bluuebunny/crossref_metadata_2025_split huggingface dataset:
Vaccines Containing de-N-Acetyl Sialic Acid Elicit Antibodies Protective against Neisseria meningitidis Groups B and C
Authors: Moe Gregory R. , Bhandari Tamara S. , Flitter Becca A. 
Published: May 2009

Abstract
Murine mAbs that were produced by immunization with a vaccine containing the N-propionyl derivative of Neisseria meningitidis group B (MenB) capsular polysaccharide (NPr MBPS) mediate protective responses against MenB but were not reactive with unmodified MBPS or chemically identical human polysialic acid (PSA). Recently, we showed that some of the mAbs were reactive with MBPS derivatives that contain de-N-acetyl sialic acid residues. In this study we evaluated the immunogenicity of de-N-acetyl sialic acid-containing derivatives of PSA (de-N-acetyl PSA) in mice. Four de-N-acetyl PSA Ags were prepared and conjugated to tetanus toxoid, including completely de-N-acetylated PSA. All of the vaccines elicited anti-de-N-acetyl PSA responses (titers ≥1/10,000), but only vaccines enriched for nonreducing end de-N-acetyl residues by treatment with exoneuraminidase or complete de-N-acetylation elicited high titers against the homologous Ag. Also, nonreducing end de-N-acetyl residue-enriched vaccines elicited IgM and IgG Abs of all subclasses that could bind to MenB. The results suggest that the zwitterionic characteristic of neuraminic acid, particularly at the nonreducing end, may be important for processing and presentation mechanisms that stimulate T cells. Abs elicited by all four vaccines were able to activate deposition of human complement proteins and passively protect against challenge by MenB in the infant rat model of meningococcal bacteremia. Some vaccine antisera mediated bactericidal activity against a N. meningitidis group C strain with human complement. Thus, de-N-acetyl PSA Ags are immunogenic and elicit Abs that can be protective against MenB and N. meningitidis group C strains.
The Adaptor Molecule MyD88 Directly Promotes CD8 T Cell Responses to Vaccinia Virus
Authors: Zhao Yuan , De Trez Carl , Flynn Rachel , Ware Carl F. , Croft Michael , Salek-Ardakani Shahram 
Published: May 2009

Abstract
Vaccinia virus (VACV) elicits a robust CD8 T cell response that plays an important role in host resistance. To date, there is little information on the molecules that are essential to generate large pools of VACV-specific effector CD8 T cells. In this study, we show that the adaptor molecule MyD88 is critical for the magnitude of primary CD8 T cell responses to both dominant and subdominant VACV epitopes. MyD88−/− mice exhibit profound reduction in CD8 T cell expansion and antiviral cytokine production. Surprisingly, the defect was not due to impaired APC function, as MyD88−/− dendritic cells matured normally and were able to promote strong CD8 T cell priming following VACV infection. Rather, adoptive transfer experiments demonstrated that intrinsic MyD88-dependent pathways in CD8 T cells were critical. MyD88-deficient CD8 T cells failed to accumulate in wild-type hosts and poor expansion of MyD88-deficient VACV-specific CD8 T cells resulted after virus infection. In contrast, no defect was evident in the absence of TRIF, TLR2, TLR4, TLR9, and IL-1R. Together, our results highlight an important role for MyD88 in initial antiviral CD8 T cell responses and suggest that targeting this pathway may be useful in promoting and sustaining anti-VACV immunity.
PD-1 and CTLA-4 Inhibitory Cosignaling Pathways in HIV Infection and the Potential for Therapeutic Intervention
Authors: Kaufmann Daniel E. , Walker Bruce D. 
Published: May 2009

Abstract
The balance between proinflammatory mechanisms and the dampening of excessive immune activation is critical for successful clearance of a pathogen without harm to the host. In particular, molecules of the B7:CD28 family play a critical role in regulating T cell activation and peripheral tolerance. Chronic pathogens like HIV, which is characterized by ongoing viral replication despite detectable virus-specific T cell responses, and cancer cells have exploited these pathways to attenuate Ag-specific T cell immunity. This review summarizes evidence that molecules of the B7:CD28 family, PD-1, CTLA-4, and their ligands, play an active and reversible role in virus-specific T cell exhaustion associated with HIV infection in humans and in the SIV model in macaques. We discuss the potential for immunotherapeutic interventions based on manipulation of these inhibitory networks, the promising data obtained with blockade of the PD-1 pathway in animal models, and the challenges to such therapies.
Activation of Melanoma Differentiation-Associated Gene 5 Causes Rapid Involution of the Thymus
Authors: Anz David , Thaler Raffael , Stephan Nicolas , Waibler Zoe , Trauscheid Michael J. , Scholz Christoph , Kalinke Ulrich , Barchet Winfried , Endres Stefan , Bourquin Carole 
Published: May 2009

