bluuebunny/crossref_metadata_2025_split huggingface dataset:
CCR4 Participation in Th Type 1 (Mycobacterial) and Th Type 2 (Schistosomal) Anamnestic Pulmonary Granulomatous Responses
Authors: Freeman Christine M. , Stolberg Valerie R. , Chiu Bo-Chin , Lukacs Nicholas W. , Kunkel Steven L. , Chensue Stephen W. 
Published: April 2014

Abstract
CCR4 is purported to be a Th type 2 (Th2) cell-biased receptor but its functional role is unclear. Recent studies suggest that chemokine receptor expression and function are more complex in vivo and raise doubts regarding restricted CCR4 expression by Th2 cells. To address these issues, we analyzed the role of CCR4 in highly polarized models of Th type 1 (Th1) and Th2 cell-mediated pulmonary granulomas, respectively, elicited by i.v. challenge of primed mice with either mycobacterial purified protein derivative or schistosomal egg Ag-coated beads. CCR4 agonists were expressed during both responses, correlating with a shift of CCR4+CD4+ T cells from blood to lungs. CCL22 dominated in draining nodes during the Th1 response. Analysis of CD4+ effector T cells revealed CCR4 expression and CCR4-mediated chemotaxis by both IFN-γ and IL-4 producers. Studies of CCR4 knockout (CCR4−/−) mice showed partial impairment of the local type-2 cytokine response and surprisingly strong impairment of the Th1 response with abrogated IFN-γ production during secondary but not primary challenge. Adoptive transfer indicated CCR4−/−CD4+ Th1 cell function was defective but this could not be reconstituted with wild-type (CCR4+/+) CD4+ T cells indicating involvement of another CCR4+ population. Coculture of CCR4+/+CD4+ T cells and CCR4−/− dendritic cells revealed intact IL-2 but impaired IFN-γ production, pointing to a role for CCR4+ dendritic cells in effector cell expression. Therefore, CCR4 is not Th2-restricted and was required for sustenance and expression of the Th1 effector/memory response to mycobacterial Ags.
Killing of Normal Melanocytes, Combined with Heat Shock Protein 70 and CD40L Expression, Cures Large Established Melanomas
Authors: Sanchez-Perez Luis , Kottke Timothy , Daniels Gregory A. , Diaz Rosa Maria , Thompson Jill , Pulido Jose , Melcher Alan , Vile Richard G. 
Published: April 2014

AbstractPreviously, we showed that nine intradermal injections of a plasmid in which the HSVtk suicide gene is expressed from a melanocyte-specific promoter (Tyr-HSVtk), combined with a plasmid expressing heat shock protein 70 (CMV-hsp70), along with systemic ganciclovir, kills normal melanocytes and raises a CD8+ T cell response that is potent enough to eradicate small, 3-day established B16 tumors. We show in this study that, in that regimen, hsp70 acts as a potent immune adjuvant through TLR-4 signaling and local induction of TNF-α. hsp70 is required for migration of APC resident in the skin to the draining lymph nodes to present Ags, derived from the killing of normal melanocytes, to naive T cells. The addition of a plasmid expressing CD40L increased therapeutic efficacy, such that only six plasmid injections were now required to cure large, 9-day established tumors. Generation of potent immunological memory against rechallenge in cured mice accompanied these therapeutic gains, as did induction of aggressive autoimmune symptoms. Expression of CD40L, along with hsp70, increased both the frequency and activity of T cells activated against melanocyte-derived Ags. In this way, addition of CD40L to the hsp70-induced inflammatory killing of melanocytes can be used to cure large established tumors and to confer immunological memory against tumor cells, although a concomitant increase in autoimmune sequelae also is produced.
Gliadin-Specific Type 1 Regulatory T Cells from the Intestinal Mucosa of Treated Celiac Patients Inhibit Pathogenic T Cells
Authors: Gianfrani Carmen , Levings Megan K. , Sartirana Claudia , Mazzarella Giuseppe , Barba Gianvincenzo , Zanzi Delia , Camarca Alessandra , Iaquinto Gaetano , Giardullo Nicola , Auricchio Salvatore , Troncone Riccardo , Roncarolo Maria-Grazia 
Published: April 2014

