bluuebunny/crossref_metadata_2025_split huggingface dataset:
Enhanced Tumor Responses to Dendritic Cells in the Absence of CD8-Positive Cells
Authors: Ribas Antoni , Wargo Jennifer A. , Comin-Anduix Begonya , Sanetti Shelley , Schumacher Lana Y. , McLean Colin , Dissette Vivian B. , Glaspy John A. , McBride William H. , Butterfield Lisa H. , Economou James S. 
Published: April 2014

AbstractWild-type mice immunized with MART-1 melanoma Ag-engineered dendritic cells (DC) generate strong Ag-specific immunity that has an absolute requirement for both CD8+ and CD4+ T cells. DC administration to CD8α knockout mice displayed unexpectedly enhanced levels of protection to tumor challenge despite this deficiency in CD8+ T cells and the inability to mount MHC class I-restricted immune responses. This model has the following features: 1) antitumor protection is Ag independent; 2) had an absolute requirement for CD4+ and NK1.1+ cells; 3) CD4+ splenocytes are responsible for cytokine production; 4) lytic cells in microcytotoxicity assays express NK, but lack T cell markers (NK1.1+ αβTCR− CD3−); and 5) the lytic phenotype can be transferred to naive CD8α knockout mice by NK1.1+ splenocytes. Elucidation of the signaling events that activate these effective cytotoxic cells and the putative suppressive mechanisms in a wild-type environment may provide means to enhance the clinical activity of DC-based approaches.
Active Protein Kinase B Regulates TCR Responsiveness by Modulating Cytoplasmic-Nuclear Localization of NFAT and NF-κB Proteins
Authors: Patra Amiya K. , Na Shin-Young , Bommhardt Ursula 
Published: April 2014

Abstract
T cell activation leads to the induction of the transcription factors of the NFAT and NF-κB families, important regulators of T cell activation and function. In this study we demonstrate that TCR/CD3-stimulated T cells from mice expressing a constitutively active form of protein kinase B (myr PKBα) lack significant nuclear accumulation/shuttling of NFATc1 and NFATp as well as NF-κΒp65 and RelB proteins. Notably, despite this deficit in nuclear NFAT and NF-κB proteins, myr PKB T cells show lower activation threshold for proliferation, enhanced cell cycle progression and increased production of Th1 and Th2 cytokines similar to signals provided by CD28 costimulation. The enhanced T cell response correlates with increased expression of cyclins D3 and B1 and cytokine-induced Src homology 2 protein, and inactivation of the forkhead transcription factor FKHR. In addition, coimmunoprecipitation studies indicate a direct regulation of NFATc1 by active PKB. Together, our results demonstrate that the positive regulatory role of myr PKB on TCR responsiveness, subsequent cell division, and effector function is linked to a negative regulatory mechanism on the nuclear accumulation/shuttling of NFAT and NF-κΒ proteins.
Costimulation of CD8 T Cell Responses by OX40
Authors: Bansal-Pakala Pratima , Halteman Beth S. , Cheng Mary Huey-Yu , Croft Michael 
Published: April 2014

AbstractThe persistence of functional CD8 T cell responses is dependent on checkpoints established during priming. Although naive CD8 cells can proliferate with a short period of stimulation, CD4 help, inflammation, and/or high peptide affinity are necessary for the survival of CTL and for effective priming. Using OX40-deficient CD8 cells specific for a defined Ag, and agonist and antagonist OX40 reagents, we show that OX40/OX40 ligand interactions can determine the extent of expansion of CD8 T cells during responses to conventional protein Ag and can provide sufficient signals to confer CTL-mediated protection against tumor growth. OX40 signaling primarily functions to maintain CTL survival during the initial rounds of cell division after Ag encounter. Thus, OX40 is one of the costimulatory molecules that can contribute signals to regulate the accumulation of Ag-reactive CD8 cells during immune responses.
Differential Requirement for the CD40-CD154 Costimulatory Pathway during Th Cell Priming by CD8α+ and CD8α− Murine Dendritic Cell Subsets
Authors: Yasumi Takahiro , Katamura Kenji , Yoshioka Takakazu , Meguro Taka-aki , Nishikomori Ryuta , Heike Toshio , Inobe Manabu , Kon Shigeyuki , Uede Toshimitsu , Nakahata Tatsutoshi 
Published: April 2014