Abstract
In the course of infection, the detection of pathogen-associated molecular patterns by specialized pattern recognition receptors in the host leads to activation of the innate immune system. Whereas the subsequent induction of adaptive immune responses in secondary lymphoid organs is well described, little is known about the effects of pathogen-associated molecular pattern-induced activation on primary lymphoid organs. Here we show that activation of innate immunity through the virus-sensing melanoma differentiation-associated gene 5 (MDA-5) receptor causes a rapid involution of the thymus. We observed a strong decrease in thymic cellularity associated with characteristic alterations in thymic subpopulations and microanatomy. In contrast, immune stimulation with potent TLR agonists did not lead to thymic involution or induce changes in thymic subpopulations, demonstrating that thymic pathology is not a general consequence of innate immune activation. We determined that suppression of thymocyte proliferation and enhanced apoptosis are the essential cellular mechanisms involved in the decrease in thymic size upon MDA-5 activation. Further, thymic involution critically depended on type I IFN. Strikingly however, no direct action of type I IFN on thymocytes was required, given that the decrease in thymic size was still observed in mice with a selective deletion of the type I IFN receptor on T cells. All changes observed were self-limiting, given that cessation of MDA-5 activation led to a rapid recovery of thymic size. We show for the first time that the in vivo activation of the virus-sensing MDA-5 receptor leads to a rapid and reversible involution of the thymus.
Effector/Memory but Not Naive Regulatory T Cells Are Responsible for the Loss of Concomitant Tumor Immunity
Authors: Lin Yung-Chang , Chang Li-Yuan , Huang Ching-Tai , Peng Hui-Min , Dutta Avijit , Chen Tse-Ching , Yeh Chau-Ting , Lin Chun-Yen 
Published: May 2009

Abstract
The phenomenon of concomitant tumor immunity involves a tumor-bearing host rejecting another similar tumor at a distant site and suggests the existence of tumor-specific immunity. Loss of this immunity may contribute to tumor metastasis. However, mechanisms underlying the loss of concomitant immunity are largely unknown. We set up a concomitant tumor immunity model in which this immunity is gradually lost as the primary tumor progresses. We found that CD8+ T cells, especially tumor-infiltrating CD8+ T cells, from mice that lost concomitant tumor immunity, possessed potent antitumor properties and strongly expressed effector molecules. Furthermore, effector/memory regulatory T cells (Treg cells, CD103+CD4+Foxp3+ T cells) increased as the primary tumor progressed. They initially accumulated around the tumor and in the spleen at later points. Not only did these cells more greatly express killing molecules, they also suppressed the functions of tumor-bearing CD8+ T cells in vitro and in vivo. Finally, we show that these effector/memory Treg cells inhibit concomitant tumor immunity in vivo. Taken together, data suggest that effector/memory Treg cells are responsible for the loss of concomitant tumor immunity associated with tumor progression.
Involvement of Glycoreceptors in Galactoxylomannan-Induced T Cell Death
Authors: Pericolini Eva , Gabrielli Elena , Cenci Elio , De Jesus Magdia , Bistoni Francesco , Casadevall Arturo , Vecchiarelli Anna 
Published: May 2009

Abstract
The major virulence factor of Cryptococcus neoformans is its capsular polysaccharide, which is also released into tissues. The shed polysaccharide is composed of glucuronoxylomannan, galactoxylomannan (GalXM), and mannoproteins. In a previous study, we demonstrated a direct interaction of purified soluble GalXM with T cells that induced their apoptosis. In this study, we focus on the mechanisms involved in the apoptotic effect of GalXM. In our experimental system, we analyzed the effect of GalXM on purified human T cells and Jurkat cells, a T cell line routinely used for apoptotic studies. Our results reveal that GalXM activates the extrinsic and intrinsic apoptotic pathways through the cleavage and recruitment of caspase-8. Caspase-8 elicits the downstream executioner caspase-3, caspase-6, and caspase-7 both directly and indirectly, via Bid cleavage and caspase-9 activation. These effects appeared to be primarily mediated by the interaction of GalXM with the glycoreceptors, which differed in human T and Jurkat cells. CD45 was primarily involved in Jurkat cells apoptosis while CD7 and CD43 mediated human T cell apoptosis. Our results highlight a new mechanism by which a microbial product can contribute to virulence through direct interaction with T cell glycoreceptors, thereby triggering lymphocyte apoptosis.
Tumor-Educated CD11bhighIalow Regulatory Dendritic Cells Suppress T Cell Response through Arginase I
Authors: Liu Qiuyan , Zhang Chaoxiong , Sun Anna , Zheng Yuanyuan , Wang Li , Cao Xuetao 
Published: May 2009

