bluuebunny/crossref_metadata_2025_split huggingface dataset:
IL-10 Is Required for Optimal CD8 T Cell Memory followingListeria monocytogenesInfection
Authors: Foulds Kathryn E. , Rotte Masashi J. , Seder Robert A. 
Published: April 2014

AbstractIL-10 is an important immunoregulatory cytokine that plays a central role in maintaining a balance between protective immunity against infection and limiting proinflammatory responses to self or cross-reactive Ags. We examined the full effects of IL-10 deficiency on the establishment and quality of T cell memory using murine listeriosis as a model system. IL-10−/− mice had reduced bacterial loads and a shorter duration of primary infection than did wild-type mice. However, the number of Ag-specific T cells in secondary lymphoid and nonlymphoid organs was diminished in IL-10−/− mice, compared with wild-type mice, at the peak of the effector response. Moreover, the frequency and protective capacity of memory T cells also were reduced in IL-10−/− mice when assessed up to 100 days postinfection. Remarkably, this effect was more pronounced for CD8 T cells than CD4 T cells. To address whether differences in the number of bacteria and duration of primary infection could explain these findings, both strains of mice were treated with ampicillin 24 hours after primary infection. Despite there being more comparable bacterial loads during primary infection, IL-10−/− mice still generated fewer memory CD8 T cells and were less protected against secondary infection than were wild-type mice. Finally, the adoptive transfer of purified CD8 T cells from previously infected wild-type mice into naive recipients conferred better protection than the transfer of CD8 T cells from immune IL-10−/− mice. Overall, these data show that IL-10 plays an unexpected role in promoting and/or sustaining CD8 T cell memory following Listeria monocytogenes infection.
TWEAK Is a Novel Arthritogenic Mediator
Authors: Perper Stuart J. , Browning Beth , Burkly Linda C. , Weng Shawn , Gao Cindy , Giza Keith , Su Lihe , Tarilonte Leticia , Crowell Thomas , Rajman Luis , Runkel Laura , Scott Martin , Atkins Gerald J. , Findlay David M. , Zheng Timothy S. , Hess Henry 
Published: April 2014

AbstractTNF-like weak inducer of apoptosis (TWEAK) is a TNF family member with pleiotropic effects on a variety of cell types, one of which is the induction of proinflammatory cytokines by synovial fibroblasts derived from rheumatoid arthritis (RA) patients. In this study, we report that the serum TWEAK level was dramatically elevated during mouse collagen-induced arthritis (CIA) and blocking TWEAK by a neutralizing mAb significantly reduced the clinical severity of CIA. Histological analyses also revealed that TWEAK inhibition diminished joint inflammation, synovial angiogenesis, as well as cartilage and bone erosion. Anti-TWEAK treatment proved efficacious when administered just before the disease onset but not during the priming phase of CIA. Consistent with this, TWEAK inhibition did not affect either cellular or humoral responses to collagen. In contrast, TWEAK inhibition significantly reduced serum levels of a panel of arthritogenic mediators, including chemokines such as MIP-1β (CCL-4), lymphotactin (XCL-1), IFN-γ-inducible protein 10 (IP-10) (CXCL-10), MCP-1 (CCL-2), and RANTES (CCL-5), as well as the matrix metalloprotease-9. Exploring the possible role of the TWEAK/Fn14 pathway in human RA pathogenesis, we showed that TWEAK can target human primary chondrocytes and osteoblast-like cells, in addition to synovial fibroblasts. We further demonstrated that TWEAK induced the production of matrix metalloproteases in human chondrocytes and potently inhibited chondrogenesis and osteogenesis using in vitro models. These results provide evidence for a novel cytokine pathway that contributes to joint tissue inflammation, angiogenesis, and damage, as well as may inhibit endogenous repair, suggesting that TWEAK may be a new therapeutic target for human RA.
CCL2 Regulates Angiogenesis via Activation of Ets-1 Transcription Factor
Authors: Stamatovic Svetlana M. , Keep Richard F. , Mostarica-Stojkovic Marija , Andjelkovic Anuska V. 
Published: April 2014

