bluuebunny/crossref_metadata_2025_split huggingface dataset:
Immunization with Glucose-6-Phosphate Isomerase Induces T Cell-Dependent Peripheral Polyarthritis in Genetically Unaltered Mice
Authors: Schubert David , Maier Bert , Morawietz Lars , Krenn Veit , Kamradt Thomas 
Published: April 2014

Abstract
Rheumatoid arthritis is a chronic inflammatory disease primarily affecting the joints. The search for arthritogenic autoantigens that trigger autoimmune responses in rheumatoid arthritis has largely focused on cartilage- or joint-specific Ags. In this study, we show that immunization with the ubiquitously expressed glycolytic enzyme glucose-6-phosphate isomerase (G6PI) induces severe peripheral symmetric polyarthritis in normal mice. In genetically unaltered mice, T cells are indispensable for both the induction and the effector phase of G6PI-induced arthritis. Arthritis is cured by depletion of CD4+ cells. In contrast, Abs and FcγR+ effector cells are necessary but not sufficient for G6PI-induced arthritis in genetically unaltered mice. Thus, the complex pathogenesis of G6PI-induced arthritis in normal mice differs strongly from the spontaneously occurring arthritis in the transgenic K/B × N model where Abs against G6PI alone suffice to induce the disease. G6PI-induced arthritis demonstrates for the first time the induction of organ-specific disease by systemic autoimmunity in genetically unaltered mice. Both the induction and effector phase of arthritis induced by a systemic autoimmune response can be dissected and preventive and therapeutic strategies evaluated in this model.
Deletion of the Mouse Meprin β Metalloprotease Gene Diminishes the Ability of Leukocytes to Disseminate through Extracellular Matrix
Authors: Crisman Jacqueline M. , Zhang Binzhi , Norman Lourdes P. , Bond Judith S. 
Published: April 2014

Abstract
Meprins are metalloendopeptidases expressed by leukocytes in the lamina propria of the human inflamed bowel, that degrade extracellular matrix proteins in vitro implicating them in leukocyte transmigration events. The aims of these studies were to 1) examine the expression of meprins in the mouse mesenteric lymph node, 2) determine whether macrophages express meprins, and 3) determine whether deletion of the meprin β gene (Mep-1β) mitigated the ability of leukocytes to disseminate through extracellular matrix in vitro. These studies show that meprin α and β are expressed in leukocytes of the mouse mesenteric lymph node, and meprin α, but not β, decreased during intestinal inflammation. Deletion of Mep-1β gene decreased the ability of leukocytes to migrate through matrigel compared with wild-type leukocytes. Meprin β, but not α, was detected in cortical and medullary macrophages of the lymph node. Thus overall, meprin β is expressed by leukocytes in the draining lymph node of the intestine, regardless of the inflammatory status of the animal, and is likely to contribute to leukocyte transmigration events important to intestinal immune responses. Thus, the expression of meprins by leukocytes of the intestinal immune system may have important implications for diseases such as inflammatory bowel diseases, which are aggravated by leukocyte infiltration.
IL-4-Dependent Th2 Collateral Priming to Inhaled Antigens Independent of Toll-Like Receptor 4 and Myeloid Differentiation Factor 88
Authors: Eisenbarth Stephanie C. , Zhadkevich Alex , Ranney Patricia , Herrick Christina A. , Bottomly Kim 
Published: April 2014

Abstract
Allergic asthma is an inflammatory lung disease thought to be initiated and directed by type 2 helper T cells responding to environmental Ags. The mechanisms by which allergens induce Th2-adaptive immune responses are not well understood, although it is now clear that innate immune signals are required to promote DC activation and Th2 sensitization to inhaled proteins. However, the effect of ongoing Th2 inflammation, as seen in chronic asthma, on naive lymphocyte activation has not been explored. It has been noted that patients with atopic disorders demonstrate an increased risk of developing sensitivities to new allergens. This suggests that signals from an adaptive immune response may facilitate sensitization to new Ags. We used a Th2-adoptive transfer murine model of asthma to identify a novel mechanism, termed “collateral priming,” in which naive CD4+ T cells are activated by adaptive rather than innate immune signals. Th2 priming to newly encountered Ags was dependent on the production of IL-4 by the transferred Th2 population but was independent of Toll-like receptor 4 signaling and the myeloid differentiation factor 88 Toll-like receptor signaling pathway. These results identify a novel mechanism of T cell priming in which an Ag-specific adaptive immune response initiates distinct Ag-specific T cell responses in the absence of classical innate immune system triggering signals.
Multiepitope Trojan Antigen Peptide Vaccines for the Induction of Antitumor CTL and Th Immune Responses
Authors: Lu Jun , Higashimoto Yuichiro , Appella Ettore , Celis Esteban 
Published: April 2014

