bluuebunny/crossref_metadata_2025_split huggingface dataset:
Costimulation Blockade Inhibits Allergic Sensitization but Does Not Affect Established Allergy in a Murine Model of Grass Pollen Allergy
Authors: Linhart Birgit , Bigenzahn Sinda , Hartl Arnulf , Lupinek Christian , Thalhamer Josef , Valenta Rudolf , Wekerle Thomas 
Published: April 2014

Abstract
Type I allergy is characterized by the development of an initial Th2-dependent allergen-specific IgE response, which is boosted upon a subsequent allergen encounter. Although the immediate symptoms of allergy are mainly IgE-mediated, allergen-specific T cell responses contribute to the late phase as well as to the chronic manifestations of allergy. This study investigates the potential of costimulation blockade with CTLA4Ig and an anti-CD154 mAb for modifying the allergic immune response to the major timothy grass pollen allergen Phl p 5 in a mouse model. BALB/c mice were treated with the costimulation blockers at the time of primary sensitization to the Phl p 5 allergen or at the time of a secondary allergen challenge. Costimulation blockade (CTLA4Ig plus anti-CD154 or anti-CD154 alone) at the time of sensitization prevented the development of allergen-specific IgE, IgM, IgG, and IgA responses compared with untreated but sensitized mice. However, costimulation blockade had no influence on established IgE responses in sensitized mice. Immediate-type reactions as analyzed by a rat basophil leukemia cell mediator release assay were only suppressed by early treatment but not by a costimulation blockade after sensitization. CTLA4Ig given alone failed to suppress both the primary and the secondary allergen-specific Ab responses. Allergen-specific T cell activation was suppressed in mice by early as well as by a late costimulation blockade, suggesting that IgE responses in sensitized mice are independent of T cell help. Our results indicate that T cell suppression alone without active immune regulation or a shifting of the Th2/Th1 balance is not sufficient for the treatment of established IgE responses in an allergy.
Unravelling the Complexity of T Cell Abnormalities in Common Variable Immunodeficiency
Authors: Giovannetti Antonello , Pierdominici Marina , Mazzetta Francesca , Marziali Marco , Renzi Cristina , Mileo Anna Maria , De Felice Marco , Mora Barbara , Esposito Antonella , Carello Rossella , Pizzuti Antonio , Paggi Marco G. , Paganelli Roberto , Malorni Walter , Aiuti Fernando 
Published: April 2014

Abstract
We investigated several phenotypic and functional parameters of T cell-mediated immunity in a large series of common variable immunodeficiency (CVID) patients. We demonstrated that the vast majority of CVID patients presented multiple T cell abnormalities intimately related among them, the severity of which was reflected in a parallel loss of CD4+ naive T cells. A strong correlation between the number of CD4+ naive T cells and clinical features was observed, supporting the subgrouping of patients according to their number of naive CD4+ T lymphocytes. A reduced thymic output and disrupted CD4+ and CD8+ TCR repertoires paralleled the contraction of CD4+ naive T cell pools. The evaluation of activation markers and cytokine production indicated a strong T cell activation that was significantly related to the increased levels of T cell turnover and apoptosis. Finally, discrete genetic profiles could be demonstrated in groups of patients showing extremely diverse T cell subset composition and function. Naive CD4+ T cell levels were significantly associated with the switched memory B cell-based classification, although the concordance between the respective subgroups did not exceed 58.8%. In conclusion, our data highlight the key role played by the T cell compartment in the pathogenesis of CVID, pointing to the need to consider this aspect for classification of this disease.
NK Cells and Cancer
Authors: Zamai Loris , Ponti Cristina , Mirandola Prisco , Gobbi Giuliana , Papa Stefano , Galeotti Laura , Cocco Lucio , Vitale Marco 
Published: April 2014

Abstract
In this review, we overview the main features and functions of NK cells, focusing on their role in cell-mediated immune response to tumor cells. In parallel, we discuss the information available in the field of NK cell receptors and offer a wide general overview of functional aspects of cell targeting and killing, focusing on the recent acknowledgments on the efficacy of NK cells after cytokine and mAb administration in cancer therapy. Since efficacy of NK cell-based immunotherapy has been proven in KIR-mismatch regimens or in TRAIL-dependent apoptosis, the ability to manipulate the balance of activating and inhibitory receptors on NK cells and of their cognate ligands, as well as the sensitivity of tumor cells to apoptosis, opens new perspectives for NK cell-based immunotherapy.
Cutting Edge: Immature Human Dendritic Cells Express Latency-Associated Peptide and Inhibit T Cell Activation in a TGF-β-Dependent Manner
Authors: Gandhi Roopali , Anderson David E. , Weiner Howard L. 
Published: April 2014