AbstractDendritic cells (DCs) regulate the development of distinct Th populations and thereby provoke appropriate immune responses to various kinds of Ags. In the present work, we investigated the role CD40-CD154 interactions play during the process of Th cell priming by CD8α+ and CD8α− murine DC subsets, which have been reported to differently regulate the Th response. Adoptive transfer of Ag-pulsed CD8α+ DCs induced a Th1 response and the production of IgG2a Abs, whereas transfer of CD8α− DCs induced Th2 cells and IgE Abs in vivo. Induction of distinct Th populations by each DC subset was also confirmed in vitro. Although interruption of CD80/CD86-CD28 interactions inhibited Th cell priming by both DC subsets, disruption of CD40-CD154 interactions only inhibited the induction of the Th1 response by CD8α+ DCs in vivo. CD40-CD154 interactions were not required for the proliferation of Ag-specific naive Th cells stimulated by either DC subset, but were indispensable in the production of IL-12 from CD8α+ DCs and their induction of Th1 cells in vitro. Taken together, in our immunization model of Ag-pulsed DC transfer, CD40-CD154 interactions play an important role in the development of CD8α+ DC-driven Th1 responses but not CD8α− DC-driven Th2 responses to protein Ags.
The Inositol 3-Phosphatase PTEN Negatively Regulates Fcγ Receptor Signaling, but Supports Toll-Like Receptor 4 Signaling in Murine Peritoneal Macrophages
Authors: Cao Xianhua , Wei Guo , Fang Huiqing , Guo Jianping , Weinstein Michael , Marsh Clay B. , Ostrowski Michael C. , Tridandapani Susheela 
Published: April 2014

Abstract
FcγR clustering in macrophages activates signaling events that result in phagocytosis. Phagocytosis is accompanied by the generation harmful byproducts such as reactive oxygen radicals and production of inflammatory cytokines, which mandate that the phagocytic process be subject to a tight regulation. The molecular mechanisms involved in this regulation are not fully understood. In this study, we have examined the role of the inositol 3-phosphatase and tensin homologue deleted on chromosome 10 (PTEN) in FcγR-induced macrophage function. We demonstrate that in ex vivo murine peritoneal macrophages that are deficient in PTEN expression, FcγR-induced Akt and extracellular signal-regulated kinase phosphorylation are enhanced. Notably, PTEN−/− macrophages showed constitutively high phosphorylation of Akt. However, PTEN did not seem to influence tyrosine phosphorylation events induced by FcγR clustering. Furthermore, PTEN−/− macrophages displayed enhanced phagocytic ability. Likewise, FcγR-induced production of TNF-α, IL-6, and IL-10 was significantly elevated in PTEN−/− macrophages. Surprisingly, LPS-induced TNF-α production was down-regulated in PTEN−/− macrophages. Analyzing the molecular events leading to PTEN influence on LPS/Toll-like receptor 4 (TLR4) signaling, we found that LPS-induced activation of mitogen-activated protein kinases is suppressed in PTEN−/− cells. Previous reports indicated that LPS-induced mitogen-activated protein kinase activation is down-regulated by phosphatidylinositol 3-kinase through the activation of Akt. Our observation that Akt activation is basally enhanced in PTEN−/− cells suggests that PTEN supports TLR4-induced inflammatory responses by suppressing the activation of Akt. Thus, we conclude that PTEN is a negative regulator of FcγR signaling, but a positive regulator of TLR4 signaling. These findings are the first to demonstrate a role for PTEN in FcγR- and TLR4-mediated macrophage inflammatory response.
Pax-5 Is Essential for κ Sterile Transcription during Igκ Chain Gene Rearrangement
Authors: Sato Hiromu , Saito-Ohara Fumiko , Inazawa Johji , Kudo Akira 
Published: April 2014

Abstract
Pax-5 is the key regulator in B cell development. Pax-5-deficient mice show defects in B cell commitment and recombination of IgH chain gene rearrangement from DJ to VDJ. Previously, we found that Pax-5 bound to KI and KII sites, which play a crucial role in κ-chain gene rearrangement. However, the function of Pax-5 in Igκ chain gene rearrangement has not been investigated. To address this issue, we newly established pre-BI cell lines expressing the pre-B cell receptor from Pax-5-deficient mice and used them in an in vitro culture system, in which κ-chain gene rearrangement is induced by removing IL-7. By examining the Pax-5-deficient pre-BI (knockout (KO)) cells, we show in this study that, despite recombination-activating gene 1 and 2 expression, these KO cells did not rearrange the κ-chain gene following the absence of κ sterile transcription. Consistent with these data, fluorescent in situ hybridization analyses revealed that the Jκ locus in KO cells was located at the nuclear periphery as a repressive compartment. Transfection of KO cells with Pax-5 constructs indicated that the transactivation domain of Pax-5 was required for κ sterile transcription and κ-chain gene rearrangement. Moreover, the hormone-inducible system in KO cells demonstrated that Pax-5 directly functioned in κ sterile transcription. These results indicate that Pax-5 is necessary for κ sterile transcription during Igκ chain gene rearrangement.
Listeriolysin O fromListeria monocytogenesIs a Lymphocyte Apoptogenic Molecule
Authors: Carrero Javier A. , Calderon Boris , Unanue Emil R. 
Published: April 2014