Abstract
Celiac disease (CD) results from a permanent intolerance to dietary gluten and is due to a massive T cell-mediated immune response to gliadin, the main component of gluten. In this disease, the regulation of immune responses to dietary gliadin is altered. Herein, we investigated whether IL-10 could modulate anti-gliadin immune responses and whether gliadin-specific type 1 regulatory T (Tr1) cells could be isolated from the intestinal mucosa of CD patients in remission. Short-term T cell lines were generated from jejunal biopsies, either freshly processed or cultured ex vivo with gliadin in the presence or absence of IL-10. Ex vivo stimulation of CD biopsies with gliadin in the presence of IL-10 resulted in suppression of Ag-specific proliferation and cytokine production, indicating that pathogenic T cells are susceptible to IL-10-mediated immune regulation. T cell clones generated from intestinal T cell lines were tested for gliadin specificity by cytokine production and proliferative responses. The majority of gliadin-specific T cell clones had a Th0 cytokine production profile with secretion of IL-2, IL-4, IFN-γ, and IL-10 and proliferated in response to gliadin. Tr1 cell clones were also isolated. These Tr1 cells were anergic, restricted by DQ2 (a CD-associated HLA), and produced IL-10 and IFN-γ, but little or no IL-2 or IL-4 upon activation with gliadin or polyclonal stimuli. Importantly, gliadin-specific Tr1 cell clones suppressed proliferation of pathogenic Th0 cells. In conclusion, dietary Ag-specific Tr1 cells are present in the human intestinal mucosa, and strategies to boost their numbers and/or function may offer new therapeutic opportunities to restore gut homeostasis.
Innate Immunity in Multiple Sclerosis: Myeloid Dendritic Cells in Secondary Progressive Multiple Sclerosis Are Activated and Drive a Proinflammatory Immune Response
Authors: Karni Arnon , Abraham Michal , Monsonego Alon , Cai Guifang , Freeman Gordon J. , Hafler David , Khoury Samia J. , Weiner Howard L. 
Published: April 2014

Abstract
Multiple sclerosis (MS) is postulated to be a T cell-mediated autoimmune disease characterized clinically by a relapsing-remitting (RR) stage followed by a secondary progressive (SP) phase. The progressive phase is felt to be secondary to neuronal degenerative changes triggered by inflammation. The status of the innate immune system and its relationship to the stages of MS is not well understood. Dendritic cells (DCs) are professional APCs that are central cells of the innate immune system and have the unique capacity to induce primary immune responses. We investigated circulating myeloid DCs isolated directly from the blood to determine whether there were abnormalities in myeloid DCs in MS and whether they were related to disease stage. We found that SP-MS subjects had an increased percentage of DCs expressing CD80, a decreased percentage expressing PD-L1, and an increased percentage producing IL-12 and TNF-α compared with RR-MS or controls. A higher percentage of DCs from both RR and SP-MS patients expressed CD40 compared with controls. We then investigated the polarization effect of DCs from MS patients on naive T cells taken from cord blood using a MLR assay. Whereas DCs from RR-MS induced higher levels of Th1 (IFN-γ, TNF-α) and Th2 (IL-4, IL-13) cytokines compared with controls, DCs from SP-MS only induced a polarized Th1 response. These results demonstrate abnormalities of DCs in MS and may explain the immunologic basis for the different stages and clinical patterns of MS.
Increased Frequencies of Cochlin-Specific T Cells in Patients with Autoimmune Sensorineural Hearing Loss
Authors: Baek Moo-Jin , Park Hyun-Min , Johnson Justin M. , Altuntas Cengiz Z. , Jane-wit Daniel , Jaini Ritika , Solares C. Arturo , Thomas Dawn M. , Ball Edward J. , Robertson Nahid G. , Morton Cynthia C. , Hughes Gordon B. , Tuohy Vincent K. 
Published: April 2014