Abstract
We describe in this study a strategy to produce synthetic vaccines based on a single polypeptide capable of eliciting strong immune responses to a combination CTL and Th epitopes with the purpose of treating malignancies or preventing infectious diseases. This strategy is based on the capacity of Trojan Ags to deliver exogenous Ags into the intracellular compartments, where processing into MHC-binding peptides takes place. Our previous work demonstrated that Trojan Ags containing a CTL epitope localized to intracellular compartments, where MHC class I-binding peptides were generated in a TAP-independent fashion by the action of various exopeptidases and the endopeptidase furin. In this study, we report that Trojan Ags containing several CTL epitopes joined via furin-sensitive linkers generated all of the corresponding MHC class I-binding peptides, which were recognized by CTL. However, Trojan Ags prepared with furin-resistant linkers failed to produce the MHC class I-binding peptides. We also present data indicating that Trojan Ags bearing both CTL and Th epitopes can generate the corresponding MHC class I- and II-binding peptides, which are capable of stimulating T cell responses. Most significantly, in vivo vaccination of mice with a single injection of multiepitope Trojan Ags resulted in strong CTL and Th responses that translated into significant antitumor responses in a model of malignant melanoma. The overall results indicate that Trojan Ags prepared with furin-sensitive linkers are ideal candidates for producing synthetic multiepitope vaccines for the induction of CTL and Th responses that could be used against a variety of diseases, including cancer.
Pregnancy-Specific Down-Regulation of NF-κB Expression in T Cells in Humans Is Essential for the Maintenance of the Cytokine Profile Required for Pregnancy Success
Authors: McCracken Sharon A. , Gallery Eileen , Morris Jonathan M. 
Published: April 2014

Abstract
It is accepted that human pregnancy is associated with a shift away from Th1 type and a bias toward Th2-type immune responses. The molecular mechanisms that regulate this shift are as yet unknown. We assessed the expression and activity of NF-κB, a transcription factor that plays a central role in regulating immune responses. We isolated T cells from PBMCs from nonpregnant and pregnant females and demonstrated that the NF-κB/IκB signaling pathway is down-regulated in T cells in pregnancy. Using Western blotting, high levels of NF-κB (p65) were detected in all nuclear fractions of T cells from nonpregnant females. In contrast, low levels of p65 were detected in nuclear fractions from T cells from pregnant females. Levels of IκBα and -β were also higher in cytoplasmic fractions from T cells from nonpregnant than from pregnant females. The reduction in p65 levels in pregnancy was reflected in the activity of NF-κB in EMSA; T cells from pregnant females contain less active NF-κB than from nonpregnant females. Stimulation of T cells from nonpregnant females with PMA/ionomycin resulted in IκBα degradation, p65 translocation, and subsequent production of the Th1 cytokines IFN-γ and IL-2. In contrast, PMA stimulation had no effect on NF-κB activity in T cells from pregnant females, and this was reflected in reduced Th1 cytokine production. Using the inhibitor of NF-κB activity, SN50, we were able to show that NF-κB activity was essential for the production of Th1 cytokines, suggesting that specific down-regulation of NF-κB in T cells throughout gestation is paramount to pregnancy success through specific regulation of cytokine production.
Mycobacterium tuberculosis Resides in Nonacidified Vacuoles in Endocytically Competent Alveolar Macrophages from Patients with Tuberculosis and HIV Infection
Authors: Mwandumba Henry C. , Russell David G. , Nyirenda Mukanthu H. , Anderson Jennifer , White Sarah A. , Molyneux Malcolm E. , Squire S. Bertel 
Published: April 2014

