bluuebunny/crossref_metadata_2025_split huggingface dataset:
Persistence of Infectious HIV on Follicular Dendritic Cells
Authors: Smith Beverly A. , Gartner Suzanne , Liu Yiling , Perelson Alan S. , Stilianakis Nikolaos I. , Keele Brandon F. , Kerkering Thomas M. , Ferreira-Gonzalez Andrea , Szakal Andras K. , Tew John G. , Burton Gregory F. 
Published: April 2014

AbstractFollicular dendritic cells (FDCs) trap Ags and retain them in their native state for many months. Shortly after infection, HIV particles are trapped on FDCs and can be observed until the follicular network is destroyed. We sought to determine whether FDCs could maintain trapped virus in an infectious state for long periods of time. Because virus replication would replenish the HIV reservoir and thus falsely prolong recovery of infectious virus, we used a nonpermissive murine model to examine maintenance of HIV infectivity in vivo. We also examined human FDCs in vitro to determine whether they could maintain HIV infectivity. FDC-trapped virus remained infectious in vivo at all time points examined over a 9-mo period. Remarkably, as few as 100 FDCs were sufficient to transmit infection throughout the 9-mo period. Human FDCs maintained HIV infectivity for at least 25 days in vitro, whereas virus without FDCs lost infectivity after only a few days. These data indicate that HIV retained on FDCs can be long lived even in the absence of viral replication and suggest that FDCs stabilize and protect HIV, thus providing a long-term reservoir of infectious virus. These trapped stores of HIV may be replenished with replicating virus that persists even under highly active antiretroviral therapy and would likely be capable of causing infection on cessation of drug therapy.
Normal B Cells Express51p1-Encoded Ig Heavy Chains That Are Distinct From Those Expressed by Chronic Lymphocytic Leukemia B Cells
Authors: Widhopf George F. , Kipps Thomas J. 
Published: April 2014

Abstract51p1 is an allele of VH1-69 that frequently is expressed by chronic lymphocytic leukemia (CLL) B cells with little or no somatic mutation. The rearranged 51p1 genes expressed by CLL B cells have a distinctive use of D segments D3-3/DXP4 and D3-10/DXP′1, a favored use of JH6, and a longer third complementarity-determining region than the rearranged Ig genes used by CLL B cells that express VH1 genes other than VH1-69. We examined the 51p1-encoded Ig expressed by blood B cells of healthy donors. In contrast to the infrequent use of JH4 by 51p1-expressing CLL (e.g., 4%), 36% of the rearranged 51p1 sequences from normal blood B cells used JH4. Furthermore, the D segment use of the rearranged 51p1 sequences from normal blood B cells was not restricted, but reflected the D segment use of nonselected IgH of normal B cells. Finally, the mean length of the third complementarity-determining region for the 51p1 genes of normal blood B cells was 14.6 ± 4.3 (SD) codons. This is significantly shorter than that noted for 51p1-expressing CLL B cells (18.8 ± 3.2; p &lt; 0.0001, n = 51). This study demonstrates that the 51p1-encoded IgH expressed in CLL are not representative of the 51p1-encoded IgH expressed by normal blood B cells, indicating that CLL B cells express IgH that are distinctive from those found in the normal adult blood B cell repertoire.
Cutting Edge: FISP (IL-4-Induced Secreted Protein), a Novel Cytokine-Like Molecule Secreted by Th2 Cells
Authors: Schaefer Gabriele , Venkataraman Chandrasekar , Schindler Ulrike 
Published: April 2014

Abstract
Th cell subsets, namely Th1 and Th2 cells, play an important role in mounting an immune response against invading pathogens. Several genes are selectively up-regulated during differentiation and effector phases of Th subsets. In this study, we report the identification of a novel cytokine-like molecule designated FISP (IL-4-induced secreted protein), which is selectively expressed and secreted by Th2 cells. Detectable levels of FISP are observed only 3 days after initiation of Th2 differentiation. Expression of FISP in developing Th cells requires at least two signals: TCR signaling involving protein kinase C activation and STAT6-dependent IL-4R signaling.
Cutting Edge: Antigen-Independent CD8 T Cell Proliferation
Authors: Wong Phillip , Pamer Eric G. 
Published: April 2014

