p457–496) was identified downstream from the peptide-binding groove that inhibits cytokine production and maturation of DC stimulated by HSP70 or CD40L. The p38 MAP kinase phosphorylation is critical in the alternative CD40-HSP70 pathway and is inhibited by p457–496 but enhanced by p407–426.
Nucleosome, the Main Autoantigen in Systemic Lupus Erythematosus, Induces Direct Dendritic Cell Activation via a MyD88-Independent Pathway: Consequences on Inflammation
Authors: Decker Patrice , Singh-Jasuja Harpreet , Haager Sabine , Kötter Ina , Rammensee Hans-Georg 
Published: April 2014

AbstractNucleosome is the major autoantigen in systemic lupus erythematosus. It is found as a circulating complex in the sera of patients and seems to play a key role in disease development. In this study, we show for the first time that physiologic concentrations of purified nucleosomes directly induce in vitro dendritic cell (DC) maturation of mouse bone marrow-derived DC, human monocyte-derived DC (MDDC), and purified human myeloid DC as observed by stimulation of allogenic cells in MLR, cytokine secretion, and CD86 up-regulation. Importantly, nucleosomes act as free complexes without the need for immune complex formation or for the presence of unmethylated CpG DNA motifs, and we thus identified a new mechanism of DC activation by nucleosomes. We have clearly demonstrated that this activation is nucleosome-specific and endotoxin-independent. Particularly, nucleosomes induce MDDC to secrete cytokines known to be detected in high concentrations in the sera of patients. Moreover, activated MDDC secrete IL-8, a neutrophil chemoattractant also detected in patient sera, and thus might favor the inflammation observed in patients. Both normal and lupus MDDC are sensitive to nucleosome-induced activation. Finally, injection of purified nucleosomes to normal mice induces in vivo DC maturation. Altogether, these results strengthen the key role of nucleosomes in systemic lupus erythematosus and might explain how peripheral tolerance is broken in patients.
Amelioration of Established Experimental Autoimmune Encephalomyelitis by an MHC Anchor-Substituted Variant of Proteolipid Protein 139–151
Authors: Margot Carrie D. , Ford Mandy L. , Evavold Brian D. 
Published: April 2014

AbstractMurine experimental autoimmune encephalomyelitis (EAE) is a CD4+ T cell-mediated autoimmune disorder directed against myelin proteins within the CNS. We propose that variant peptides containing amino acid substitutions at MHC anchor residues will provide a unique means to controlling the polyclonal autoimmune T cell response. In this study, we have identified an MHC variant of proteolipid protein (PLP) 139–151 (145D) that renders PLP139–151-specific T cell lines anergic in vitro, as defined by a significant reduction in proliferation and IL-2 production following challenge with wild-type peptide. In vivo administration of 145D before challenge with PLP139–151 results in a significant reduction in disease severity and incidence. Importantly, we demonstrate the ability of an MHC variant peptide to ameliorate established EAE. An advantage to this treatment is that the MHC variant peptide does not induce an acute hypersensitivity reaction. This is in contrast to previous work in the PLP139–151 model demonstrating that anaphylactic shock resulting in death occurs upon rechallenge with the encephalitogenic peptide. Taken together, these data demonstrate the effectiveness of MHC anchor-substituted peptides in the treatment of EAE and suggest their utility in the treatment of other autoimmune disorders.
Small Rho GTPases Regulate Antigen Presentation in Dendritic Cells
Authors: Shurin Galina V. , Tourkova Irina L. , Chatta Gurkamal S. , Schmidt Gudula , Wei Sheng , Djeu Julie Y. , Shurin Michael R. 
Published: April 2014