Abstract
Alveolar macrophages (AM) are the first professional phagocytes encountered by aerosols containing infections in the lungs, and their phagocytic capacity may be affected by these infections or environmental particles. The aim of this study was to evaluate the innate endocytic and phagocytic properties of human AM obtained from patients with pulmonary tuberculosis and to characterize the vacuoles in which Mycobacterium tuberculosis bacilli reside in vivo. AM were obtained by bronchoalveolar lavage from patients with suspected tuberculosis and from asymptomatic volunteers (controls). Clinical case definitions were based on mycobacterial culture of respiratory specimens and HIV serology. To assess phagocytosis, endocytosis, and acidification of the endosomal system, AM were cultured with IgG-coated polystyrene beads, dextran, and a pH-sensitive reporter (3-(2,4-dinitroanilino)-3-amino-N-methyldipropylamine) and were evaluated by light and immunoelectron microscopy. Cells from 89 patients and 10 controls were studied. We found no significant difference between the two groups in the ability of AM either to ingest beads and dextran or to deliver them to acidified lysosomes. In AM from patients with tuberculosis, the bacilli were located in vacuoles that failed to accumulate endocytosed material and were not acidified. We concluded that AM from patients with tuberculosis and HIV infections were competent to endocytose and phagocytose material and to deliver the material to functional, acidified lysosomes. M. tuberculosis residing in these AM arrests the progression of their phagosomes, which fail to fuse with acidified lysosomes. This confirms, for the first time in humans with tuberculosis and HIV, the conclusions from previous animal and in vitro studies.
Treatment of Melanoma with 5-Fluorouracil or Dacarbazine In Vitro Sensitizes Cells to Antigen-Specific CTL Lysis through Perforin/Granzyme- and Fas-Mediated Pathways
Authors: Yang Sixun , Haluska Frank G. 
Published: April 2014

Abstract
Several factors may influence sensitivity of melanoma cells to CTL lysis. One is the avidity of the CTL TCR. A second is that certain cytotoxic drugs have been reported to sensitize cancer cells to CTL lysis through Fas-mediated apoptosis. In this study, we examined whether antineoplastic agents 5-fluorouracil (5-FU) and dacarbazine (DTIC) sensitize melanoma cells to lysis of G209 peptide-specific CTL. Our results show that CTL generated from PBMC are HLA-A2 restricted and gp100 specific. Treatment with 5-FU or DTIC sensitized melanoma cells to lysis of G209-specific CTL. Most importantly, 5-FU- or DTIC-treated melanoma cells also became sensitive to low-avidity CTL, which per se are less cytolytic to melanomas. We sought to identify apoptotic pathways mediating this effect. The enhanced cytolysis was mediated through the perforin/granzyme pathway. Although 5-FU up-regulated FasR expression on melanoma cells, sensitization was not blocked by anti-Fas Ab, and the G209-specific CTL was Fas ligand (FasL) negative. However, when G209-specific CTL were stimulated to express FasL, FasL signaling also contributed to enhanced cytolysis. DTIC treatment, which did not increase FasR expression, also sensitized FasL-mediated killing induced by neutralizing anti-Fas Ab. For CD95L-positive G209-specific CTL, the sensitization was primarily mediated through the perforin/granzyme pathway regardless of up-regulation of FasR. The findings demonstrate that cytotoxic drug-mediated sensitization primes both perforin/granzyme and Fas-mediated killing by melanoma-specific CTL. Considering that most of autoreactive antitumor CTL are low avidity, the findings provide experimental basis for understanding cytotoxic and immunologic therapeutic synergy in melanoma.
Angiogenesis-Inflammation Cross-Talk: Vascular Endothelial Growth Factor Is Secreted by Activated T Cells and Induces Th1 Polarization
Authors: Mor Felix , Quintana Francisco J. , Cohen Irun R. 
Published: April 2014

AbstractVascular endothelial growth factor (VEGF) and its receptors are critical in angiogenesis. The main player in the secretion and response to VEGF is the endothelial cell. We initiated this study to test whether T cells can secrete VEGF and are able to respond to it. Here we show that VEGF is secreted by T cells on stimulation by specific Ag or by IL-2 and by hypoxia; thus, activated T cells might enhance angiogenesis. Hypoxia also induced the expression in T cells of VEGFR2, suggesting that T cells might also respond to VEGF. Indeed, VEGF augmented IFN-γ and inhibited IL-10 secretion by T cells responding to mitogen or Ag; thus, VEGF can enhance a Th1 phenotype. Encephalitogenic T cells stimulated in the presence of VEGF caused more severe and prolonged encephalomyelitis. Thus, T cells can play a role in angiogenesis by delivering VEGF to inflammatory sites, and VEGF can augment proinflammatory T cell differentiation.
Cutting Edge: The Ontogeny and Function of Va14Ja18 Natural T Lymphocytes Require Signal Processing by Protein Kinase Cθ and NF-κB
Authors: Stanic Aleksandar K. , Bezbradica Jelena S. , Park Jang-June , Van Kaer Luc , Boothby Mark R. , Joyce Sebastian 
Published: April 2014

