bluuebunny/crossref_metadata_2025_split huggingface dataset:
Cutting Edge Commentary: Origins of B-1 Cells
Authors: Wortis Henry H. , Berland Robert 
Published: April 2014

Abstract
The origin of B-1a cells, a minority population of B cells that express CD5, are abundant in coelomic cavities, and often produce autoantibodies, has been the subject of study for many years. Accumulating evidence demonstrates that the hypothesis that only B cells arising in fetal or neonatal tissues have the potential to become B-1a cells cannot be true. Rather, B cell receptor-mediated signaling initiated by ligation of autoantigen has now been shown to be required for induction of the B-1a phenotype. Furthermore, cells with a functional B-1a phenotype can be induced from adult precursors by appropriate Ag. At the same time, microenvironment-specific events may determine the likelihood that a given B cell, either adult or fetal derived, enters this pathway. CD5 expression and possibly localization to the peritoneum appear to provide some protection to autoreactive cells otherwise slated for elimination.
Cutting Edge: Peripheral Neuropeptides Attract Immature and Arrest Mature Blood-Derived Dendritic Cells
Authors: Dunzendorfer Stefan , Kaser Arthur , Meierhofer Christian , Tilg Herbert , Wiedermann Christian J. 
Published: April 2014

Abstract
Dendritic cells (DC) are highly motile and play a key role in mediating immune responses in various tissues and lymphatic organs. We investigated locomotion of mononuclear cell-derived DC at different maturation stages toward gradients of sensory neuropeptides in vitro. Calcitonin gene-related peptide, vasoactive intestinal polypeptide, secretin, and secretoneurin induced immature DC chemotaxis comparable to the potency of RANTES, whereas substance P and macrophage-inflammatory protein-3β stimulated immature cell migration only slightly. Checkerboard analyses revealed a true chemotactic response induced by neuropeptides. Upon maturation of DC, neuropeptides inhibited spontaneous, macrophage-inflammatory protein-3β- and 6Ckine-induced cell migration. Maturation-dependent changes in migratory behavior coincided with distinct neuropeptide-induced signal transduction in DC. Peripheral neuropeptides might guide immature DC to peripheral nerve fibers where high concentrations of these peptides can arrest the meanwhile matured cells. It seems that one function of sensory nerves is to fasten DC at sites of inflammation.
Cutting Edge: Stat6-Dependent Substrate Depletion Regulates Nitric Oxide Production
Authors: Rutschman Robert , Lang Roland , Hesse Matthias , Ihle James N. , Wynn Thomas A. , Murray Peter J. 
Published: April 2014

AbstractThe cytokines IL-4 and IL-13 inhibit the production of NO from activated macrophages through an unresolved molecular mechanism. We show here that IL-4 and IL-13 regulate NO production through depletion of arginine, the substrate of inducible NO synthase (iNOS). Inhibition of NO production from murine macrophages stimulated with LPS and IFN-γ by IL-4 or IL-13 was dependent on Stat6, cell density in the cultures, and pretreatment for at least 6 h. IL-4/IL-13 did not interfere with the expression or activity of iNOS but up-regulated arginase I (the liver isoform of arginase) in a Stat6-dependent manner. Addition of exogenous arginine completely restored NO production in IL-4-treated macrophages. Furthermore, impaired killing of the intracellular pathogen Toxoplasma gondii in IL-4-treated macrophages was overcome by supplementing l-arginine. The simple system of regulated substrate competition between arginase and iNOS has implications for understanding the physiological regulation of NO production.
Novel Secondary Ig VH Gene Rearrangement and In-Frame Ig Heavy Chain Complementarity-Determining Region III Insertion/Deletion Variants in De Novo Follicular Lymphoma
Authors: Kobrin Carol B. , Bendandi Maurizio , Kwak Larry W. 
Published: April 2014