AbstractInfection of mice with Listeria monocytogenes caused marked lymphocyte apoptosis in the white pulp of the spleen on day 2 postinfection. We prove in this study that listeriolysin O (LLO), a pore-forming molecule and a major virulence factor of Listeria, could directly induce murine lymphocyte apoptosis both in vivo and in vitro at nanomolar and subnanomolar doses. Induction of apoptosis by LLO was rapid, with caspase activation seen as early as 30 min post-treatment. T cells lost their mitochondrial membrane potential and exposed phosphatidylserine within 8 h of treatment. Incubation of lymphocytes with a pan-caspase inhibitor blocked DNA laddering and caspase-3 activation, but did not block phosphatidylserine exposure or loss of mitochondrial membrane potential. We describe a novel function for LLO: induction of lymphocyte apoptosis with rapid kinetics, effected by both caspase-dependent and -independent pathways.
Activated Primary and Memory CD8 T Cells Migrate to Nonlymphoid Tissues Regardless of Site of Activation or Tissue of Origin
Authors: Masopust David , Vezys Vaiva , Usherwood Edward J. , Cauley Linda S. , Olson Sara , Marzo Amanda L. , Ward Richard L. , Woodland David L. , Lefrançois Leo 
Published: April 2014

AbstractFollowing activation within secondary lymphoid tissue, CD8 T cells must migrate to targets, such as infected self tissue, allografts, and tumors, to mediate contact-dependent effector functions. To test whether the pattern of migration of activated CD8 T cells was dependent on the site of Ag encounter, we examined the distribution of mouse Ag-specific CD8 T cells following local challenges. Our findings indicated that activated CD8 T cells migrated pervasively to all nonlymphoid organs irrespective of the site of initial Ag engagement. Using an adoptive transfer system, migration of nonlymphoid memory cells was also examined. Although some limited preference for the tissue of origin was noted, transferred CD8 memory T cells from various nonlymphoid tissues migrated promiscuously, except to the intestinal mucosa, supporting the concept that distinct memory pools may exist. However, regardless of the tissue of origin, reactivation of transferred memory cells resulted in widespread dissemination of new effector cells. These data indicated that recently activated primary or memory CD8 T cells were transiently endowed with the ability to traffic to all nonlymphoid organs, while memory cell trafficking was more restricted. These observations will help refine our understanding of effector and memory CD8 T cell migration patterns.
Burn Injury Initiates a Shift in Superantigen-Induced T Cell Responses and Host Survival
Authors: Zang Yan , Dolan Sinead M. , Choileain Niamh Ni , Kriynovich Sara J. , Murphy Thomas J. , Sayles Peter , Mannick John A. , Lederer James A. 
Published: April 2014

Abstract
Severe injury induces a temporal shift in immune reactivity that can cause serious complications or even death. We previously reported that mice exposed to bacterial superantigen (SAg) early after injury undergo a strong SAg response with lethal consequences. This study compares the early and late effects of burn injury on SAg reactivity in vivo to establish how injury influences adaptive immune responses. We found that mice challenged with ordinarily sublethal doses of staphylococcal enterotoxin A or staphylococcal enterotoxin B at 1 day after burn injury exhibited high mortality, whereas no mortality occurred at 7 days after injury. This shift in mortality correlated with higher Th2-type cytokines (IL-4 and IL-10) being expressed by CD4+ and CD8+ T cells from burn as opposed to sham mice at 7 days after injury. Lymph node cells from burn-injured mice also produced higher levels of Th2-type cytokines at 7 days after injury. The results of cell-mixing studies using CD4+ and CD8+ T cells mixed with APCs from sham or burn mice suggested that changes in both T cells and APCs are involved in the altered SAg response. Finally, the biological significance of altered SAg reactivity following injury was shown by demonstrating that blocking IL-10 activity in vivo caused higher SAg-induced mortality at 7 days after injury. These findings support the idea that injury promotes a Th2-type shift in adaptive immune reactivity. Although prior studies link this counterinflammatory-type response to lowered resistance to infection, the present results suggest it may sometimes benefit the injured host.
CTLA-4 Blockage Increases Resistance to Infection with the Intracellular ProtozoanTrypanosoma cruzi
Authors: Martins Gislâine Aparecida , Tadokoro Carlos Eduardo , Silva Roberta Borges , Silva João Santana , Rizzo Luiz Vicente 
Published: April 2014