AbstractRecent analyses of CD8 T cell responses to Listeria monocytogenes infection demonstrate that the duration of in vivo T cell proliferation is not determined by the amount or duration of Ag presentation. However, the extent to which T lymphocytes are capable of proliferating in the absence of Ag is unknown. Herein we demonstrate that CD8 T lymphocytes undergo up to eight rounds of proliferation in the absence of Ag following transient, 2.5-h in vitro antigenic stimulation. Ag-independent expansion of CD8 T cells is driven by IL-2 and is further augmented by IL-7 or IL-15. These experiments clearly demonstrate that CD8 T cells undergo prolonged proliferation following transient Ag exposure and support the notion that in vivo CD8 T cell expansion following infection can be uncoupled from Ag presentation.
Cutting Edge: A Single MHC Anchor Residue Alters the Conformation of a Peptide-MHC Complex Inducing T Cells That Survive Negative Selection
Authors: Peterson Daniel A. , DiPaolo Richard J. , Kanagawa Osami , Unanue Emil R. 
Published: April 2014

AbstractWe generated transgenic mice that expressed hen egg-white lysozyme (HEL) under a class II MHC promoter. The A7 line expressed HEL with a point mutation in the Asp52 residue, the main anchor amino acid responsible for the selection of the chemically dominant family of peptides (52–60) by I-Ak molecules. Mice expressing HEL with Ala52 were completely unresponsive when immunized with the same protein, i.e., HEL A52. However, the same mice immunized with wild-type HEL elicited T cells that recognized a conformation of the 52–61 core sequence uniquely different between Asp52 and Ala52 containing peptides. Importantly, some T cells also recognized the HEL A52 peptide given exogenously but not the same peptide processed from HEL A52 protein. Thus, a core MHC anchor residue influences markedly the specificity of the T cells. We discuss the relevance of these findings to autoimmunity and vaccination with altered peptides.
Cutting Edge: Systemic Inhibition of Angiogenesis Underlies Resistance to Tumors During Acute Toxoplasmosis
Authors: Hunter Christopher A. , Yu Duonan , Gee Michael , Ngo Cam V. , Sevignani Cinzia , Goldschmidt Michael , Golovkina Tatyana V. , Evans Sydney , Lee William F. , Thomas-Tikhonenko Andrei 
Published: April 2014

Abstract
The ability of various infections to suppress neoplastic growth has been well documented. This phenomenon has been traditionally attributed to infection-induced concomitant, cell-mediated antitumor immunity. We found that infection with Toxoplasma gondii effectively blocked neoplastic growth of a nonimmunogenic B16.F10 melanoma. Moreover, this effect was independent of cytotoxic T or NK cells, production of NO by macrophages, or the function of the cytokines IL-12 and TNF-α. These findings suggested that antitumor cytotoxicity was not the primary mechanism of resistance. However, infection was accompanied by strong, systemic suppression of angiogenesis, both in a model system and inside the nascent tumor. This suppression resulted in severe hypoxia and avascular necrosis that are incompatible with progressive neoplastic growth. Our results identify the suppression of tumor neovascularization as a novel mechanism critical for infection-induced resistance to tumors.
Human Dendritic Cells Are Activated by Chimeric Human Papillomavirus Type-16 Virus-Like Particles and Induce Epitope-Specific Human T Cell Responses In Vitro
Authors: Rudolf Michael P. , Fausch Steven C. , Da Silva Diane M. , Kast W. Martin 
Published: April 2014

Abstract
Human papillomavirus (HPV)-derived chimeric virus-like particles (VLPs) are the leading candidate vaccine for the treatment or prevention of cervical cancer in humans. Dendritic cells (DCs) are the most potent inducers of immune responses and here we show for the first time evidence for binding of chimeric HPV-16 VLPs to human peripheral blood-derived DCs. Incubation of immature human DCs with VLPs for 48 h induced a significant up-regulation of the CD80 and CD83 molecules as well as secretion of IL-12. Confocal microscopy analysis revealed that cell surface-bound chimeric VLPs were taken up by DCs. Moreover, DCs loaded with chimeric HPV-16 L1L2-E7 VLPs induced an HLA-*0201-restricted human T cell response in vitro specific for E7-derived peptides. These results clearly demonstrate that immature human DCs are fully activated by chimeric HPV-16 VLPs and subsequently are capable of inducing endogenously processed epitope-specific human T cell responses in vitro. Overall, these findings could explain the high immunogenicity and efficiency of VLPs as vaccines.
Distinct BMI-1 and EZH2 Expression Patterns in Thymocytes and Mature T Cells Suggest a Role for Polycomb Genes in Human T Cell Differentiation
Authors: Raaphorst Frank M. , Otte Arie P. , van Kemenade Folkert J. , Blokzijl Tjasso , Fieret Elly , Hamer Karien M. , Satijn David P. E. , Meijer Chris J. L. M. 
Published: April 2014