Abstract
Human germinal center B cell tumors retain the ability of their nontransformed counterparts to somatically hypermutate Ig V genes by nucleotide substitution. Among a survey of 60 primary previously untreated, clonal, follicular lymphomas we have identified a rare VH rearrangement variant and two other in-frame nucleotide insertion/deletion variants within complementarity-determining region III of the Ig heavy chain. The neoplastic origin of the VH rearrangement variant was directly demonstrated in cells isolated by microdissection from malignant follicles. In all three cases a common clonal origin for the variants was demonstrated by complementarity-determining region III nucleotide sequence homology and shared somatic mutations in germline encoded positions in framework region IV. The monoclonal nature of the tumors was independently confirmed by demonstrating a single t(14;18) translocation breakpoint in the two cases with a detectable translocation. All the variants occurred in functional VH rearrangements, which in two cases were directly shown to encode functional Ab molecules. Both recombination-activating genes 1 and 2 were expressed in lymph node tumor cells containing the VH rearrangement variant, although recombination-activating gene expression among a panel of lymphomas was not limited to this variant.
Effector Function of Resting T Cells: Activation of Synovial Fibroblasts
Authors: Yamamura Yuji , Gupta Raj , Morita Yoshitaka , He Xiaogang , Pai Rajiv , Endres Judith , Freiberg Andrew , Chung Kevin , Fox David A. 
Published: April 2014

Abstract
Synovial tissue in rheumatoid arthritis is characterized by infiltration with large numbers of T lymphocytes and APCs as well as hyperplasia of synovial fibroblasts. Current understanding of the pathogenesis of RA includes the concept that synovial fibroblasts, which are essential to cartilage and bone destruction, are regulated by cytokines derived primarily from monocyte-macrophage cells. Recently it has been found that synovial fibroblasts can also function as accessory cells for T cell activation by superantigens and other stimuli. We have now found that highly purified resting T cells, even in the absence of T cell mitogens, induce activation of synovial fibroblasts when cocultured for 6–24 h. Such activation was evident by induction or augmentation of mRNA for stromelysin, IL-6, and IL-8, gene products important in joint inflammation and joint destruction. Furthermore, increased production of IL-6 and IL-8 was quantitated by intracellular cytokine staining and flow cytometry. This technique, previously used for analysis of T cell function, was readily adaptable for assays of synovial fibroblasts. Resting T cells also induced synovial fibroblasts to produce PGE2, indicating activation of expression of the cyclooxygenase 2 gene. Synergy was observed between the effects of IL-17, a cytokine derived from stimulated T cells that activates fibroblasts, and resting T lymphocytes. Various subsets of T cells, CD4+, CD8+, CD45RO+, and CD45RA+ all had comparable ability to induce synovial fibroblast activation. These results establish an Ag-independent effector function for resting T cells that is likely to be important in inflammatory compartments in which large numbers of T lymphocytes and fibroblasts can come into direct contact with each other.
IFN-γ-Dependent Inhibition of Tumor Angiogenesis by Tumor-Infiltrating CD4+ T Cells Requires Tumor Responsiveness to IFN-γ
Authors: Beatty Gregory L. , Paterson Yvonne 
Published: April 2014

Abstract
The importance of CD4+ T cells in the induction of an optimal antitumor immune response has largely been attributed to their ability to provide costimulatory signals for the priming of MHC class I-restricted CD8+ CTL. However, many reports have demonstrated a requirement for CD4+ T cells in the effector phase of tumor rejection indicating a greater responsibility for CD4+ T cells in controlling tumor outgrowth. We demonstrate here a critical role for CD4+ T cells in restraining initial tumor development through the inhibition of tumor angiogenesis. Using a tumor variant that is unresponsive to IFN-γ, we show that tumor responsiveness to IFN-γ is necessary for IFN-γ-dependent inhibition of tumor angiogenesis by CD4+ T cells. These studies reveal a pivotal role for CD4+ T cells in controlling early tumor development through inhibition of tumor angiogenesis.
Oral QS-21 Requires Early IL-4 Help for Induction of Mucosal and Systemic Immunity
Authors: Boyaka Prosper N. , Marinaro Mariarosaria , Jackson Raymond J. , van Ginkel Frederik W. , Cormet-Boyaka Estelle , Kirk Kevin L. , Kensil Charlotte R. , McGhee Jerry R. 
Published: April 2014