Abstract
Although recent studies have suggested that CC chemokine CCL2 may directly affect the angiogenesis, the signaling events involved in such regulation remain to be determined. This study investigated a potential signal mechanism involved in CCL2-induced angiogenesis. Our in vitro and in vivo (hemangioma model of angiogenesis) experiments confirmed earlier findings that CCL2 can induce angiogenesis directly. Using a gene array analysis, CCL2 was found to induce expression of several angiogenic factors in brain endothelial cells. Among the most prominent was an up-regulation in Ets-1 transcription factor. CCL2 induced a significant increase in Ets-1 mRNA and protein expression as well as Ets-1 DNA-binding activity. Importantly, Ets-1 antisense oligonucleotide markedly abrogated in vitro CCL2-induced angiogenesis, suggesting that Ets-1 is critically involved in this process. Activation of Ets-1 by CCL2 further regulated some of Ets-1 target molecules including β3 integrins. CCL2 induced significant up-regulation of β3 mRNA and protein expression, and this effect of CCL2 was prevented by the Ets-1 antisense oligonucleotide. The functional regulation of Ets-1 activity by CCL2 was dependent on ERK-1/2 cascade. Inhibition of ERK1/2 activity by PD98509 prevented CCL2-induced increases in Ets-1 DNA-binding activity and Ets-1 mRNA expression. Based on these findings, we suggest that Ets-1 transcription factor plays a critical role in CCL2 actions on brain endothelial cells and CCL2-induced angiogenesis.
Papillomavirus-Like Particles Are an Effective Platform for Amyloid-β Immunization in Rabbits and Transgenic Mice
Authors: Zamora Eduardo , Handisurya Alessandra , Shafti-Keramat Saeed , Borchelt David , Rudow Gay , Conant Katherine , Cox Christopher , Troncoso Juan C. , Kirnbauer Reinhard 
Published: April 2014

AbstractImmunization with amyloid-β (Aβ) prevents the deposition of Aβ in the brain and memory deficits in transgenic mouse models of Alzheimer’s disease (AD), opening the possibility for immunotherapy of AD in humans. Unfortunately, the first human trial of Aβ vaccination was complicated, in a small number of vaccinees, by cell-mediated meningoencephalitis. To develop an Aβ vaccine that lacks the potential to induce autoimmune encephalitis, we have generated papillomavirus-like particles (VLP) that display 1–9 aa of Aβ protein repetitively on the viral capsid surface (Aβ-VLP). This Aβ peptide was chosen because it contains a functional B cell epitope, but lacks known T cell epitopes. Rabbit and mouse vaccinations with Aβ-VLP were well tolerated and induced high-titer autoAb against Aβ, that inhibited effectively assembly of Aβ1–42 peptides into neurotoxic fibrils in vitro. Following Aβ-VLP immunizations of APP/presenilin 1 transgenic mice, a model for human AD, we observed trends for reduced Aβ deposits in the brain and increased numbers of activated microglia. Furthermore, Aβ-VLP vaccinated mice also showed increased levels of Aβ in plasma, suggesting efflux from the brain into the vascular compartment. These results indicate that the Aβ-VLP vaccine induces an effective humoral immune response to Aβ and may thus form a basis to develop a safe and efficient immunotherapy for human AD.
Paucity of Clinical Disease despite Serological Autoimmunity and Kidney Pathology in Lupus-Prone New Zealand Mixed 2328 Mice Deficient in BAFF
Authors: Jacob Chaim O. , Pricop Luminita , Putterman Chaim , Koss Michael N. , Liu Yi , Kollaros Maria , Bixler Sarah A. , Ambrose Christine M. , Scott Martin L. , Stohl William 
Published: April 2014