Abstract
Dendritic cells (DC) are involved in the regulation of innate and adaptive immunity. However, the molecular mechanisms maintaining DC function remain to be elucidated. In this study, we report on the role of small Rho GTPases: Cdc42, Rac1, and RhoA in the regulation of DC adherence, Ag presentation, migration, chemotaxis, and endocytosis. Murine DC were transfected with vaccinia virus-based constructs, encoding dominant-negative or constitutively active (ca) mutant forms of Rho GTPases. We demonstrate that Cdc42 plays a major role in the regulation of DC adhesion, because caCdc42-transfected DC had significant up-regulation of adhesion to extracellular matrix, which was blocked by the Rho GTPase inhibitor toxin B (ToxB). In contrast, caRho-transfected DC only modestly elevated DC adhesion, and caRac had no effect. Additionally, caCdc42 and caRho increased the ability of DC to present OVA peptide to specific T cells. This effect was abrogated by ToxB. Activation of Cdc42 in DC significantly inhibited spontaneous and chemokine-induced DC migration. Furthermore, uptake of dextran 40 by DC was significantly enhanced by Rho GTPase activators cytotoxic necrotizing factor 1 and PMA, and reduced by ToxB. caCdc42 also increased endocytotic activity of DC, whereas dominant-negative Cdc42 blocked it. Thus, Rho GTPases Cdc42, RhoA, and Rac1 regulate DC functions that are critical for DC-mediated immune responses in vivo.
The Role of Intercellular Adhesion Molecule-1/LFA-1 Interactions in the Generation of Tumor-Specific CD8+ T Cell Responses
Authors: Jenkinson S. Rhiannon , Williams Neil A. , Morgan David J. 
Published: April 2014

AbstractThe activation of naive CD4+ T cells requires both TCR engagement and a second costimulatory signal mediated by the interaction of CD28 with CD80/CD86 expressed on professional APC. However, the situation for naive CD8+ T cells is less clear. Although evidence indicates that induction of CD8+ T cell responses is also dependent on professional APC, the ability of some tumors, which do not express CD80/CD86, to induce CTL suggests that other pathways of costimulation exist for the activation of CD8+ T cells. We examined the ability of tumor cells expressing different levels of a tumor-specific Ag to directly prime CD8+ T cells. We demonstrate that CD8+ T cells are directly activated by tumor cells in a CD80/CD86-CD28 independent manner. In this system, costimulation requires ICAM-1/LFA-1 interaction. This results in the generation of CTL capable of inhibiting tumor growth in vivo, and maintaining long-term survival.
Quantitating Effector and Regulatory T Lymphocytes in Immune Responses by Limiting Dilution Analysis Modeling
Authors: Bonnefoix Thierry , Bonnefoix Philippe , Perron Pascal , Mi Jian-Qing , Ng Wan Fai , Lechler Robert , Bensa Jean-Claude , Cahn Jean-Yves , Leroux Dominique 
Published: April 2014

AbstractAlthough there is currently no doubt that regulatory lymphocytes represent a master player in the immune system, a major unresolved problem is the accurate quantitation of these cells among unfractionated cell populations. This difficulty mainly arises because there are no specific immunophenotypic markers that can reliably discriminate between effector and regulatory lymphocytes. To face this problem, we have developed computational models of limiting dilution analyses addressing the question of the accurate estimation of the frequencies of effector and regulatory cells functionally engaged in an immune response. A set of generic equations were provided to form a framework for modeling limiting dilution data, enabling discrimination between qualitatively different models of suppression. These models include either one or two subpopulations of regulatory cells, featured by either low or potent regulatory activity. The potential of this modeling approach was illustrated by the accurate determination of the frequencies of effector and regulatory T lymphocytes in one real limiting dilution experiment of CD4+CD25+ T lymphocytes performed in the context of an allogeneic response in the human system. The crucial advantage of the limiting dilution method over the “static, phenotype-based” method is the dynamic evaluation of effector and regulatory T cell biology through their actual functional activity.
A Role for Caspases in Controlling IL-4 Expression in T Cells
Authors: Sehra Sarita , Patel Dipak , Kusam Saritha , Wang Zheng-Yu , Chang Cheong-Hee , Dent Alexander L. 
Published: April 2014