Abstract
Autoimmune sensorineural hearing loss (ASNHL) is the most common cause of sudden hearing loss in adults. Although autoimmune etiopathogenic events have long been suspected in ASNHL, inner ear-specific Ags capable of targeting T cell autoreactivity have not been identified in ASNHL. In this study, we show by ELISPOT analysis that compared with normal hearing age- and sex-matched control subjects, ASNHL patients have significantly higher frequencies of circulating T cells producing either IFN-γ (p = 0.0001) or IL-5 (p = 0.03) in response to recombinant human cochlin, the most abundant inner ear protein. In some patients, cochlin responsiveness involved both CD4+ and CD8+ T cells whereas other patients showed cochlin responsiveness confined to CD8+ T cells. ASNHL patients also showed significantly elevated cochlin-specific serum Ab titers compared with both normal hearing age- and sex-matched control subjects and patients with noise- and/or age-related hearing loss (p &lt; 0.05 at all dilutions tested through 1/2048). Our study is the first to show T cell responsiveness to an inner ear-specific protein in ASNHL patients, and implicates cochlin as a prominent target Ag for mediating autoimmune inner ear inflammation and hearing loss.
CD45neg but Not CD45pos Human Myeloma Cells Are Sensitive to the Inhibition of IGF-1 Signaling by a Murine Anti-IGF-1R Monoclonal Antibody, mAVE1642
Authors: Descamps Géraldine , Wuillème-Toumi Soraya , Trichet Valérie , Venot Corinne , Debussche Laurent , Hercend Thierry , Collette Madeleine , Robillard Nelly , Bataille Régis , Amiot Martine 
Published: April 2014

Abstract
Insulin-like growth factor 1 (IGF-1) is a well-known growth factor for myeloma cells. Thus, therapeutic strategies targeting IGF-1R have been proposed for multiple myeloma treatment. In this study, we investigated the effect of the antagonistic anti-IGF-1R murineAVE1642 Ab (mAVE1642). We show that mAVE1642 selectively inhibits IGF-1R but not insulin signaling in human myeloma cell lines. Since we have previously shown the functional relevance of CD45 expression in the growth of myeloma cells and the association of CD45-negative (CD45neg) status with a less favorable clinical outcome, both CD45-positive (CD45pos) and CD45neg myeloma cell lines were selected for our study. We found that mAVE1642 strongly inhibits the growth of CD45neg myeloma cell lines, leading to a G1 growth arrest, whereas it has almost no effect on the growth of CD45pos myeloma cell lines. Furthermore, mAVE1642 binding induced a significant reduction of IGF-1R expression. We next demonstrated that the overexpression of IGF-1R in the CD45pos myeloma cell line increased Akt phosphorylation but was not sufficient to sensitize these cells to mAVE1642. In contrast, we generated a stable CD45-silencing XG-1 cell line and showed that it became sensitive to mAVE1642. Thus, for the first time, we provided direct evidence that the expression of CD45 renders cells resistant to mAVE1642. Taken together, these results support that therapy directed against IGF-1R can be beneficial in treating CD45neg patients.
Cutting Edge: Paracrine, but Not Autocrine, IL-2 Signaling Is Sustained during Early Antiviral CD4 T Cell Response
Authors: Long Meixiao , Adler Adam J. 
Published: April 2014

Abstract
IL-2 is expressed predominantly by activated T cells, and regulates T cell function by activating, via its receptor, the latent transcription factor STAT5. This signaling can occur in either a paracrine (between cells) or an autocrine (same cell) manner, although the kinetics by which these two signaling modes operate during in vivo T cell responses are unknown. In the current study, IL-2 expression and signaling in a clonotypic population of antiviral CD4+ T cells was analyzed by flow cytometry during the initial 24 h of priming. IL-2 expression and STAT5 activation peaked in parallel, but surprisingly, were almost completely mutually exclusive. Thus, only paracrine IL-2 signaling could be observed. As an additional indication of the efficiency of paracrine IL-2 signaling, polyclonal CD4+CD25+Foxp3+ regulatory T cells displayed detectable STAT5 activation under steady-state conditions, which was strongly enhanced by neighboring IL-2-expressing antiviral CD4 cells.
Cutting Edge: Rho Activation and Actin Polarization Are Dependent on Plexin-A1 in Dendritic Cells
Authors: Eun So-Young , O’Connor Brian P. , Wong Athena W. , van Deventer Hendrick W. , Taxman Debra J. , Reed William , Li Ping , Blum Janice S. , McKinnon Karen P. , Ting Jenny P.-Y. 
Published: April 2014