AbstractConstitutive overexpression of B cell-activating factor belonging to the TNF family (BAFF) promotes development of systemic lupus erythematosus (SLE), and treatment of SLE mice with BAFF antagonists ameliorates disease. To determine whether SLE can develop de novo in BAFF-deficient hosts, BAFF-deficient New Zealand Mixed (NZM) 2328 (NZM.Baff−/−) mice were generated. In NZM.Baff−/− mice, spleen B cells (including CD5+ B1a and CD5− B1b B cells), germinal centers, Ig-secreting cells, and T cells were reduced in comparison to NZM.Baff+/+ mice. Serum total Ig and autoantibody levels were reduced at 4–6 mo but approached wild-type levels with increasing age, indicating that autoreactive B cells can survive and secrete autoantibodies despite the complete absence of BAFF. At least some of these autoantibodies are nephrophilic in that glomerular deposition of total IgG and IgG1 (but not of IgG2a, IgG2b, or C3) was substantial in NZM.Baff−/− mice by 12–13 mo of age. Despite proliferative glomerulonephritis, highlighted by widespread glomerular hyaline thrombi, being common among NZM.Baff−/− mice by 6–7 mo of age, severe proteinuria and mortality were greatly attenuated. These results demonstrate that the lifelong absence of BAFF does not protect NZM 2328 mice from serological autoimmunity and renal pathology. Nevertheless, the character of the renal pathology is altered, and the mice are largely spared from clinically overt disease (severe proteinuria and premature death). These observations may have profound ramifications for the use of BAFF antagonists in human SLE and related diseases.
Calcineurin Is Expressed and Plays a Critical Role in Inflammatory Arthritis
Authors: Yoo Seung-Ah , Park Bo-Hyoung , Park Gyeong-Sin , Koh Hae-Seok , Lee Mi-Sook , Ryu Sung Ho , Miyazawa Keiji , Park Sung-Hwan , Cho Chul-Soo , Kim Wan-Uk 
Published: April 2014

AbstractCalcineurin is a calcium-activated phosphatase to mediate lymphocyte activation and neuron signaling, but its role in inflammatory arthritis remains largely unknown. In this study, we demonstrate that calcineurin was highly expressed in the lining layer, infiltrating leukocytes, and endothelial cells of rheumatoid synovium. The basal expression levels of calcineurin were higher in the cultured synoviocytes of rheumatoid arthritis patients than those of osteoarthritis patients. The calcineurin activity in the synoviocytes was increased by the stimulation with proinflammatory cytokines such as IL-1β and TNF-α. Moreover, rheumatoid arthritis synoviocytes had an enlarged intracellular Ca2+ store and showed a higher degree of [Ca2+]i release for calcineurin activity than osteoarthritis synoviocytes when stimulated with either TNF-α or phorbol myristate acetate. IL-10, an anti-inflammatory cytokine, failed to increase the Ca2+ and calcineurin activity. The targeted inhibition of calcineurin by the overexpression of calcineurin-binding protein 1, a natural calcineurin antagonist, inhibited the production of IL-6 and matrix metalloproteinase-2 by rheumatoid synoviocytes in a similar manner to the calcineurin inhibitor, cyclosporin A. Moreover, the abundant calcineurin expression was found in the invading pannus in the joints of mice with collagen-induced arthritis. In these mice, calcineurin activity in the cultured synovial and lymph node cells correlated well with the severity of arthritis, but which was suppressed by cyclosporin A treatment. Taken together, our data suggest that the abnormal activation of Ca2+ and calcineurin in the synoviocytes may contribute to the pathogenesis of chronic arthritis and thus provide a potential target for controlling inflammatory arthritis.
Spontaneous CD4+ T Cell Responses against TRAG-3 in Patients with Melanoma and Breast Cancers
Authors: Janjic Bratislav , Andrade Pedro , Wang Xiao-Fei , Fourcade Julien , Almunia Christine , Kudela Pavol , Brufsky Adam , Jacobs Samuel , Friedland David , Stoller Ronald , Gillet Daniel , Herberman Ronald B. , Kirkwood John M. , Maillere Bernard , Zarour Hassane M. 
Published: April 2014