AbstractAlthough caspase activation is critical for T cell proliferation following activation, the role of caspases in T cell differentiation is unclear. In this study, we have examined the effect of inhibition of caspases on the process of Th1/Th2 differentiation. Naive CD4+ T cells activated under neutral differentiation conditions in the presence of the pan caspase inhibitor benzyloxycarbonyl-Val-Ala-Asp (Z-VAD) fluoromethylketone showed increased Th2 cell differentiation concomitant with an up-regulation of GATA-3. Z-VAD induced optimal Th2 differentiation when T cells were stimulated under strong primary activation conditions. Treatment of naive CD4+ T cells with Z-VAD under strong activation conditions led to a 6-fold increase in IL-4 mRNA compared with control-treated T cells. The Z-VAD-induced increase in IL-4 transcription occurred within 24 h of activation and was independent of Stat6. IFN-γ mRNA expression was not affected by Z-VAD at the 24-h time point. Z-VAD did not augment IL-4 expression from a committed Th2 cell, suggesting that caspases regulate IL-4 expression specifically during primary T cell activation. Z-VAD did not augment IL-12-driven Th1 differentiation. Activation of T cells in the presence of Z-VAD led to a specific increase in the expression of the transcription factor c-fos. Lastly, retrovirus-mediated expression of the antiapoptotic protein Bcl-2 resulted in an enhancement of Th2 cytokine expression, suggesting that inhibition of caspase activation by Bcl-2 can also modulate IL-4 expression. These findings reveal a novel regulatory mechanism of cytokine expression by caspases, and may explain how signaling pathways that inhibit apoptosis tend to promote Th2 differentiation.
Transplantation Tolerance in NF-κB-Impaired Mice Is Not Due to Regulation but Is Prevented by Transgenic Expression of Bcl-xL
Authors: Zhou Ping , Balin Samuel J. , Mashayekhi Mona , Hwang Kwang Woo , Palucki David A. , Alegre Maria-Luisa 
Published: April 2014

AbstractNF-κB is a key regulator of transcription after TCR and costimulatory receptor ligation. To determine the role of T cell-intrinsic NF-κB activation in acute allograft rejection, we used IκBαΔN-Tg mice (H-2b) that express an inhibitor of NF-κB restricted to the T cell compartment. We have previously shown that these mice permanently accept fully allogeneic (H-2d) cardiac grafts and secondary donor skin grafts, and that splenocytes from these tolerant mice have reduced alloreactivity when restimulated in vitro. These results were compatible with either deletion or suppression of allospecific T cells as possible mechanisms of tolerance. The aim of this study was to investigate the mechanism of transplant tolerance in these mice. IκBαΔN-Tg mice did not have increased numbers or function of CD4+CD25+ regulatory T cells either before or after cardiac transplantation. In addition, tolerance could not be transferred to fresh NF-κB-competent T cells and was not permissive for linked suppression to skin grafts sharing donor and third-party alloantigens, suggesting that dominant suppression is not the mechanism by which IκBαΔN-Tg mice achieve tolerance. In contrast, overexpression of the antiapoptotic protein Bcl-xL in T cells from IκBαΔN-Tg mice resulted in effective rejection of cardiac allografts and correlated with an increased frequency of splenocytes producing IFN-γ in response to alloantigen. Together, these results suggest that the death of alloreactive T cells may be partly responsible for the transplantation tolerance observed in mice with defective T cell-intrinsic NF-κB activation.
Solvent Accessibility of Native and Hydrolyzed Human Complement Protein 3 Analyzed by Hydrogen/Deuterium Exchange and Mass Spectrometry
Authors: Winters Michael S. , Spellman Daniel S. , Lambris John D. 
Published: April 2014