Abstract
We recently identified expression of the semaphorin receptor, plexin-A1, in dendritic cells (DCs); however, its function in these cells remains to be elucidated. To investigate function and maximize physiological relevance, we devised a retroviral approach to ablate plexin-A1 gene expression using small hairpin RNA (shRNA) in primary bone marrow-derived DCs. We show that plexin-A1 localizes within the cytoplasm of immature DCs, becomes membrane-associated, and is enriched at the immune synapse in mature DCs. Reducing plexin-A1 expression with shRNA greatly reduced actin polarization as well as Rho activation without affecting Rac or Cdc42 activation. A Rho inhibitor, C3, also reduced actin polarization. These changes were accompanied by the near-ablation of T cell activation. We propose a mechanism of adaptive immune regulation in which plexin-A1 controls Rho activation and actin cytoskeletal rearrangements in DCs that is associated with enhanced DC-T cell interactions.
Cutting Edge: Uniqueness of Lymphoid Chemokine Requirement for the Initiation and Maturation of Nasopharynx-Associated Lymphoid Tissue Organogenesis
Authors: Fukuyama Satoshi , Nagatake Takahiro , Kim Dong-Young , Takamura Kaoru , Park Eun Jeong , Kaisho Tsuneyasu , Tanaka Norimitsu , Kurono Yuichi , Kiyono Hiroshi 
Published: April 2014

Abstract
CD3−CD4+CD45+ inducer cells are required for the initiation of mucosa-associated organogenesis of both nasopharynx-associated lymphoid tissues (NALT) and Peyer’s patches (PP) in the aerodigestive tract. CXCL13−/− mice and mice carrying the paucity of lymph node T cell (plt) mutation and lacking expression of CCL19 and CCL21 accumulate CD3−CD4+CD45+ cells at the site of NALT but not of PP genesis. Although NALT was observed to develop in adult CXCL13−/− and plt/plt mice, the formation of germinal centers in CXCL13−/− mice was affected, and their population of B cells was much lower than in the NALT of CXCL13+/− mice. Similarly, fewer T cells were observed in the NALT of plt/plt mice than in control mice. These findings indicate that the initiation of NALT organogenesis is independent of CXCL13, CCL19, and CCL21. However, the expression of these lymphoid chemokines is essential for the maturation of NALT microarchitecture.
Preferential Involvement of Tim-3 in the Regulation of Hepatic CD8+ T Cells in Murine Acute Graft-versus-Host Disease
Authors: Oikawa Tsunekazu , Kamimura Yosuke , Akiba Hisaya , Yagita Hideo , Okumura Ko , Takahashi Hiroki , Zeniya Mikio , Tajiri Hisao , Azuma Miyuki 
Published: April 2014

Abstract
Tim-3, a member of the T cell Ig mucin (TIM) family regulates effector Th1 responses. We examined Tim-3 and its ligand expression as well as the effects of anti-Tim-3 mAb treatment in a murine model of acute graft-vs-host disease (aGVHD). In mice with aGVHD, Tim-3 expression was markedly up-regulated on splenic and hepatic CD4+ and CD8+ T cells, dendritic cells (DCs), and macrophages, and this was especially dramatic in hepatic CD8+ T cells. Both donor- and host-derived CD8+ T cells induced similar levels of Tim-3. Tim-3 ligand expression was also up-regulated in splenic T cells, DCs, and macrophages, but not in the hepatic lymphocytes. The administration of anti-Tim-3 mAbs accelerated aGVHD, as demonstrated by body weight loss, reduction in total splenocyte number, and infiltration of lymphocytes in the liver. IFN-γ expression by splenic and hepatic CD4+ and CD8+ T cells was significantly augmented by anti-Tim-3 mAb treatment. In addition, the cytotoxicity against host alloantigen by donor CD8+ T cells was enhanced. These results demonstrate that the anti-Tim-3 treatment in aGVHD augmented the activation of effector T cells expressing IFN-γ or exerting cytotoxicity. Our results suggest that Tim-3 may play a crucial role in the regulation of CD8+ T cells responsible for the maintenance of hepatic homeostasis and tolerance.
Dual Ligand Stimulation of RAW 264.7 Cells Uncovers Feedback Mechanisms That Regulate TLR-Mediated Gene Expression
Authors: Zhu Xiaocui , Chang Mi Sook , Hsueh Robert C. , Taussig Ron , Smith Kelly D. , Simon Melvin I. , Choi Sangdun 
Published: April 2014