AbstractRecent studies have revealed an important role for CTLA-4 as a negative regulator of T cell activation. In the present study, we evaluated the importance of CTLA-4 to the immune response against the intracellular protozoan, Trypanosoma cruzi, the causative agent of Chagas’ disease. We observed that the expression of CTLA-4 in spleen cells from naive mice cultured in the presence of live trypomastigote forms of T. cruzi increases over time of exposure. Furthermore, spleen cells harvested from recently infected mice showed a significant increase in the expression of CTLA-4 when compared with spleen cells from noninfected mice. Blockage of CTLA-4 in vitro and/or in vivo did not restore the lymphoproliferative response decreased during the acute phase of infection, but it resulted in a significant increase of NO production in vivo and in vitro. Moreover, the production of IFN-γ in response to parasite Ags was significantly increased in spleen cells from anti-CTLA-4-treated infected mice when compared with the production found in cells from IgG-treated infected mice. CTLA-4 blockade in vivo also resulted in increased resistance to infection with the Y and Colombian strains of T. cruzi. Taken together these results indicate that CTLA-4 engagement is implicated in the modulation of the immune response against T. cruzi by acting in the mechanisms that control IFN-γ and NO production during the acute phase of the infection.
Selective Impairments in Dendritic Cell-Associated Function Distinguish Hepatitis C Virus and HIV Infection
Authors: Anthony Donald D. , Yonkers Nicole L. , Post Anthony B. , Asaad Robert , Heinzel Frederick P. , Lederman Michael M. , Lehmann Paul V. , Valdez Hernan 
Published: April 2014

AbstractImpaired APC functions may play important roles in chronicity of hepatitis C virus (HCV) and HIV infections. To investigate the separate and combined effects of HCV and HIV infection on immature dendritic cells (DCs), we evaluated myeloid-derived DC (MDC) and plasmacytoid-derived DC (PDC) frequencies and functions, measured by Toll-like receptor ligand-induced IFN-α and IL-12, in healthy controls and subjects with chronic HCV, HIV, and HCV-HIV infection. To evaluate the relation between innate and adaptive immunity, we measured HCV-specific IFN-γ-producing T cell frequency. MDC frequencies tended to be reduced in HIV infection (1.8-fold), while PDC frequencies were minimally reduced in HCV infection (1.4-fold). In contrast, a striking reduction in non-PDC-associated IFN-α production was observed in HIV-infected subjects (17-fold), while PDC-associated IFN-α production was markedly reduced in HCV-infected subjects (20-fold). Both non-PDC and PDC functions were impaired in HCV-HIV coinfection. MDC-associated IL-12 production was markedly reduced in both HCV and HIV-infected subjects (over 10-fold). Functional defects were attenuated with slowly progressive HIV infection. The proportion of subjects with HCV-specific T cell responses, and the number of Ags recognized were reduced in HCV-HIV subjects as compared with HCV singly infected subjects. A positive association was observed between MDC-associated IL-12 production and HCV-specific T cell frequency in HCV-infected subjects. These results indicate that immature DC function is dysregulated in HIV and HCV infections, but differentially, and that these defects are attenuated in slowly progressive HIV infection. These selectively different impairments may contribute to the reduced adaptive immune response to HCV in HCV-HIV coinfection.
Timed Ablation of Regulatory CD4+ T Cells Can Prevent Murine AIDS Progression
Authors: Beilharz Manfred W. , Sammels Leanne M. , Paun Andrea , Shaw Kathryn , van Eeden Pauline , Watson Mark W. , Ashdown Martin L. 
Published: April 2014