Abstract
Tumors can induce generation and accumulation of the immunosuppressive cells such as regulatory T cells in the tumor microenvironment, contributing to tumor escape from immunological attack. Although dendritic cell (DC)-based cancer vaccine can initiate antitumor immune response, regulatory DC subsets involved in the tolerance induction attracted much attention recently. Our previous studies demonstrate that the stromal microenvironment of the spleen, lung, and liver can program generation of CD11clowCD11bhighIalow DCs with regulatory function (CD11bhighIalow regulatory DCs). However, whether and how the tumor microenvironment can program generation of CD11bhighIalow regulatory DCs remain to be investigated. In this study, we used the freshly isolated tumor cells to mimic tumor microenvironment to coculture DCs and found that the freshly isolated tumor cells could drive DCs to differentiate into regulatory DCs with a CD11clowCD11bhighIalow phenotype and high expression of IL-10, NO, vascular endothelial growth factor, and arginase I. Tumor-educated CD11bhighIalow regulatory DCs inhibited CD4+ T cell proliferation both in vitro and in vivo. 3LL lung cancer-derived TGF-β and PGE2 were responsible for the generation of regulatory DCs. PGE2 was the main inducer of arginase I in regulatory DCs. Arginase I played a major role in the suppression of T cell response by regulatory DCs induced by 3LL lung cancer. A natural counterpart of CD11bhighIalow DCs was identified in tumor tissue, and CD11bhighIalow DCs sorted from 3LL lung cancer tissue expressed arginase I and inhibited T cell response. Therefore, tumors can educate DCs to differentiate into a regulatory DC subset, which contributes to constitution of the immunosuppressive tumor microenvironment and promotes tumor immune escape.
IL-1R Type I-Dependent Hemopoietic Stem Cell Proliferation Is Necessary for Inflammatory Granulopoiesis and Reactive Neutrophilia
Authors: Ueda Yoshihiro , Cain Derek W. , Kuraoka Masayuki , Kondo Motonari , Kelsoe Garnett 
Published: May 2009

Abstract
Infections and inflammation trigger neutrophilias that are supported by a hematopoietic program of accelerated granulopoiesis known as emergency granulopoiesis. The intrinsic factors that drive reactive neutrophilias and emergency granulopoiesis have been inferred but not demonstrated. Here, we show that alum cannot elicit reactive neutrophilias in IL-1R type I (IL-1RI)−/− mice, whereas other inflammatory responses, including eosinophilia and Ab production, remain intact. Analysis of this specific impairment revealed an unanticipated role for IL-1RI in supporting increased proliferation by granulocyte/macrophage progenitors and, surprisingly, multipotent progenitors and hematopoietic stem cells (HSC). Indeed, HSC and multipotent progenitor proliferative responses were most suppressed in IL-1RI−/− mice, suggesting a critical role for their proliferation in inflammatory granulopoiesis. Whereas IL-1 drives increased HSC proliferation directly in vitro, IL-1RI expression by radiation-resistant host cells was both necessary and sufficient for alum-induced HSC, multipotent progenitor, and granulocyte/macrophage progenitor proliferation and reactive neutrophilias in radiation chimeric mice. Thus, IL-1 plays a necessary, but indirect, role in the support of alum-induced neutrophilias by expanding both pluripotent and myeloid progenitor compartments to accelerate granulopoiesis.
Mesenchymal Stromal Cells Ameliorate Experimental Autoimmune Encephalomyelitis by Inhibiting CD4 Th17 T Cells in a CC Chemokine Ligand 2-Dependent Manner
Authors: Rafei Moutih , Campeau Philippe M. , Aguilar-Mahecha Adriana , Buchanan Marguerite , Williams Patrick , Birman Elena , Yuan Shala , Young Yoon Kow , Boivin Marie-Noëlle , Forner Kathy , Basik Mark , Galipeau Jacques 
Published: May 2009