Abstract
The highly purified saponin derivative, QS-21, from the Quillaja saponaria Molina tree has been proved to be safe for parenteral administration and represents a potential alternative to bacterial enterotoxin derivatives as a mucosal adjuvant. Here we report that p.o. administration of QS-21 with the vaccine protein tetanus toxoid elicited strong serum IgM and IgG Ab responses, which were only slightly enhanced by further oral immunization. The IgG Ab subclass responses were predominantly IgG1 followed by IgG2b for the 50-μg p.o. dose of QS-21, whereas the 250-μg p.o. dose also induced IgG2a and IgG3 Abs. Low oral QS-21 doses induced transient IgE Ab responses 7 days after the primary immunization, whereas no IgE Ab responses were seen in mice given the higher QS-21 dose. Further, low but not high p.o. QS-21 doses triggered Ag-specific secretory IgA (S-IgA) Ab responses. Th cell responses showed higher IFN-γ (Th1-type) and lower IL-5, IL-6, and IL-10 (Th2-type) secretion after the high QS-21 p.o. dose than after low doses. Interestingly, the mucosal adjuvant activity of low oral QS-21 doses was diminished in IL-4−/− mice, suggesting a role for this cytokine in the initiation of mucosal immunity by oral QS-21. In summary, our results show that oral QS-21 enhances immunity to coadministered Ag and that different doses of QS-21 lead to distinct patterns of cytokine and serum Ab responses. We also show that an early IL-4 response is required for the induction of mucosal immunity by oral QS-21 as adjuvant.
Vγ2 TCR Repertoire Overlap in Different Anatomical Compartments of Healthy, Unrelated Rhesus Macaques
Authors: MacDougall Alex V. , Enders Patrick , Hatfield Glen , Pauza David C. , Rakasz Eva 
Published: April 2014

Abstract
γδ T cells show preferential homing that is characterized by biased TCR repertoire at different anatomical locations. The processes that regulate this compartmentalization are largely unknown. A model that allows repeated multiple sample procurement under different conditions and enables with relatively straightforward extrapolation to a human situation will facilitate our understanding. The peripheral blood Vγ2 T cell population is the best-characterized human γδ T cell subset. To determine its diversity at multiple immunocompartments matching blood, colon, and vagina samples from rhesus macaques were investigated. Four joining segments used in Vγ2-Jγ transcripts were identified, including one segment with no human counterpart. Like in humans, the rhesus peripheral blood Vγ2 TCR repertoire was limited and contained common sequences that were shared by genetically heterogeneous animals. Furthermore, this subset comprised several phylogenetically conserved Vγ2 complementarity-determining region 3 (CDR3) motifs between rhesus and humans. Common sequences were also found within the colon and vagina of the same animal, and within the peripheral blood and intestine of different unrelated animals. These results validate rhesus macaques as a useful model for γδ TCR repertoire and homing studies. Moreover, they provide evidence that the concept of limited but overlapping Vγ TCR repertoire between unrelated individuals can be extended including the mucosa of the digestive and reproductive tract.
Induction of Hyporesponsiveness and Impaired T Lymphocyte Activation by the CD31 Receptor:Ligand Pathway in T Cells
Authors: Prager Elisabeth , Staffler Günther , Majdic Otto , Säemann Marcus D. , Godár Samuel , Zlabinger Gerhard J. , Stockinger Hannes 
Published: April 2014

AbstractCD31 is a member of the Ig superfamily expressed on various cell types of the vasculature, including a certain subpopulation of T lymphocytes. Previous reports suggest that interaction of CD31 with its heterophilic ligand on T cells (T cell CD31 ligand) plays a regulatory role in T lymphocyte activation. Here we demonstrate that a soluble rCD31-receptorglobulin (CD31Rg) specifically down-regulated the proliferation of human peripheral blood CD31− T lymphocytes stimulated via CD3 and CD28 mAbs. Notably, engagement of the T cell CD31 ligand by CD31Rg during primary stimulation also induced a prolonged unresponsive state in T cells. Retroviral transduction of CD31 into CD31− Th clones resulted in a significant inhibition of their proliferative capacity. When cocultured with purified CD31− T lymphocytes, irradiated CD31-transduced Th clones counterregulated the CD3/CD28-mediated activation of these cells. Furthermore, primary stimulation in the presence of CD31-transduced Th clones induced a comparable state of hyporesponsiveness in the T cell responders as the soluble CD31Rg. Thus, by counterregulating the activation of cognate T lymphocytes, CD31-expressing T cells might contribute to the establishment and maintenance of peripheral tolerance.
Protection Against Diabetes and Improved NK/NKT Cell Performance in NOD.NK1.1 Mice Congenic at the NK Complex
Authors: Carnaud Claude , Gombert Jean-Marc , Donnars Olivier , Garchon Henri-Jean , Herbelin André 
Published: April 2014