AbstractThe taxol resistance gene TRAG-3 was initially isolated from cancer cell lines that became resistant to taxol in vitro. TRAG-3 is a cancer germline Ag expressed by tumors of different histological types including the majority of melanoma, breast, and lung cancers. In the present study, we report that patients with stage IV melanoma and breast cancers developed spontaneous IFN-γ-producing CD4+ T cell responses against a single immunodominant and promiscuous peptide epitope from TRAG-3 presented in the context of multiple HLA-DR molecules. The TRAG-3-specific CD4+ T cells and clones were expanded in vitro and recognized not only peptide pulsed APCs but also autologous dendritic cells (DCs) loaded with the TRAG-3 protein. All stage IV melanoma patients with TRAG-3-expressing tumors developed spontaneous CD4+ T cell responses against TRAG-3, demonstrating its strong immunogenicity. None of these patients had detectable IgG Ab responses against TRAG-3. TCRβ gene usage studies of TRAG-3-specific CD4+ T cell clones from a melanoma patient and a normal donor suggested a restricted TCR repertoire in patients with TRAG-3-expressing tumors. Altogether, our data define a novel profile of spontaneous immune responses to cancer germline Ag-expressing tumors, showing that spontaneous TRAG-3-specific CD4+ T cells are directed against a single immunodominant epitope and exist independently of Ab responses. Because of its immunodominance, peptide TRAG-334–48 is of particular interest for the monitoring of spontaneous immune responses in patients with TRAG-3-expressing tumors and for the development of cancer vaccines.
B-1 B Cell Development
Authors: Hardy Richard R. 
Published: April 2014

AbstractCD5+ B cells have attracted considerable interest because of their association with self-reactivity, autoimmunity, and leukemia. In mice, CD5+ B cells are readily generated from fetal/neonatal precursors, but inefficiently from precursors in adult. One model proposed to explain this difference is that their production occurs through a distinctive developmental process, termed B-1, that enriches pre-B cells with novel germline VDJs and that requires positive selection of newly formed B cells by self-Ag. In contrast, follicular B cells are generated throughout adult life in a developmental process termed B-2, selecting VDJs that pair well with surrogate L chain, and whose maturation appears relatively independent of antigenic selection. In the present study, I focus on processes that shape the repertoire of mouse CD5+ B cells, describing the differences between B-1 and B-2 development, and propose a model encompassing both in the generation of functional B cell subpopulations.
Cutting Edge: Interleukin 4-Dependent Mast Cell Proliferation Requires Autocrine/Intracrine Cysteinyl Leukotriene-Induced Signaling
Authors: Jiang Yongfeng , Kanaoka Yoshihide , Feng Chunl , Nocka Karl , Rao Sudhir , Boyce Joshua A. 
Published: April 2014

AbstractReactive mastocytosis (RM) in epithelial surfaces is a consistent Th2-associated feature of allergic disease. RM fails to develop in mice lacking leukotriene (LT) C4 synthase (LTC4S), which is required for cysteinyl leukotriene (cys-LT) production. We now report that IL-4, which induces LTC4S expression by mast cells (MCs), requires cys-LTs, the cys-LT type 1 receptor (CysLT1), and Gi proteins to promote MC proliferation. LTD4 (10–1000 nM) enhanced proliferation of human MCs in a CysLT1-dependent, pertussis toxin-sensitive manner. LTD4-induced phosphorylation of ERK required transactivation of c-kit. IL-4-driven comitogenesis was likewise sensitive to pertussis toxin or a CysLT1-selective antagonist and was attenuated by treatment with leukotriene synthesis inhibitors. Mouse MCs lacking LTC4S or CysLT1 showed substantially diminished IL-4-induced comitogenesis. Thus, IL-4 induces proliferation in part by inducing LTC4S and cys-LT generation, which causes CysLT1 to transactivate c-kit in RM.
Cutting Edge: IL-23 Cross-Regulates IL-12 Production in T Cell-Dependent Experimental Colitis
Authors: Becker Christoph , Dornhoff Heike , Neufert Clemens , Fantini Massimo C. , Wirtz Stefan , Huebner Sabine , Nikolaev Alexei , Lehr Hans-Anton , Murphy Andrew J. , Valenzuela David M. , Yancopoulos George D. , Galle Peter R. , Karow Margaret , Neurath Markus F. 
Published: April 2014