Abstract
The administration of ex vivo culture-expanded mesenchymal stromal cells (MSCs) has been shown to reverse symptomatic neuroinflammation observed in experimental autoimmune encephalomyelitis (EAE). The mechanism by which this therapeutic effect occurs remains unknown. In an effort to decipher MSC mode of action, we found that MSC conditioned medium inhibits EAE-derived CD4 T cell activation by suppressing STAT3 phosphorylation via MSC-derived CCL2. Further analysis demonstrates that the effect is dependent on MSC-driven matrix metalloproteinase proteolytic processing of CCL2 to an antagonistic derivative. We also show that antagonistic CCL2 suppresses phosphorylation of AKT and leads to a reciprocal increased phosphorylation of ERK associated with an up-regulation of B7.H1 in CD4 T cells derived from EAE mice. CD4 T cell infiltration of the spinal cord of MSC-treated group was robustly decreased along with reduced plasma levels of IL-17 and TNF-α levels and in vitro from restimulated splenocytes. The key role of MSC-derived CCL2 was confirmed by the observed loss of function of CCL2−/− MSCs in EAE mice. In summary, this is the first report of MSCs modulating EAE biology via the paracrine conversion of CCL2 from agonist to antagonist of CD4 Th17 cell function.
Adeno-Associated Virus Capsid Structure Drives CD4-Dependent CD8+ T Cell Response to Vector Encoded Proteins
Authors: Mays Lauren E. , Vandenberghe Luk H. , Xiao Ru , Bell Peter , Nam Hyun-Joo , Agbandje-McKenna Mavis , Wilson James M. 
Published: May 2009

Abstract
The immunological sequelae of adeno-associated virus (AAV)-mediated gene transfer in vivo is quite complex. In murine models, most AAV capsids are associated with minimal or dysfunctional T cell responses to antigenic transgene products. In this study we compared T cell activation against AAV2/8 and AAV2/rh32.33 vectors expressing nuclear-targeted LacZ (nLacZ), GFP, or firefly luciferase in murine skeletal muscle. We show that, unlike AAV8, AAVrh32.33 yields qualitatively and quantitatively robust T cell responses to both the capsid and transgene product. AAV2/rh32.33.CB.nLacZ, but not AAV2/8, drives a high degree of cellular infiltration and a loss of detectable transgene expression in C57BL/6 mice. However, cellular immunity to AAVrh32.33 is ablated in the absence of CD4, CD40L, or CD28, permitting stable β-galactosidase expression. Treatment of CD40L−/− mice with the CD40 agonist, FGK45, failed to restore the CD8 response to AAV2/rh32.33.nLacZ, suggesting that additional factors are involved. Our results suggest that specific domains within the AAVrh32.33 capsid augment the adaptive response to both capsid and transgene Ags in a CD4-dependent pathway involving CD40L signaling and CD28 costimulation. Structural comparison of the AAV8 and rh32.33 capsids has identified key differences that may drive differential immunity by affecting tropism, Ag presentation or the activation of innate immunity. This murine model of AAV-mediated cytotoxicity allows us to delineate the mechanism of viral immune activation, which is relevant to the translation of AAV technology in higher order species.
Naive CD4 T Cell Proliferation Is Controlled by Mammalian Target of Rapamycin Regulation of GRAIL Expression
Authors: Lin Jack T. , Lineberry Neil B. , Kattah Michael G. , Su Leon L. , Utz Paul J. , Fathman C. Garrison , Wu Linda 
Published: May 2009

Abstract
In this study, we demonstrate that the E3 ubiquitin ligase gene related to anergy in lymphocytes (GRAIL) is expressed in quiescent naive mouse and human CD4 T cells and has a functional role in inhibiting naive T cell proliferation. Following TCR engagement, CD28 costimulation results in the expression of IL-2 whose signaling through its receptor activates the Akt-mammalian target of rapamycin (mTOR) pathway. Activation of mTOR allows selective mRNA translation, including the epistatic regulator of GRAIL, Otubain-1 (Otub1), whose expression results in the degradation of GRAIL and allows T cell proliferation. The activation of mTOR appears to be the critical component of IL-2R signaling regulating GRAIL expression. CTLA4-Ig treatment blocks CD28 costimulation and resultant IL-2 expression, whereas rapamycin and anti-IL-2 treatment block mTOR activation downstream of IL-2R signaling. Thus, all three of these biotherapeutics inhibit mTOR-dependent translation of mRNA transcripts, resulting in blockade of Otub1 expression, maintenance of GRAIL, and inhibition of CD4 T cell proliferation. These observations provide a mechanistic pathway sequentially linking CD28 costimulation, IL-2R signaling, and mTOR activation as important requirements for naive CD4 T cell proliferation through the regulation of Otub1 and GRAIL expression. Our findings also extend the role of GRAIL beyond anergy induction and maintenance, suggesting that endogenous GRAIL regulates general cell cycle and proliferation of primary naive CD4 T cells.
Expansion of Antigen-Specific Regulatory T Cells with the Topical Vitamin D Analog Calcipotriol
Authors: Ghoreishi Mehran , Bach Paxton , Obst Jennifer , Komba Mitsuhiro , Fleet James C. , Dutz Jan P. 
Published: May 2009