AbstractTo characterize how signaling by TLR ligands can be modulated by non-TLR ligands, murine RAW 264.7 cells were treated with LPS, IFN-γ, 2-methyl-thio-ATP (2MA), PGE2, and isoproterenol (ISO). Ligands were applied individually and in combination with LPS, for 1, 2, and 4 h, and transcriptional changes were measured using customized oligo arrays. We used nonadditive transcriptional responses to dual ligands (responses that were reproducibly greater or less than the expected additive responses) as a measure of pathway interaction. Our analysis suggests that cross-talk is limited; &lt;24% of the features with significant responses to the single ligands responded nonadditively to a dual ligand pair. PGE2 and ISO mainly attenuated, while 2MA enhanced, LPS-induced transcriptional changes. IFN-γ and LPS cross-regulated the transcriptional response induced by each other: while LPS preferentially enhanced IFN-γ-induced changes in gene expression at 1 h, IFN-γ signaling primarily attenuated LPS-induced changes at 4 h. Our data suggest specific cross-talk mechanisms: 1) LPS enhances the expression of IFN-γ- response genes by augmenting STAT1 activity and by activating NF-κB, which synergizes with IFN-γ-induced transcriptional factors; 2) IFN-γ attenuates the late LPS transcriptional response by increasing the expression of suppressor of cytokine signaling 1 and cytokine-inducible SH2-containing protein expression; 3) 2MA modulates LPS secondary transcriptional response by increasing IFN-β and inhibiting IL-10 gene expression; 4) PGE2 and ISO similarly regulate the LPS transcriptional response. They increase IL-10 transcription, resulting in attenuated expression of known IL-10-suppressed genes.
Transient Receptor Potential Vanilloid Subtype 1 Mediates Microglial Cell Death In Vivo and In Vitro via Ca2+-Mediated Mitochondrial Damage and CytochromecRelease
Authors: Kim Sang R. , Kim Seung U. , Oh Uhtaek , Jin Byung K. 
Published: April 2014

AbstractThe present study examined the expression of transient receptor potential vanilloid subtype 1 (TRPV1) in microglia, and its association with microglial cell death. In vitro cell cultures, RT-PCR, Western blot analysis, and immunocytochemical staining experiments revealed that rat microglia and a human microglia cell line (HMO6) showed TRPV1 expression. Furthermore, exposure of these cells to TRPV1 agonists, capsaicin (CAP) and resiniferatoxin (RTX), triggered cell death. This effect was ameliorated by the TRPV1 antagonists, capsazepine and iodo-resiniferatoxin (I-RTX), suggesting that TRPV1 is directly involved. Further examinations revealed that TRPV1-induced toxicity was accompanied by increases in intracellular Ca2+, and mitochondrial damage; these effects were inhibited by capsazepine, I-RTX, and the intracellular Ca2+ chelator BAPTA-AM. Treatment of cells with CAP or RTX led to increased mitochondrial cytochrome c release and enhanced immunoreactivity to cleaved caspase-3. In contrast, the caspase-3 inhibitor z-DEVD-fmk protected microglia from CAP- or RTX-induced toxicity. In vivo, we also found that intranigral injection of CAP or 12-hydroperoxyeicosatetraenoic acid, an endogenous agonist of TRPV1, into the rat brain produced microglial damage via TRPV1 in the substantia nigra, as visualized by immunocytochemistry. To our knowledge, this study is the first to demonstrate that microglia express TRPV1, and that activation of this receptor may contribute to microglial damage via Ca2+ signaling and mitochondrial disruption.
Three Memory Subsets of Human CD8+ T Cells Differently Expressing Three Cytolytic Effector Molecules
Authors: Takata Hiroshi , Takiguchi Masafumi 
Published: April 2014