Abstract
The NK1.1 cell surface receptor, which belongs to the NKR-P1 gene cluster, has been bred onto nonobese diabetic (NOD) mice for two purposes. The first was to tag NK and NKT cells for easier experimental identification of those subsets and better analysis of their implication in type 1 diabetes. The second was to produce a congenic strain carrying Idd6, a susceptibility locus that has been repeatedly mapped in the vicinity of the NKR-P1 gene cluster and the NK complex, to explore the impact of this locus upon autoimmune diabetes. NOD.NK1.1 mice express the NK1.1 marker selectively on the surface of their NK and NKT cell subsets. In addition, the mice manifest reduced disease incidence and improved NK and NKT cell performance, as compared with wild-type NOD mice. The association of those two features in the same congenic strain constitutes a strong argument in favor of Idd6 being associated to the NK complex. This could explain at the same time the multiple alterations of innate immunity reported in NOD mice and the fact that disease onset can be readily modified by boosting the innate immune system of the mouse.
Microbial Lipopeptides Stimulate Dendritic Cell Maturation Via Toll-Like Receptor 2
Authors: Hertz Cheryl J. , Kiertscher Sylvia M. , Godowski Paul J. , Bouis Deborah A. , Norgard Michael V. , Roth Michael D. , Modlin Robert L. 
Published: April 2014

AbstractThe ability of dendritic cells (DC) to initiate immune responses in naive T cells is dependent upon a maturation process that allows the cells to develop their potent Ag-presenting capacity. Although immature DC can be derived in vitro by treatment of peripheral blood monocytes with GM-CSF and IL-4, additional signals such as those provided by TNF-α, CD40 ligand, or LPS are required for complete maturation and maximum APC function. Because we recently found that microbial lipoproteins can activate monocytes and DC through Toll-like receptor (TLR) 2, we also investigated whether lipoproteins can drive DC maturation. Immature DC were cultured with or without lipoproteins and were monitored for expression of cell surface markers indicative of maturation. Stimulation with lipopeptides increased expression of CD83, MHC class II, CD80, CD86, CD54, and CD58, and decreased CD32 expression and endocytic activity; these lipopeptide-matured DC also displayed enhanced T cell stimulatory capacity in MLR, as measured by T cell proliferation and IFN-γ secretion. The lipid moiety of the lipopeptide was found to be essential for induction of maturation. Preincubation of maturing DC with an anti-TLR2 blocking Ab before addition of lipopeptide blocked the phenotypic and functional changes associated with DC maturation. These results demonstrate that lipopeptides can stimulate DC maturation via TLR2, providing a mechanism by which products of bacteria can participate in the initiation of an immune response.
Colocalization of FcγRI-Targeted Antigen With Class I MHC: Implications for Antigen Processing
Authors: Guyre Cheryl A. , Barreda Marc E. , Swink Sharon L. , Fanger Michael W. 
Published: April 2014

Abstract
The high-affinity receptor for IgG (CD64 or FcγRI) is constitutively expressed exclusively on professional APCs (monocytes, macrophages, and dendritic cells). When Ag is targeted specifically to FcγRI, Ag presentation is markedly enhanced, although the mechanism of this enhancement is unknown. In an effort to elucidate the pathways involved in FcγRI targeting, we developed a model targeted Ag using enhanced green fluorescent protein (eGFP). This molecule, wH22xeGFP, consists of the entire humanized anti-FcγRI mAb H22 with eGFP genetically fused to the C-terminal end of each CH3 domain. wH22xeGFP binds within the ligand-binding region by its Fc end, as well as outside the ligand-binding region by its Fab ends, thereby cross-linking FcγRI. Confocal microscopy studies revealed that wH22xeGFP was rapidly internalized by the high-FcγRI-expressing cell line U937 10.6, but did not associate with intracellular proteins Rab4, Rab5a, or Lamp-1, suggesting that the targeted fusion protein was not localized in early endosomes, recycling vesicles, or lysosomes. Interestingly, wH22xeGFP was found colocalized with intracellular MHC class I, suggesting that FcγRI-targeted Ags may converge upon a class I processing pathway. These data are in agreement with studies in the mouse showing that FcγRI targeting can lead to Ag-specific activation of cytotoxic T cells. Data obtained from these studies should lead to a better understanding of how Ags targeted to FcγRI are processed and under what conditions they lead to presentation of antigenic peptides in MHC class I, as a foundation for the use of FcγRI-targeted Ags as vaccines.
Regulation of Inhibitory and Activating Killer-Cell Ig-Like Receptor Expression Occurs in T Cells After Termination of TCR Rearrangements
Authors: Vely Frédéric , Peyrat Marie-Alix , Couedel Christelle , Morcet Jean-François , Halary Franck , Davodeau François , Romagne François , Scotet Emmanuel , Saulquin Xavier , Houssaint Elisabeth , Schleinitz Nicolas , Moretta Alessandro , Vivier Eric , Bonneville Marc 
Published: April 2014