Abstract
BMI-1 and EZH2 Polycomb-group (PcG) proteins belong to two distinct protein complexes involved in the regulation of hematopoiesis. Using unique PcG-specific antisera and triple immunofluorescence, we found that mature resting peripheral T cells expressed BMI-1, whereas dividing blasts were EZH2+. By contrast, subcapsular immature double-negative (DN) (CD4−/CD8−) T cells in the thymus coexpressed BMI-1 and EZH2 or were BMI-1 single positive. Their descendants, double-positive (DP; CD4+/CD8+) cortical thymocytes, expressed EZH2 without BMI-1. Most EZH2+ DN and DP thymocytes were dividing, while DN BMI-1+/EZH2− thymocytes were resting and proliferation was occasionally noted in DN BMI-1+/EZH2+ cells. Maturation of DP cortical thymocytes to single-positive (CD4+/CD8− or CD8+/CD4−) medullar thymocytes correlated with decreased detectability of EZH2 and continued relative absence of BMI-1. Our data show that BMI-1 and EZH2 expression in mature peripheral T cells is mutually exclusive and linked to proliferation status, and that this pattern is not yet established in thymocytes of the cortex and medulla. T cell stage-specific PcG expression profiles suggest that PcG genes contribute to regulation of T cell differentiation. They probably reflect stabilization of cell type-specific gene expression and irreversibility of lineage choice. The difference in PcG expression between medullar thymocytes and mature interfollicular T cells indicates that additional maturation processes occur after thymocyte transportation from the thymus.
A Requirement for IL-2/IL-2 Receptor Signaling in Intrathymic Negative Selection
Authors: Bassiri Hamid , Carding Simon R. 
Published: April 2014

AbstractThe nature of the signals that influence thymocyte selection and determine the fate of CD4+8+ (double positive) thymocytes remains unclear. Cytokines produced locally in the thymus may modulate signals delivered by TCR-MHC/peptide interactions and thereby influence the fate of double-positive thymocytes. Because the IL-2/IL-2R signaling pathway has been implicated in thymocyte and peripheral T cell survival, we investigated the possibility that IL-2/IL-2R interactions contribute to the deletion of self-reactive, Ag-specific thymocytes. By using nontransgenic and transgenic IL-2-sufficient and -deficient animal model systems, we have shown that during TCR-mediated thymocyte apoptosis, IL-2 protein is expressed in situ in the thymus, and apoptotic thymocytes up-regulate expression of IL-2Rs. IL-2R+ double-positive and CD4 single-positive thymocytes undergoing activation-induced cell death bind and internalize IL-2. IL-2-deficient thymocytes are resistant to TCR/CD3-mediated apoptotic death, which is overcome by providing exogenous IL-2 to IL-2−/− mice. Furthermore, disruption or blockade of IL-2/IL-2R interactions in vivo during Ag-mediated selection rescues some MHC class II-restricted thymocytes from apoptosis. Collectively, these findings provide evidence for the direct involvement of the IL-2/IL-2R signaling pathway in the deletion of Ag-specific thymocyte populations and suggest that CD4 T cell hyperplasia and autoimmunity in IL-2−/− mice is a consequence of ineffective deletion of self-reactive T cells.
Inhibition of Antigen-Induced Mediator Release from IgE-Sensitized Cells by a Monoclonal Anti-FcεRI α-Chain Receptor Antibody: Implications for the Involvement of the Membrane-Proximal α-Chain Region in FcεRI-Mediated Cell Activation
Authors: Nechansky Andreas , Robertson Michael W. , Albrecht Bettina A. , Apgar John R. , Kricek Franz 
Published: April 2014