Abstract
The rapid and robust immunoregulatory cytokine response of Va14Ja18 natural T (iNKT) cells to glycolipid Ags determines their diverse functions. Unlike conventional T cells, iNKT lymphocyte ontogeny absolutely requires NF-κB signaling. However, the precise role of NF-κB in iNKT cell function and the identity of upstream signals that activate NF-κB in this T cell subset remain unknown. Using mice in which iNKT cell ontogeny has been rescued despite inhibition of NF-κB signaling, we demonstrate that iNKT cell function requires NF-κB in a lymphocyte-intrinsic manner. Furthermore, the ontogeny of functional iNKT cells requires signaling through protein kinase Cθ, which is dispensable for conventional T lymphocyte development. The unique requirement of protein kinase Cθ implies that signals emanating from the TCR activate NF-κB during iNKT cell development and function. Thus, we conclude that NF-κB signaling plays a crucial role at distinct levels of iNKT cell biology.
Cutting Edge: Optical Microspectrophotometry Supports the Existence of Gel Phase Lipid Rafts at the Lamellipodium of Neutrophils: Apparent Role in Calcium Signaling
Authors: Kindzelskii Andrei L. , Sitrin Robert G. , Petty Howard R. 
Published: April 2014

Abstract
Although much progress has been made in elucidating the biochemical properties of lipid rafts, there has been less success in identifying these structures within living cell membranes, which has led to some concern regarding their existence. One difficulty in analyzing lipid rafts using optical microscopy is their small size. We now test the existence of lipid rafts in polarized neutrophils, which redistribute lipid raft markers into comparatively large lamellipodia. Optical microspectrophotometry of Laurdan-labeled neutrophils revealed a large blue shift at lamellipodia relative to cell bodies. This blue shift disappeared after exposure to methyl-β-cyclodextrin (mβCD), which disrupts lipid rafts. The Ca2+ channel transient receptor potential-like channel-1, a lipid raft marker, traffics to lamellipodia, but redistributes uniformly about cells after exposure to mβCD. This is accompanied by disruption of Ca2+ waves normally initiated at lamellipodia. Thus, mβCD-sensitive lipid-ordered domains are present at and participate in signaling from the lamellipodia of living neutrophils.
Cutting Edge: Ligation of the Glucocorticoid-Induced TNF Receptor Enhances Autoreactive CD4+ T Cell Activation and Experimental Autoimmune Encephalomyelitis
Authors: Kohm Adam P. , Williams Julie S. , Miller Stephen D. 
Published: April 2014

Abstract
The glucocorticoid-induced TNFR (GITR) is expressed at high levels on resting CD4+CD25+ T regulatory (TR) cells and regulates their suppressive phenotype. Accordingly, we show that anti-GITR mAb treatment of SJL mice with proteolipid protein 139–151-induced experimental autoimmune encephalomyelitis significantly exacerbated clinical disease severity and CNS inflammation, and induced elevated levels of Ag-specific T cell proliferation and cytokine production. Interestingly, prior depletion of TR cells failed to result in exacerbated experimental autoimmune encephalomyelitis suggesting alternative targets for the anti-GITR mAb treatment. Importantly, naive CD4+CD25− T cells up-regulated GITR expression in an activation-dependent manner and anti-GITR mAb treatment enhanced the level of CD4+ T cell activation, proliferation, and cytokine production in the absence of TR cells both in vivo and in vitro. Taken together, these findings suggest a dual functional role for GITR as GITR cross-linking both inactivates TR cells and increases CD4+CD25− T cell effector function, thus enhancing T cell immunity.
B Cell-Dependent TCR Diversification
Authors: João Cristina , Ogle Brenda M. , Gay-Rabinstein Carlota , Platt Jeffrey L. , Cascalho Marilia 
Published: April 2014

AbstractT cell diversity was once thought to depend on the interaction of T cell precursors with thymic epithelial cells. Recent evidence suggests, however, that diversity might arise through the interaction of developing T cells with other cells, the identity of which is not known. In this study we show that T cell diversity is driven by B cells and Ig. The TCR Vβ diversity of thymocytes in mice that lack B cells and Ig is reduced to 6 × 102 from wild-type values of 1.1 × 108; in mice with oligoclonal B cells, the TCR Vβ diversity of thymocytes is 0.01% that in wild-type mice. Adoptive transfer of diverse B cells or administration of polyclonal Ig increases thymocyte diversity in mice that lack B cells 8- and 7-fold, respectively, whereas adoptive transfer of monoclonal B cells or monoclonal Ig does not. These findings reveal a heretofore unrecognized and vital function of B cells and Ig for generation of T cell diversity and suggest a potential approach to immune reconstitution.
Cellular FLIP Long Form-Transgenic Mice Manifest a Th2 Cytokine Bias and Enhanced Allergic Airway Inflammation
Authors: Wu Wenfang , Rinaldi Lisa , Fortner Karen A. , Russell Jennifer Q. , Tschopp Jürg , Irvin Charles , Budd Ralph C. 
Published: April 2014