Abstract
1,25-Dihydroxyvitamin D3 is immunosuppressive both in vivo and in vitro. Topical vitamin D analogs such as calcipotriol alter keratinocyte function, but their effects on cutaneous immune responses are less well understood. We demonstrate that exposure of the skin to calcipotriol before transcutaneous immunization with OVA protein and CpG adjuvant prevents Ag-specific CD8+ T cell priming coincident with Langerhans cell depletion in the skin. Immunization through calcipotriol-treated skin induces CD4+CD25+ regulatory T cells (Treg) that prevent subsequent Ag-specific CD8+ T cell proliferation and IFN-γ production. Treg induced by calcipotriol are able to inhibit the induction and the elicitation of protein contact hypersensitivity. Topical calcipotriol treatment also induces RANKL (receptor activator of NF-κB ligand) expression by keratinocytes, a TNF family member involved in modulation of skin dendritic cells. UV light B induces Ag-specific tolerance when it is applied before transcutaneous immunization. We suggest that UV light B-induced tolerance is induced via a vitamin D receptor-dependent mechanism as vitamin D receptor (VDR) knockout mice fail to increase FoxP3+ Treg in their peripheral draining lymph node following irradiation. Additionally, keratinocytes of VDR−/− mice fail to induce RANKL upon UV irradiation or calcipotriol treatment. The in vivo expansion of Ag-specific Treg with the topical application of the vitamin D analog calcipotriol followed by transcutaneous immunization is a simple method to augment functional Ag-specific CD4+CD25+Foxp3+ Treg populations and mimics Ag-specific UV-induced tolerance.
A Network Modeling Approach to Analysis of the Th2 Memory Responses Underlying Human Atopic Disease
Authors: Bosco Anthony , McKenna Kathy L. , Firth Martin J. , Sly Peter D. , Holt Patrick G. 
Published: May 2009

Abstract
Complex cellular functions within immunoinflammatory cascades are conducted by networks of interacting genes. In this study, we employed a network modeling approach to dissect and interpret global gene expression patterns in allergen-induced Th cell responses that underpin human atopic disease. We demonstrate that a subnet of interconnected genes enriched for Th2 and regulatory T cell-associated signatures plus many novel genes is hardwired into the atopic response and is a hallmark of atopy at the systems level. We show that activation of this subnet is stabilized via hyperconnected “hub” genes, the selective disruption of which can collapse the entire network in a comprehensive fashion. Finally, we investigated gene expression in different Th cell subsets and show that regulatory T cell- and Th2-associated signatures partition at different stages of Th memory cell differentiation. Moreover, we demonstrate the parallel presence of a core element of the Th2-associated gene signature in bystander naive cells, which can be reproduced by rIL-4. These findings indicate that network analysis provides significant additional insight into atopic mechanisms beyond that achievable with conventional microarray analyses, predicting functional interactions between novel genes and previously recognized members of the allergic cascade. This approach provides novel opportunities for design of therapeutic strategies that target entire networks of genes rather than individual effector molecules.
Antigen-Specific Blockade of Lethal CD8 T-Cell Mediated Autoimmunity in a Mouse Model of Multiple Sclerosis
Authors: Na Shin-Young , Eujen Heike , Göbel Kerstin , Meuth Sven G. , Martens Kati , Wiendl Heinz , Hünig Thomas 
Published: May 2009

Abstract
Increasing evidence implies CD8 T cells in tissue-specific autoimmune diseases including multiple sclerosis. mAbs specific for MHC class I molecules presenting a dominant autoantigenic peptide may allow selective immunotherapy in such settings. We demonstrate the prophylactic and therapeutic efficacy of such a mAb in a transgenic mouse model of lethal demyelinating disease in which a neo-self Ag expressed by oligodendrocytes is targeted by CD8 T cells with transgenic Ag receptors. Mechanistic studies performed in vitro and in vivo indicate that it is the low expression of MHC class I on oligodendrocytes, which makes this form of Ag-specific intervention possible.