Abstract
A small fraction of T cells expresses killer-cell Ig-like receptors (KIR), a family of MHC class I-specific receptors that can modulate TCR-dependent activation of effector functions. Although KIR+ cells are enriched within Ag-experienced T cell subsets, the precise relationships between KIR+ and KIR− T cells and the stage of KIR induction on these lymphocytes remain unclear. In this study, we compared KIR− and KIR+ αβ T cell clones, sorted by means of the CD158b (KIR2DL2/KIR2DL3/KIR2DS2) specific mAb GL183. We isolated several pairs of CD158b+ and CD158b− αβ T cell clones sharing identical productive and nonproductive TCR transcripts. We showed that expression of functional KIR on T cells is regulated after termination of TCR rearrangements. Transcriptional regulation of KIR genes was documented in multiple T cell clones generated from the same donor, and the presence of KIR transcripts was also detected in KIR− T cells. These results document a complex regulation of KIR expression in T cells at both pre and posttranscriptional levels, under the control of yet undefined signals provided in vivo.
Comparison of a T Cell Clone and of T Cells from a TCR Transgenic Mouse: TCR Transgenic T Cells Specific for Self-Antigen Are Atypical
Authors: Dobbs Cathleen M. , Haskins Kathryn 
Published: April 2014

Abstract
It has been widely assumed that T cells from TCR-transgenic (Tg) mice better represent the behavior of T cells from normal mice than do in vitro cultures of T cell clones. We have found that autoreactive T cells arising in the presumably more physiological environment of the BDC-2.5 TCR-Tg mouse, despite being apparently “naive” in surface phenotype, are highly activated functionally and do not resemble CD4+ T cells from a spontaneously diabetic nonobese diabetic (NOD) mouse or the NOD-derived, diabetogenic CD4+ T cell clone of origin, BDC-2.5. Our results suggest that autoreactive T cells cloned from the spontaneously diabetic NOD mouse more closely resemble effector T cells arising during the natural disease process.
Selective Gene Expression and Activation-Dependent Regulation of Vasoactive Intestinal Peptide Receptor Type 1 and Type 2 in Human T Cells
Authors: Lara-Marquez Maria L. , O’Dorisio M. Sue , O’Dorisio Thomas M. , Shah Manisha H. , Karacay Bahri 
Published: April 2014

Abstract
Vasoactive intestinal peptide (VIP) has potent antiproliferative and anti-inflammatory functions in the immune system. Two structurally distinct G-protein-associated receptors, VIP receptor type 1 (VPAC1) and VIP receptor type 2 (VPAC2), mediate the biological effects of VIP. The regulation of VIP receptor gene expression and the distribution of these receptors in different compartments of the human immune systems are unknown. This study reports, for the first time, a quantitative analysis of VPAC1 and VPAC2 mRNA expression in resting and activated T cells as well as in resting monocytes. Purified human peripheral blood CD4+ T cells and CD8+ T cells were stimulated via the TCR/CD3 receptor complex. Using the novel fluorometric-based kinetic (real-time) RT-PCR, we determined that VPAC1 is constitutively expressed in resting T cells and monocytes; the levels of expression were significantly higher in monocytes and CD4+ T cells than in CD8+ T cells. VPAC1 mRNA expression is significantly higher relative to VPAC2 in resting CD4+ T cells and CD8+ T cells. VPAC2 is expressed at very low levels in resting T cells but is not detectable in resting monocytes. In vitro stimulation of Th cells with soluble anti-CD3 plus PMA induced a T cell activation-dependent down-regulation of VPAC1. VPAC1 is down-regulated under conditions of optimal T cell stimulation. Our results suggest that selective VIP effects on T cell function may be mediated via selective expression of VPAC1 and VPAC2 on T cells and monocytes. Furthermore, down-regulation of VPAC1 in CD4+ T cell subpopulations is highly correlated with T cell activation.