Abstract
Cellular FLIP long form (c-FLIPL) is a caspase-defective homologue of caspase-8 that blocks apoptosis by death receptors. The expression of c-FLIPL in T cells can also augment extracellular signal-regulated kinase phosphorylation after TCR ligation via the association of c-FLIPL with Raf-1. This contributes to the hyperproliferative capacity of T cells from c-FLIPL-transgenic mice. In this study we show that activated CD4+ T cells from c-FLIPL-transgenic mice produce increased amounts of Th2 cytokines and decreased amounts of Th1 cytokines. This correlates with increased serum concentrations of the Th2-dependent IgG1 and IgE. The Th2 bias of c-FLIPL-transgenic CD4+ T cells parallels impaired NF-κB activity and increased levels of GATA-3, which contribute, respectively, to decreased IFN-γ and increased Th2 cytokines. The Th2 bias of c-FLIPL-transgenic mice extends to an enhanced sensitivity to OVA-induced asthma. Taken together, these results show that c-FLIPL can influence cytokine gene expression to promote Th2-driven allergic reaction, in addition to its traditional role of blocking caspase activation induced by death receptors.
A Toll-Like Receptor 2 Ligand Stimulates Th2 Responses In Vivo, via Induction of Extracellular Signal-Regulated Kinase Mitogen-Activated Protein Kinase and c-Fos in Dendritic Cells
Authors: Dillon Stephanie , Agrawal Anshu , Van Dyke Thomas , Landreth Gary , McCauley Laurie , Koh Amy , Maliszewski Charles , Akira Shizuo , Pulendran Bali 
Published: April 2014

AbstractThe adaptive immune system can generate distinct classes of responses, but the mechanisms that determine this are poorly understood. In this study, we demonstrate that different Toll-like receptor (TLR) ligands induce distinct dendritic cell (DC) activation and immune responses in vivo. Thus, Escherichia coli LPS (TLR-4 stimulus), activates DCs to produce abundant IL-12(p70), but little IL-10, and stimulates Th1 and Tc1 responses. In contrast, Pam-3-cys (TLR-2 stimulus) elicits less IL-12(p70), but abundant IL-10, and favors Th2 and T cytotoxic 2 (Tc2) responses. These distinct responses likely occur via differences in extracellular signal-regulated kinase signaling in DCs. Thus, Pam-3-cys induces enhanced extracellular signal-regulated kinase signaling, compared with LPS, resulting in suppressed IL-12(p70) and enhanced IL-10 production, as well as enhanced induction of the transcription factor, c-Fos. Interestingly, DCs from c-fos−/− mice produce more IL-12(p70), but less IL-10, compared with control DCs. Therefore, different TLR ligands induce distinct cytokines and signaling in DCs, and differentially bias Th responses in vivo.
Feline Immunodeficiency Virus Infection Phenotypically and Functionally Activates Immunosuppressive CD4+CD25+ T Regulatory Cells
Authors: Vahlenkamp Thomas W. , Tompkins Mary B. , Tompkins Wayne A. F. 
Published: April 2014

Abstract
Disease progression of feline immunodeficiency virus (FIV) infection is characterized by up-regulation of B7.1 and B7.2 costimulatory molecules and their ligand CTLA4 on CD4+ and CD8+ T cells. The CD4+CTLA4+B7+ phenotype described in FIV+ cats is reminiscent of CD4+CD25+CTLA4+ cells, a phenotype described for immunosuppressive T regulatory (Treg) cells. In the present study, we describe the phenotypic and functional characteristics of CD4+CD25+ T cells in PBMC and lymph nodes (LN) of FIV+ and control cats. Similar to Treg cells, feline CD4+CD25+ but not CD4+CD25− T cells directly isolated from LN of FIV+ cats do not produce IL-2 and fail to proliferate in response to mitogen stimulation. Unstimulated CD4+CD25+ T cells from FIV+ cats significantly suppress the proliferative response and the IL-2 production of Con A-stimulated autologous CD4+CD25− T cells compared with unstimulated CD4+CD25+ T cells from FIV− cats. Flow-cytometric analysis confirmed the apparent activation phenotype of the CD4+CD25+ cells in LN of chronically FIV+ cats, because these cells showed significant up-regulation of expression of costimulatory molecules B7.1, B7.2, and CTLA4. These FIV-activated, anergic, immunosuppressive CD25+CTLA4+B7+CD4+ Treg-like cells may contribute to the progressive loss of T cell immune function that is characteristic of FIV infection.