Abstract
Dendritic cells (DCs) play a critical role in both initiating immune responses and in maintaining peripheral tolerance. However, the exact mechanism by which DCs instruct/influence the generation of effector vs regulatory T cells is not clear. In this study, we present evidence that TGF-β, an important immunoregulatory molecule, is present on the surface of ex vivo immature human DCs bound by latency-associated peptide (LAP). Maturation of DCs upon stimulation with LPS results in loss of membrane-bound LAP and up-regulation of HLA class II and costimulatory molecules. The presence of LAP on immature DCs selectively inhibits Th1 cell but not Th17 cell differentiation and is required for differentiation and/or survival of Foxp3-positive regulatory T cells. Taken together, our results indicate that surface expression of TGF-β on DCs in association with LAP is one of the mechanisms by which immature DCs limit T cell activation and thus prevent autoimmune responses.
Cutting Edge: Limiting Amounts of IL-7 Do Not Control Contraction of CD4+ T Cell Responses
Authors: Tripathi Pulak , Mitchell Thomas C. , Finkelman Fred , Hildeman David A. 
Published: April 2014

Abstract
During the acute T cell response most effector T cells die while some survive and become memory T cells. Selective expression of CD127 (IL-7Rα) on effector T cells has been proposed to engender their survival into the memory pool. We assessed the role of IL-7 in effector T cell survival using MHC class II tetramers to track a CD4+ T cell response following infection with a recombinant vaccinia virus (rVV-2W1S). Exogenous IL-7 prevented the contraction of the 2W1S-specific CD4+ T cell response after rVV-2W1S infection. IL-7 increased proliferation of, and Bcl-2 expression within, 2W1S-specific T cells; the latter was required for IL-7-driven prevention of contraction. Conversely, in vivo neutralization of IL-7 or Bcl-2 did not exacerbate the contraction of 2W1S-specific CD4+ T cells. These data suggest that IL-7 administration may enhance the survival of effector T cells but that IL-7 is not the limiting factor during normal contraction of the response.
The T Cell Costimulator TL1A Is Induced by FcγR Signaling in Human Monocytes and Dendritic Cells
Authors: Prehn John L. , Thomas Lisa S. , Landers Carol J. , Yu Qi T. , Michelsen Kathrin S. , Targan Stephan R. 
Published: April 2014

Abstract
The recently described TL1A/DR3 ligand/receptor pair mediates strong costimulation of Th1 cells. Activation of T and NK cells induces DR3 expression, permitting soluble recombinant TL1A to increase IFN-γ production and proliferation of these cells. Gut T cells and macrophages express TL1A, especially in Crohn’s disease (CD), and there is a strong association between CD and tl1a single nucleotide polymorphisms. Murine studies implicate TL1A in gut inflammation. To determine whether professional T cell-activating cells can express TL1A, fresh blood monocytes and monocyte-derived dendritic cells were stimulated with various activating ligands, including TLR agonists, IFN-γ, and immune complexes. FcγR stimulation strongly induced TL1A mRNA in both cell types, which correlated with the detection of TL1A on the cell surface and in cell culture medium. TLR agonists capable of inducing IL-6 and TNF-α in monocytes and dendritic cells did not induce surface nor soluble TL1A. Furthermore, we demonstrate that TL1A production in monocytes leads to enhancement of T cell responses. The induction of TL1A on APCs via specific pathway stimulation suggests a role for TL1A in Th1 responses to pathogens, and in CD.
15-Deoxy-Δ12,14-Prostaglandin J2 Negatively Regulates rankl Gene Expression in Activated T Lymphocytes: Role of NF-κB and Early Growth Response Transcription Factors
Authors: Fionda Cinzia , Nappi Filomena , Piccoli Mario , Frati Luigi , Santoni Angela , Cippitelli Marco 
Published: April 2014