AbstractComplement protein C3 is a 187-kDa (1641-aa) protein that plays a key role in complement activation and immune responses. Its hydrolyzed form, C3(H2O), is responsible for the initiation of the activation of alternative complement pathway. Previous analyses using mAbs, anilinonaphthalenesulfonate dyes, and functional studies have suggested that C3 is conformationally different from C3(H2O). We have used amide hydrogen/deuterium exchange and MALDI-TOF mass spectrometry to identify and localize structural differences between native C3 and C3(H2O). Both proteins were incubated in D2O for varying amounts of time, digested with pepsin, and then subjected to mass-spectrometric analysis. Of 111 C3 peptides identified in the MALDI-TOF analysis, 31 had well-resolved isotopic mass envelopes in both C3 and C3(H2O) spectra. Following the conversion of native C3 to C3(H2O), 17 of these 31 peptides exhibited a change in deuterium incorporation, suggesting a conformational change in these regions. Among the identified peptides, hydrogen/deuterium exchange data were obtained for peptides 944–967, 1211–1228, 1211–1231, 1259–1270, 1259–1273, 1295–1318, and 1319–1330, which span the factor H binding site on C3d and factor I cleavage sites, and peptides 1034–1048, 1049–1058, 1069–1080, 1130–1143, 1130–1145, 1211–1228, 1211–1231, 1259–1270, and 1259–1273, spanning 30% of the C3d region of C3. Our results suggest that hydrolysis may produce a looser (more open) structure in the C3d region, in which some of the changes affect the conversion of helical segments into coil segments facilitating interactions with factors I and H. This study represents the first detailed study mapping the regions of C3 involved in conformational transition when hydrolyzed to C3(H2O).
Molecular Basis for the High Affinity Interaction between the Thymic Leukemia Antigen and the CD8αα Molecule
Authors: Attinger Antoine , Devine Lesley , Wang-Zhu Yiran , Martin Donald , Wang Jia-huai , Reinherz Ellis L. , Kronenberg Mitchell , Cheroutre Hilde , Kavathas Paula 
Published: April 2014

AbstractThe mouse thymic leukemia (TL) Ag is a nonclassical MHC class I molecule that binds with higher affinity to CD8αα than CD8αβ. The interaction of CD8αα with TL is important for lymphocyte regulation in the intestine. Therefore, we studied the molecular basis for TL Ag binding to CD8αα. The stronger affinity of the TL Ag for CD8αα is largely mediated by three amino acids on exposed loops of the conserved α3 domain. Mutant classical class I molecules substituted with TL Ag amino acids at these positions mimic the ability to interact with CD8αα and modulate lymphocyte function. These data indicate that small changes in the α3 domain of class I molecules potentially can have profound physiologic consequences.
A Splice Variant of the TCR ζ mRNA Lacking Exon 7 Leads to the Down-Regulation of TCR ζ, the TCR/CD3 Complex, and IL-2 Production in Systemic Lupus Erythematosus T Cells
Authors: Tsuzaka Kensei , Setoyama Yumiko , Yoshimoto Keiko , Shiraishi Kiyono , Suzuki Katsuya , Abe Tohru , Takeuchi Tsutomu 
Published: April 2014

AbstractThe reduction or absence of TCR ζ-chain (ζ) expression in patients with systemic lupus erythematosus (SLE) is thought to be a factor in the pathogenesis of SLE. We previously reported a splice variant of ζ mRNA that lacks the 36-bp exon 7 (ζ mRNA/exon 7(−)) and is accompanied by the down-regulation of ζ protein in T cells from SLE patients. In this study, we show that EX7− mutants (MA5.8 cells deficient in ζ protein that have been transfected with ζ mRNA/exon 7(−)) exhibit a reduction in the expression of TCR/CD3 complex and ζ protein on their cell surface as well as a reduction in the production of IL-2 after stimulation with anti-CD3 Ab, compared with that in wild-type (WT) mutants (MA5.8 cells transfected with the WT ζ mRNA). Furthermore, real-time PCR analyses demonstrated that ζ mRNA/exon 7(−) in EX7− mutants was easily degraded compared with ζ mRNA by the WT mutants. Pulse-chase experiment showed ζ protein produced by this EX7− mutants was more rapidly decreased compared with the WT mutants. Thus, the lower stability of ζ mRNA/exon 7(−) might also be responsible for the reduced expression of the TCR/CD3 complex, including ζ protein, in SLE T cells.