Abstract
Multicolor flow cytometric analysis for the expression of three effector molecules, i.e., perforin (Per), granzyme A (GraA), and granzyme B (GraB), in human CD8+ T cells demonstrated that they included five subpopulations, implying the following pathway for the differentiation of CD8+ T cells: Per−GraA−GraB−→Per−GraA+GraB−→PerlowGraA+GraB−→ PerlowGraA+GraB+→PerhighGraA+GraB+. The analysis of the expression of these molecules in the subsets classified by the combination of the expression of CCR7 and CD45RA or by that of CD27, CD28, and CD45RA showed that functional CD8+ T cell subsets could be partially identified by these phenotypic classifications. However, the functional subsets could be precisely identified by the classification using five cell surface markers or three cell surface markers and three cytolytic molecules. Per−GraA−GraB− and Per−/lowGraA+GraB− cells were predominantly found in CCR5−CCR7+ and CCR5high/lowCCR7− subsets, respectively, of CD8+ T cells expressing the CD27+CD28+CD45RA− phenotype, whereas PerlowGraA+GraB+ cells were found in the CCR5lowCCR7− subset of those expressing this phenotype and in a part of the CCR5−/lowCCR7− subset of those expressing the CD27−/lowCD28−CD45RA−/+ phenotype. Ex vivo EBV-specific CD8+ T cells, which were Perlow/−GraA+GraB−/+ cells, hardly or very weakly killed the target cells, indicating that these were not effector T cells. These findings suggest that the Per−GraA−GraB−, Per−/lowGraA+GraB−, and PerlowGraA+GraB+ cells were central memory, early effector memory, and late effector memory T cells, respectively. Per−/lowGraA+GraB− cells gained GraB expression after TCR stimulation, indicating that early effector memory T cells could differentiate into late effector and effector T cells. The present study showed the existence of three memory subsets and the pathway for their differentiation.
Cigarette Smoke-Induced Pulmonary Inflammation and Emphysema Are Attenuated in CCR6-Deficient Mice
Authors: Bracke Ken R. , D’hulst An I. , Maes Tania , Moerloose Katrien B. , Demedts Ingel K. , Lebecque Serge , Joos Guy F. , Brusselle Guy G. 
Published: April 2014

Abstract
Chronic obstructive pulmonary disease (COPD) is mainly caused by cigarette smoking, and is characterized by an increase in inflammatory cells in the airways and pulmonary tissue. The chemokine receptor CCR6 and its ligand MIP-3α/CCL20 may be involved in the recruitment of these inflammatory cells. To investigate the role of CCR6 in the pathogenesis of COPD, we analyzed the inflammatory responses of CCR6 knockout (KO) and wild-type mice upon cigarette smoke (CS) exposure. Both subacute and chronic exposure to CS induced an increase in cells of the innate and adaptive immune system in the bronchoalveolar lavage, both in CCR6 KO and wild-type mice. However, the accumulation of dendritic cells, neutrophils, and T lymphocytes, which express CCR6, was significantly attenuated in the CCR6 KO mice, compared with their wild-type littermates. In the lung tissue of CCR6 KO mice, there was an impaired increase in dendritic cells, activated CD8+ T lymphocytes, and granulocytes. Moreover, this attenuated inflammatory response in CCR6 KO mice offered a partial protection against pulmonary emphysema, which correlated with an impaired production of MMP-12. Importantly, protein levels of MIP-3α/CCL20, the only chemokine ligand of the CCR6 receptor, and MCP-1/CCL2 were significantly increased upon CS exposure in wild-type, but not in CCR6 KO mice. In contrast, CCR6 deficiency had no effect on the development of airway wall remodeling upon chronic CS exposure. These results indicate that the interaction of CCR6 with its ligand MIP-3α contributes to the pathogenesis of CS-induced pulmonary inflammation and emphysema in this murine model of COPD.