AbstractThe interaction between human IgE and its high affinity receptor, FcεRI, is a critical event in mediating the allergic response. Aggregation of the α-chain of FcεRI (FcεRIα) occurs via cross-linking of receptor-bound IgE by Ag, resulting in cell activation and the release of mediators of hypersensitivity. Recently, we mapped the epitopes of two anti-FcεRIα mAbs, 15/1 and 5H5F8. In contrast to 15/1, mAb 5H5F8 does not inhibit IgE binding to FcεRIα. Here we demonstrate both 5H5F8 binding to FcεRI+ cells as well as a high level of IgE binding to 5H5F8-saturated cells. At the same time 5H5F8 strongly inhibits hexosaminidase release and Ca2+ flux after Ag triggering from human IgE-sensitized RBL-2H3 cells stably transfected with human FcεRIα. Further, 5H5F8 and its Fab inhibit sulfidoleukotriene and histamine release from primary human peripheral blood leukocytes, including cells bearing endogenous IgE. Furthermore, we confirm that 5H5F8 maps to a linear peptide sequence in close proximity to the cell membrane. Two chemically synthesized peptides containing the 5H5F8 epitope sequence PREKY were selected for detailed analysis of 5H5F8 and 5H5F8 Fab binding and were found to produce Kd values of similar magnitude to that observed for binding to recombinant FcεRIα. These peptides may prove useful as targets for the identification of antagonists of FcεRIα-mediated biological activity. Moreover, our data indicate that FcεRIα-mediated activation may involve a novel α-chain epitope in an early step of the cell-triggering pathway leading to cellular activation.
Histamine Induces CD86 Expression and Chemokine Production by Human Immature Dendritic Cells
Authors: Caron Gersende , Delneste Yves , Roelandts Edith , Duez Catherine , Herbault Nathalie , Magistrelli Giovanni , Bonnefoy Jean-Yves , Pestel Joel , Jeannin Pascale 
Published: April 2014

AbstractMast cells and immature dendritic cells (DC) are in close contact in peripheral tissues. Upon activation, mast cells release histamine, a mediator involved in the immediate hypersensitivity reaction. We therefore tested whether histamine could affect human DC activation and maturation. Histamine induces CD86 expression on immature DC in a dose-dependent (significant at 10−7 M) and transient manner (maximal after 24-h stimulation). Histamine also transiently up-regulates the expression of the costimulatory and accessory molecules, CD40, CD49d, CD54, CD80, and MHC class II. As a consequence, immature DC exposed for 24 h to histamine stimulate memory T cells more efficiently than untreated DC. In addition, histamine induces a potent production of IL-6, IL-8, monocyte chemoattractant protein 1, and macrophage-inflammatory protein 1α by immature DC and also up-regulates IL-1β, RANTES, and macrophage-inflammatory protein 1β but not TNF-α and IL-12 mRNA expression. Histamine activates immature DC through both the H1 and H2 receptors. However, histamine-treated DC do not have a phenotype of fully mature cells, as they do neither show significant changes in the expression of the chemokine receptors, CCR5, CCR7 and CXC chemokine receptor 4, nor expression of CD83 de novo. These data demonstrate that histamine activates immature DC and induces chemokine production, thereby suggesting that histamine, via stimulation of resident DC, may participate locally in T cell stimulation and in the late inflammatory reaction associated with allergic disorders.
Signaling Through MHC Class II Molecules Blocks CD95-Induced Apoptosis
Authors: Catlett Ian M. , Xie Ping , Hostager Bruce S. , Bishop Gail A. 
Published: April 2014

AbstractB cells are induced to express CD95 upon interaction with T cells. This interaction renders the B cells sensitive to CD95-mediated apoptosis, but ligation of proviability surface receptors is able to inhibit apoptosis induction. MHC class II is a key molecule required for Ag presentation to Th cells, productive T cell-B cell interaction, and B cell activation. We demonstrate here for the first time that MHC class II ligation also confers a rapid resistance to CD95-induced apoptosis, an affect that does not require de novo protein synthesis. Signaling through class II molecules blocks the activation of caspase 8, but does not affect the association of CD95 and Fas-associated death domain-containing protein. MHC class II ligation thus blocks proximal signaling events in the CD95-mediated apoptotic pathway.
Requirement for a Complex Array of Costimulators in the Negative Selection of Autoreactive Thymocytes In Vivo
Authors: Li Ruixia , Page Dawne M. 
Published: April 2014

AbstractAutoreactive thymocytes can be deleted at an immature stage of their development by Ag-induced apoptosis or negative selection. In addition to Ag, negative selection also requires costimulatory signals from APC. We recently used a fetal thymus organ culture system to show that CD5, CD28, and TNF cooperatively regulate deletion of autoreactive thymocytes. Although these experiments provided strong evidence for the action of several costimulators in negative selection, we wished to demonstrate a role for these molecules in a physiologically natural model where thymocytes are deleted in vivo by endogenously expressed Ags. Accordingly, we examined thymocyte deletion in costimulator-null mice in three models of autoantigen-induced negative selection. We compared CD5−/− CD28−/− mice to CD40L−/− mice, which exhibited a profound block in negative selection in all three systems. Surprisingly, only one of the three models revealed a requirement for the CD5 and CD28 costimulators in autoantigen-induced deletion. These results suggest that an extraordinarily complex array of costimulators is involved in negative selection. We predict that different sets of costimulators will be required depending on the timing of negative selection, the Ag, the signal strength, the APC, and whether Ag presentation occurs on class I or class II MHC molecules.
Role for Transcription Pax5A Factor in Maintaining Commitment to the B Cell Lineage by Selective Inhibition of Granulocyte-Macrophage Colony-Stimulating Factor Receptor Expression
Authors: Chiang Mark Y. , Monroe John G. 
Published: April 2014