Abstract
Receptor activator of NF-κB ligand (RANKL) and its receptor RANK are cell surface proteins abundantly expressed in bone and lymphoid tissues, whose interaction triggers different signaling pathways leading to activation and differentiation of osteoclasts, pivotal actors of the normal bone remodeling cycle. Moreover, RANKL may act as an immunomodulator, representing an important dendritic cell survival factor produced by activated T cells. A large body of research has shown that not only does the RANKL/RANK system regulate the physiology of bone development but also plays an important pathological role in bone destruction mediated by inflammatory disorders or bone metastatic tumors. 15-Deoxy-Δ12,14-PGJ2 (15d-PGJ2) is a cyclopentenone-type PG endowed with anti-inflammatory properties and produced by different cells, including those of the immune system. Although 15d-PGJ2 has been studied as a natural ligand of the peroxisome proliferator-activated receptor-γ nuclear receptor, relevant peroxisome proliferator-activated receptor-γ-independent actions mediated by this prostanoid have been described. In this study, we describe the effect of 15d-PGJ2 on the expression of the rankl gene in T lymphocytes. We show that 15d-PGJ2 inhibits rankl mRNA expression, protein, and rankl promoter activity by mechanisms mediated by its chemically reactive cyclopentenone moiety. Our data also indicate that 15d-PGJ2 represses rankl activation by interfering with the expression and/or activity of the transcription factors NF-κB, early growth response-2, and early growth response-3, whose altered balancing and transactivation may contribute for the repression of this gene. These results place rankl as a novel molecular target for the different immunoregulatory activities mediated by 15d-PGJ2. The physiological and pharmacological implications of these observations are discussed.
Infiltration of a Mesothelioma by IFN-γ-Producing Cells and Tumor Rejection after Depletion of Regulatory T Cells
Authors: Rudge Geordie , Barrett Simon P. , Scott Bernadette , van Driel Ian R. 
Published: April 2014

Abstract
Depletion of CD4+CD25+Foxp3+ regulatory T cells (CD25+ Treg) with an anti-CD25 Ab results in immune-mediated rejection of tolerogenic solid tumors. In this study, we have examined the immune response to a mesothelioma tumor in mice after depletion of CD25+ cells to elucidate the cellular mechanisms of CD25+ Treg, a subject over which there is currently much conjecture. Tumor rejection was found to be primarily due to the action of CD8+ T cells, although CD4+ cells appeared to play some role. Depletion of CD25+ cells resulted in an accumulation in tumor tissue of CD4+ and CD8+ T cells and NK cells that were producing the potent antitumor cytokine IFN-γ. Invasion of tumors by CD8+ T cells was partially dependent on the presence of CD4+ T cells. Although a significant increase in the proliferation and number of tumor-specific CD8+ T cells was observed in lymph nodes draining the tumor of anti-CD25-treated mice, this effect was relatively modest compared with the large increase in IFN-γ-producing T cells found in tumor tissue, which suggests that the migration of T cells into tumor tissue may also have been altered. Depletion of CD25+ cells did not appear to modulate antitumor CTL activity on a per cell basis. Our data suggests that CD25+ Treg limit the accumulation of activated T cells producing IFN-γ in the tumor tissue and, to a lesser extent, activation and/or rate of mitosis of tumor-specific T cells in lymph nodes.
The Constitutive Tyrosine Phosphorylation of CD3ζ Results from TCR-MHC Interactions That Are Independent of Thymic Selection
Authors: Becker Amy M. , DeFord-Watts Laura M. , Wuelfing Christoph , van Oers Nicolai S. C. 
Published: April 2014

Abstract
The TCR complex, when isolated from thymocytes and peripheral T cells, contains a constitutively tyrosine-phosphorylated CD3ζ molecule termed p21. Previous investigations have shown that the constitutive phosphorylation of CD3ζ results from TCR interactions with MHC molecules occurring in both the thymus and the periphery. To determine what contribution the selection environment had on this constitutive phosphorylation, we analyzed CD3ζ from several distinct class I- and II-restricted TCR-transgenic mice where thymocyte development occurred in either a selecting or a nonselecting MHC environment. Herein, we report that constitutively phosphorylated CD3ζ (p21) was present in thymocytes that developed under nonselecting peptide-MHC conditions. These findings strongly support the model that the TCR has an inherent avidity for MHC molecules before repertoire selection. Biochemical analyses of the TCR complex before and after TCR stimulation suggested that the constitutively phosphorylated CD3ζ subunit did not contribute to de novo TCR signals. These findings may have important implications for T cell functions during self-MHC recognition under normal and autoimmune circumstances.
Incomplete Depletion and Rapid Regeneration of Foxp3+ Regulatory T Cells Following Anti-CD25 Treatment in Malaria-Infected Mice
Authors: Couper Kevin N. , Blount Daniel G. , de Souza J. Brian , Suffia Isabelle , Belkaid Yasmine , Riley Eleanor M. 
Published: April 2014