Abstract
We describe successful immunotherapy of murine AIDS (MAIDS) in C57BL/6J mice based on the elimination of replicating CD4+ regulator T cells. We demonstrate that a single injection of the antimitotic drug vinblastine (Vb) given 14 days postinfection (p.i.) with LP-BM5 can prevent MAIDS progression. Treatment with anti-CD4 mAb at 14 days p.i. is similarly able to prevent MAIDS. Treatment at other time points with Vb or anti-CD4 mAb is ineffective. The effect is based on ablation of a replicating dominantly suppressive CD4+ T cell population, as indicated by adoptive transfer and in vivo depletion experiments using mAbs against CD4 as well as combinations of mAbs against the known regulatory cell surface markers CD25, GITR, and CTLA-4. Cell surface marker analysis shows a population of CD4+CD25+ cells arising shortly before day 14 p.i. Cytokine analyses show a peak in IL-10 production from day 12 to day 16 p.i. MAIDS-infected mice also have CD4+ T cells with significantly higher expression levels of CD38 and particularly CD69, which have been demonstrated to be regulator T cell markers in the Friend retroviral model. The immunotherapy appears to prevent disease progression, although no protection against reinfection with LP-BM5 is generated. These data define a new therapy for murine retroviral infection, which has potential for use in other diseases where T regulator cell-mediated immunosuppression plays a role in the disease process.
Malaria Blood Stage Parasites Activate Human Plasmacytoid Dendritic Cells and Murine Dendritic Cells through a Toll-Like Receptor 9-Dependent Pathway
Authors: Pichyangkul Sathit , Yongvanitchit Kosol , Kum-arb Utaiwan , Hemmi Hiroaki , Akira Shizuo , Krieg Arthur M. , Heppner D. Gray , Stewart V. Ann , Hasegawa Hitoshi , Looareesuwan Sornchai , Shanks G. Dennis , Miller R. Scott 
Published: April 2014

AbstractA common feature of severe Plasmodium falciparum infection is the increased systemic release of proinflammatory cytokines that contributes to the pathogenesis of malaria. Using human blood, we found that blood stage schizonts or soluble schizont extracts activated plasmacytoid dendritic cells (PDCs) to up-regulate CD86 expression and produce IFN-α. IFN-α production was also detected in malaria-infected patients, but the levels of circulating PDCs were markedly reduced, possibly because of schizont-stimulated up-regulation of CCR7, which is critical for PDC migration. The schizont-stimulated PDCs elicited a poor T cell response, but promoted γδ T cell proliferation and IFN-γ production. The schizont immune stimulatory effects could be reproduced using murine DCs and required the Toll-like receptor 9 (TLR9)-MyD88 signaling pathway. Although the only known TLR9 ligand is CpG motifs in pathogen DNA, the activity of the soluble schizont extract was far greater than that of schizont DNA, and it was heat labile and precipitable with ammonium sulfate, unlike the activity of bacterial DNA. These results demonstrate that schizont extracts contain a novel and previously unknown ligand for TLR9 and suggest that the stimulatory effects of this ligand on PDCs may play a key role in immunoregulation and immunopathogenesis of human falciparum malaria.
Effective Targeting of Pathogens to Neutrophils via Chimeric Surfactant Protein D/Anti-CD89 Protein
Authors: Tacken Paul J. , Hartshorn Kevan L. , White Mitchell R. , van Kooten Cees , van de Winkel Jan G. J. , Reid Ken B. M. , Batenburg Joseph J. 
Published: April 2014

AbstractTargeting of specific pathogens to FcRs on immune effector cells by using bispecific Abs was reported to result in effective killing of the pathogens, both in vitro and in vivo. Instead of targeting a specific pathogen to an FcR, we assessed whether a broad spectrum of pathogens can be targeted to an FcR using surfactant protein D (SP-D). SP-D is a collectin that binds a great variety of pathogens via its carbohydrate recognition domain. A recombinant trimeric fragment of SP-D (rfSP-D), consisting of the carbohydrate recognition domain and neck domain of human SP-D, was chemically cross-linked to the Fab′ of an Ab directed against the human FcαRI (CD89). In vitro, the chimeric rfSP-D/anti-CD89 protein enhanced uptake of Escherichia coli, Candida albicans, and influenza A virus by human neutrophils. Blocking of the interaction between rfSP-D/anti-CD89 and either the pathogen or CD89 abolished its stimulatory effect on pathogen uptake by neutrophils. In addition, rfSP-D/anti-CD89 stimulated killing of E. coli and C. albicans by neutrophils and enhanced neutrophil activation by influenza A virus. In conclusion, rfSP-D/anti-CD89 effectively targeted three structurally unrelated pathogens to neutrophils. (Col)lectin-based chimeric proteins may thus offer promise for therapy of infectious disease.