Abstract
During early B lymphopoiesis, developing B cells maintain lineage commitment despite the local presence of myeloid lineage-promoting cytokines such as GM-CSF and IL-3. Previous observations suggest that the B cell-specific transcription factor Pax5A (paired box 5A transcription factor) plays a role in maintaining B cell lineage commitment by limiting expansion and survival of early IL-3/GM-CSF-dependent myeloid lineage cells. To define a mechanism by which Pax5A can exert these inhibitory effects on myeloid lineage differentiation, an inducible form of the Pax5A protein was expressed in the myeloid cell line FDC-P1. This cell line models myeloid progenitors in that it responds to the survival and growth-potentiating effects of IL-3 and GM-CSF. We observed that enforced expression of Pax5A selectively suppressed proliferation in response to GM-CSF, but not IL-3. This effect was associated with specific down-regulation of GM-CSFR α-chain, but not β-chain expression. These data provide a molecular mechanism to enforce commitment to the B cell lineage despite the presence of GM-CSF, a factor that has been shown to convert early developing B cells to the myeloid lineage. Furthermore, they indicate a role for B cell Pax5A expression in maintaining rather than directing commitment to the B cell lineage.
Cell-Associated Ovalbumin Is Cross-Presented Much More Efficiently than Soluble Ovalbumin In Vivo
Authors: Li Ming , Davey Gayle M. , Sutherland Robyn M. , Kurts Christian , Lew Andrew M. , Hirst Claire , Carbone Francis R. , Heath William R. 
Published: April 2014

Abstract
To better understand the antigenic requirements for cross-presentation, we compared the in vivo efficiency of presentation of cell-associated vs soluble OVA with the OT-I (CD8) and OT-II (CD4) TCR transgenic lines. Cross-presentation of cell-associated OVA was very efficient, requiring as little as 21 ng of OVA to activate OT-II cells and 100-fold less to activate OT-I cells. In contrast, soluble OVA was presented inefficiently, requiring at least 10,000 ng OVA for activation of either T cell subset. Thus, cell-associated OVA was presented 500-fold more efficiently than soluble OVA to CD4 T cells and 50,000-fold more efficiently to CD8 T cells. These data, which represent the first quantitative in vivo analysis of cross-presentation, show that cell-associated OVA is very efficiently presented via the class I pathway.
Stage-Specific Modulation of IFN-Regulatory Factor 4 Function by Krüppel-Type Zinc Finger Proteins
Authors: Gupta Sanjay , Anthony Alissa , Pernis Alessandra B. 
Published: April 2014

AbstractOptimal humoral responses depend on the activation of Ag-specific B cells, followed by their progression toward a fully differentiated phenotype. Acquisition of stage-appropriate patterns of gene expression is crucial to this differentiation program. However, the molecular mechanisms used by B cells to modulate gene expression as they complete their maturation program are poorly understood. IFN-regulatory factor 4 (IRF-4) plays a critical role in mature B cell function. Using the transcriptional regulation of the human B cell activation marker CD23 as a model system, we have previously demonstrated that IRF-4 is induced in response to B cell-activating stimuli and that it acts as a transactivator of CD23 gene expression. We have furthermore found that IRF-4 function can be blocked by B cell lymphomas 6 (BCL-6) protein, a Krüppel-type zinc finger repressor normally expressed in germinal center B cells. However, CD23 expression is known to be down-regulated in plasma cells despite high level expression of IRF-4 and the lack of BCL-6, suggesting that in plasma cells the IRF-4-mediated induction of CD23 is prevented by its interaction with a distinct repressor. In this set of studies, we demonstrate that IRF-4 interacts with B lymphocyte-induced maturation protein/positive regulatory domain I-binding factor 1 (Blimp1/PRD1-BF1), a Krüppel-type zinc finger protein whose expression correlates with terminal B cell differentiation. Functional studies indicate that Blimp1, like BCL-6, can block IRF-4-transactivating ability. These findings thus support a model whereby IRF-4 function is modulated in a stage-specific manner by its interaction with developmentally restricted sets of Krüppel-type zinc finger proteins.