Abstract
Investigation of the role of regulatory T cells (Treg) in model systems is facilitated by their depletion using anti-CD25 Abs, but there has been considerable debate about the effectiveness of this strategy. In this study, we have compared the depletion and repopulation of CD4+CD25+Foxp3+ Treg in uninfected and malaria-infected mice using 7D4 and/or PC61 anti-CD25 Abs. We find that numbers and percentages of CD25high cells, but not Foxp3+ cells, are transiently reduced after 7D4 treatment, whereas treatment with PC61 alone or in combination with 7D4 (7D4 plus PC61) reduces but does not eliminate Foxp3+ cells for up to 2 wk. Importantly, all protocols fail to eliminate significant populations of CD25−Foxp3+ or CD25lowFoxp3+ cells, which retain potent regulatory capacity. By adoptive transfer we show that repopulation of the spleen by CD25highFoxp3+ cells results from the re-expression of CD25 on peripheral populations of CD25−Foxp3+ but not from the conversion of peripheral Foxp3− cells. CD25highFoxp3+ repopulation occurs more rapidly in 7D4-treated mice than in 7D4 plus PC61-treated mice, reflecting ongoing clearance of emergent CD25+Foxp3+ cells by persistent PC61 Ab. However, in 7D4 plus PC61-treated mice undergoing acute malaria infection, repopulation of the spleen by CD25+Foxp3+ cells occurs extremely rapidly, with malaria infection driving proliferation and CD25 expression in peripheral CD4+CD25−Foxp3+ cells and/or conversion of CD4+CD25−Foxp3− cells. Finally, we reveal an essential role for IL-2 for the re-expression of CD25 by Foxp3+ cells after anti-CD25 treatment and observe that TGF-β is required, in the absence of CD25 and IL-2, to maintain splenic Foxp3+ cell numbers and a normal ratio of Treg:non-Treg cells.
Gadd45α Regulates p38-Dependent Dendritic Cell Cytokine Production and Th1 Differentiation
Authors: Jirmanova Ludmila , Janković Dragana , Fornace Albert J. , Ashwell Jonathan D. 
Published: April 2014

Abstract
Gadd45α inhibits the activation of p38 by the T cell alternative pathway involving phosphorylation of p38 Tyr323. Given that T cell p38 may play a role in Th1 development, the response to Th-skewing Ags was analyzed in Gadd45α−/− mice. Despite constitutively increased p38 activity in Gadd45α−/− T cells, the Th1 immune response to Toxoplasma gondii Ag (STAg), was diminished. In contrast to T cells, dendritic cells (DC) lacked the alternative p38 activation pathway. Gadd45α−/− DCs responded to STAg with low levels of MAP kinase cascade-dependent p38 activation, IL-12 production, and CD40 expression. Wild-type T cells transferred into Gadd45α−/− recipients had a diminished Th1 response to STAg, whereas Gadd45α−/− T cells transferred into wild-type hosts behaved normally. Therefore, Gadd45α has tissue-specific and opposing functions on p38 activity, and Gadd45α-regulated p38 activation in DCs is a critical event in Th1 polarization in vivo.
FcεRI Aggregation Promotes Survival of Connective Tissue-Like Mast Cells but Not Mucosal-Like Mast Cells
Authors: Ekoff Maria , Strasser Andreas , Nilsson Gunnar 
Published: April 2014

Abstract
Mast cells play a critical role in IgE-dependent immediate hypersensitivity reactions. This is facilitated by their capacity to release inflammatory mediators and to undergo activation-induced survival upon cross-linking of the high-affinity IgE-receptor (FcεRI). Due to their heterogeneity, mast cells can be divided into two major groups: the connective tissue mast cells and the mucosal mast cells. We have previously shown that IL-3-dependent bone marrow-derived mast cells can undergo activation-induced survival that is dependent on the prosurvival gene A1. In this study, we have used two different protocols to develop murine connective tissue-like mast cells (CTLMC) and mucosal-like mast cells (MLMC) to investigate their capacity to survive an allergic reaction in vitro. In this study, we demonstrate that FcεRI stimulation promotes survival of CTLMC but not MLMC. Similarly, a prominent induction of A1 is observed only in CTLMC but not MLMC. MLMC have a higher basal level of the proapoptotic protein Bim compared with CTLMC. These findings demonstrate a difference among mast cell populations in their ability to undergo activation-induced survival after FcεRI stimulation, which might explain the slower turnover of CTMC in IgE-dependent reactions.
Human Dendritic Cells Acquire a Semimature Phenotype and Lymph Node Homing Potential through Interaction with CD4+CD25+ Regulatory T Cells
Authors: Bayry Jagadeesh , Triebel Frédéric , Kaveri Srini V. , Tough David F. 
Published: April 2014