AbstractAlthough IL-12 and IL-23 share the common p40 subunit, IL-23, rather than IL-12, seems to drive the pathogenesis of experimental autoimmune encephalomyelitis and arthritis, because IL-23/p19 knockout mice are protected from disease. In contrast, we describe in this study that newly created LacZ knockin mice deficient for IL-23 p19 were highly susceptible for the development of experimental T cell-mediated TNBS colitis and showed even more severe colitis than wild-type mice by endoscopic and histologic criteria. Subsequent studies revealed that dendritic cells from p19-deficient mice produce elevated levels of IL-12, and that IL-23 down-regulates IL-12 expression upon TLR ligation. Finally, in vivo blockade of IL-12 p40 in IL-23-deficient mice rescued mice from lethal colitis. Taken together, our data identify cross-regulation of IL-12 expression by IL-23 as novel key regulatory pathway during initiation of T cell dependent colitis.
Cutting Edge: Critical Role for A2A Adenosine Receptors in the T Cell-Mediated Regulation of Colitis
Authors: Naganuma Makoto , Wiznerowicz Elizabeth B. , Lappas Courtney M. , Linden Joel , Worthington Mark T. , Ernst Peter B. 
Published: April 2014

Abstract
A2A adenosine receptors (A2AAR) inhibit inflammation, although the mechanisms through which adenosine exerts its effects remain unclear. Although the transfer of regulatory Th cells blocks colitis induced by pathogenic CD45RBhigh Th cells, we show that CD45RBlow or CD25+ Th cells from A2AAR-deficient mice do not prevent disease. Moreover, CD45RBhigh Th cells from A2AAR-deficient mice were not suppressed by control CD45RBlow Th cells. A2AAR agonists suppressed the production of proinflammatory cytokines by CD45RBhigh and CD45RBlow T cells in association with a loss of mRNA stability. In contrast, anti-inflammatory cytokines, including IL-10 and TGF-β, were minimally affected. Oral administration of the A2AAR agonist ATL313 attenuated disease in mice receiving CD45RBhigh Th cells. These data suggest that A2AAR play a novel role in the control of T cell-mediated colitis by suppressing the expression of proinflammatory cytokines while sparing anti-inflammatory activity mediated by IL-10 and TGF-β.
CD103 Is a Marker for Alloantigen-Induced Regulatory CD8+ T Cells
Authors: Uss Elena , Rowshani Ajda T. , Hooibrink Berend , Lardy Neubury M. , van Lier René A. W. , ten Berge Ineke J. M. 
Published: April 2014

AbstractThe αEβ7 integrin CD103 may direct lymphocytes to its ligand E-cadherin. CD103 is expressed on T cells in lung and gut and on allograft-infiltrating T cells. Moreover, recent studies have documented expression of CD103 on CD4+ regulatory T cells. Approximately 4% of circulating CD8+ T cells bear the CD103 molecule. In this study, we show that the absence or presence of CD103 was a stable trait when purified CD103− and CD103+CD8+ T cell subsets were stimulated with a combination of CD3 and CD28 mAbs. In contrast, allostimulation induced CD103 expression on ∼25% of purified CD103−CD8+ T cells. Expression of CD103 on alloreactive cells was found to be augmented by IL-4, IL-10, or TGF-β and decreased by addition of IL-12 to MLCs. The alloantigen-induced CD103+CD8+ T cell population appeared to be polyclonal and retained CD103 expression after restimulation. Markedly, in vitro-expanded CD103+CD8+ T cells had low proliferative and cytotoxic capacity, yet produced considerable amounts of IL-10. Strikingly, they potently suppressed T cell proliferation in MLC via a cell-cell contact-dependent mechanism. Thus, human alloantigen-induced CD103+CD8+ T cells possess functional features of regulatory T cells.
Age-Related CD8+ T Cell Clonal Expansions Express Elevated Levels of CD122 and CD127 and Display Defects in Perceiving Homeostatic Signals
Authors: Messaoudi Ilhem , Warner Jessica , Nikolich-Žugich Janko 
Published: April 2014

AbstractAging is accompanied by numerous changes in T cell biology. Among the most dramatic changes at the population level are the appearance and persistence of CD8+ T cell clonal expansions (TCE), whose frequency increases steadily with age, and whose biology is incompletely understood. In this study, we examined trafficking, phenotypic makeup, and homeostatic responsiveness of TCE, which arise spontaneously in specific pathogen-free mice. We show that these cells make up a specialized subset of central memory T cells with distinguishable phenotypic characteristics, most notably the higher expression of CD122 and CD127, molecules that make up IL-15R and IL-7R, respectively, than other memory T cells. We confirm that these cells proliferate at a continuous pace upon adoptive transfer into the eulymphoid recipient, unlike their non-TCE memory-phenotype counterparts, which remain undivided and die. However, upon transfer into lymphopenic recipients, TCE fail to rapidly expand, but rather resume their slow, continuous proliferation. The above results are discussed in light of possible mechanisms that afford selective survival advantage to TCE over other T cells in an aged T lymphocyte pool.
EBV Latent Membrane Protein 2A Induces Autoreactive B Cell Activation and TLR Hypersensitivity
Authors: Wang Hongsheng , Nicholas Matilda W. , Conway Kara L. , Sen Pradip , Diz Ramiro , Tisch Roland M. , Clarke Stephen H. 
Published: April 2014

Abstract
EBV is associated with systemic lupus erythematosus (SLE), but how it might contribute to the etiology is not clear. Since EBV-encoded latent membrane protein 2A (LMP2A) interferes with normal B cell differentiation and function, we sought to determine its effect on B cell tolerance. Mice transgenic for both LMP2A and the Ig transgene 2-12H specific for the ribonucleoprotein Smith (Sm), a target of the immune system in SLE, develop a spontaneous anti-Sm response. LMP2A allows anti-Sm B cells to overcome the regulatory checkpoint at the early preplasma cell stage by a self-Ag-dependent mechanism. LMP2A induces a heightened sensitivity to TLR ligand stimulation, resulting in increased proliferation or Ab-secreting cell differentiation or both. Thus, we propose a model whereby LMP2A induces hypersensitivity to TLR stimulation, leading to activation of anti-Sm B cells through the BCR/TLR pathway. These data further implicate TLRs in the etiology of SLE and suggest a mechanistic link between EBV infection and SLE.
Humoral Immune Response to Flagellin Requires T Cells and Activation of Innate Immunity
Authors: Sanders Catherine J. , Yu Yimin , Moore Daniel A. , Williams Ifor R. , Gewirtz Andrew T. 
Published: April 2014

Abstract
Bacterial flagellin, the primary structural component of flagella, is a dominant target of humoral immunity upon infection by enteric pathogens and in Crohn’s disease. To better understand how such responses may be regulated, we sought to define, in mice, basic mechanisms that regulate generation of flagellin-specific Igs. We observed that, in response to i.p. injection with flagellin, generation of flagellin-specific Ig required activation of innate immunity in that these responses were ablated in MyD88-deficient mice and that flagellin from Helicobacter pylori, which is known not to activate TLR5, also did not elicit Abs. Mice lacking αβ T cells (TCRβnull) were completely deficient in their ability to make flagellin Abs in various contexts indicating that, in contrast to common belief, generation of flagellin-specific Ig is absolutely T cell dependent. In contrast to Ab responses to whole flagella (H serotyping), responses to flagellin monomers displayed only moderate serospecificity. Whereas neither oral nor rectal administration of flagellin elicited a strong serum Ab response, induction of colitis with dextran sodium sulfate resulted in a MyD88-dependent serum Ab response to endogenous flagellin, suggesting that, in an inflammatory milieu, TLR signaling promotes acquisition of Abs to intestinal flagellin. Thus, acquisition of a humoral immune response to flagellin requires activation of innate immunity, is T cell dependent, and can originate from flagellin in the intestinal tract in inflammatory conditions in the intestine.