Abstract
Interactions between dendritic cells (DC) and T cells are known to involve the delivery of signals in both directions. We sought to characterize the effects on human DC of contact with different subsets of activated CD4+ T cells. The results showed that interaction with CD25highCD4+ regulatory T cells (Tregs) caused DC to take on very different properties than contact with naive or memory phenotype T cells. Whereas non-Tregs stimulated DC maturation, culture with Tregs produced DC with a mixed phenotype. By many criteria, Tregs inhibited DC maturation, inducing down-regulation of costimulatory molecules and T cell stimulatory activity. However, DC exposed to Tregs also showed some changes typically associated with DC maturation, namely, increased expression of CCR7 and MHC class II molecules, and gained the ability to migrate in response to the CCR7 ligand CCL19. Both soluble factors and cell-associated molecules were shown to be involved in Treg modulation of DC, with lymphocyte activation gene 3 (LAG-3) playing a predominant role in driving maturation-associated changes. The data show that Tregs induce the generation of semimature DC with the potential to migrate into lymphoid organs, suggesting a possible mechanism by which Tregs down-modulate immune responses.
Paired Ig-Like Receptors Bind to Bacteria and Shape TLR-Mediated Cytokine Production
Authors: Nakayama Masafumi , Underhill David M. , Petersen Timothy W. , Li Bin , Kitamura Toshio , Takai Toshiyuki , Aderem Alan 
Published: April 2014

Abstract
The innate immune system uses a wide variety of pattern recognition receptors including TLRs, scavenger receptors, and lectins to identify potential pathogens. A carefully regulated balance between activation and inhibition must be kept to avoid detrimental and inappropriate inflammatory responses. In this study, we identify murine-paired Ig-like receptor (PIR)-B, and its human orthologs Ig-like transcript 2 and Ig-like transcript 5 as novel receptors for Staphylococcus aureus. PIR-B contains four ITIM motifs and is thought to be an inhibitory receptor. Expression of these receptors enables NIH3T3 cells to bind S. aureus. In mouse bone marrow-derived macrophages, masking of PIR-B by anti-PIR mAb or genetic deletion of PIR-B shows significantly impaired recognition of S. aureus and enhanced TLR-mediated inflammatory responses to the bacteria. These data suggest a novel mechanism for innate immune regulation by paired Ig-like receptor family members.
TGF-β Suppresses IFN-γ-STAT1-Dependent Gene Transcription by Enhancing STAT1-PIAS1 Interactions in Epithelia but Not Monocytes/Macrophages
Authors: Reardon Colin , McKay Derek M. 
Published: April 2014

Abstract
IFN-γ and TGF-β are important regulators of mucosal immunity, typically functioning in opposition to each other. In this study, we assessed whether TGF-β could modulate IFN-γ-induced STAT1 signaling. Model epithelial cell lines (HEp-2, HT-29, and T84) or monocytes/macrophages (THP-1 cell line, human blood mononuclear cells) were pretreated with TGF-β (1 ng/ml; 5–60 min), followed by IFN-γ exposure (20 ng/ml; 30 min), and then STAT1 transcriptional activity, DNA-binding activity, phosphorylation, and methylation were assessed. Some epithelia were transfected with an expression plasmid encoding SMAD7 to block TGF-β-SMAD signaling. Epithelia, but not macrophages, pretreated with TGF-β were hyporesponsive to IFN-γ stimulation as indicated by reduced expression of four STAT1-regulated genes and reduced STAT1 DNA binding on EMSA. However, STAT1 Tyr701-, Ser727 phosphorylation, and nuclear recruitment of STAT1 were not significantly different in IFN-γ with or without TGF-β-treated cells, indicating that the effects of TGF-β are downstream of IFN-γR-JAK-STAT1 interaction. The TGF-β effect was not dependent on ERK1/2, p38, or JNK activation but was prevented by overexpression of the inhibitory SMAD7 protein. Additional studies suggest that TGF-β blockade of IFN-γ activity in epithelia is via enhanced sequestering of STAT1 by pre-existing protein inhibitor of activated STAT1. These results demonstrate that TGF-β rapidly suppresses IFN-γ-driven STAT1 signaling by reducing DNA binding via promotion of STAT1-protein inhibitor of activated STAT1 interactions and not inhibition of STAT1 activation; an event that may be specific to epithelia and represent a novel mode of action of TGF-β.