bluuebunny/crossref_metadata_2025_split huggingface dataset:
Agrin Signalling Contributes to Cell Activation and Is Overexpressed in T Lymphocytes from Lupus Patients
Authors: Jury Elizabeth C. , Eldridge Jillian , Isenberg David A. , Kabouridis Panagiotis S. 
Published: April 2014

Abstract
It is shown in this study that the heparan sulfate proteoglycan agrin is overexpressed in T cells isolated from patients with the autoimmune disease systemic lupus erythematosus (SLE). Freshly isolated CD4+ and CD8+ subpopulations both exhibited higher expression over healthy controls, which however, gradually declined when cells were cultured in vitro. Agrin expression was induced following in vitro activation of cells via their Ag receptor, or after treatment with IFN-α, a cytokine shown to be pathogenic in lupus. Furthermore, serum from SLE patients with active disease was able to induce agrin expression when added to T cells from healthy donors, an increase that was partially blocked by neutralizing anti-IFN-α Abs. Cross-linking agrin with mAbs resulted in rapid reorganization of the actin cytoskeleton, activation of the ERK MAPK cascade, and augmentation of anti-CD3-induced proliferation and IL-10 production, indicating that agrin is a functional receptor in T cells. These results demonstrate that agrin expression in human T cells is regulated by cell activation and IFN-α, and may have an important function during cell activation with potential implications for autoimmunity.
A Novel Role of IL-2 in Organ-Specific Autoimmune Inflammation beyond Regulatory T Cell Checkpoint: Both IL-2 Knockout and Fas Mutation Prolong Lifespan of Scurfy Mice but by Different Mechanisms
Authors: Zheng Lingjie , Sharma Rahul , Gaskin Felicia , Fu Shu Man , Ju Shyr-Te 
Published: April 2014

Abstract
Mutation of the Foxp3 transcription factor in Scurfy (Sf) mice results in complete absence of the CD4+Foxp3+ regulatory T cells (Tregs), severe multiorgan autoimmune syndrome, and early death at 4 wk of age. However, Sf mice simultaneously bearing the Il2−/− (Sf.Il2−/−) or Faslpr/lpr gene (Sf.Faslpr/lpr) have extended lifespan despite totally lacking Tregs, indicating a role of IL-2 and CD95 (Fas) signaling pathways in the multiorgan autoimmune syndrome beyond the Treg checkpoint. IL-2 has been implicated in regulating lymphoproliferation and CD178 (FasL) expression. However, Sf.Il2−/− mice have increased lymphoproliferation and FasL expression. Importantly, the pattern of organ-specific autoimmune response of Sf.Il2−/−mice resembled IL-2 knockout mice whereas that of Sf.Faslpr/lpr was similar to Sf mice, indicating that the distinct and weakened autoimmune manifestation in IL-2 knockout mice was not caused by the residual Tregs. Our study demonstrated a novel role of IL-2 in regulating multiorgan autoimmune inflammation beyond the Treg checkpoint and indicated that both Il2−/− and Faslpr/lpr genes prolong the lifespan of Sf mice but by different mechanisms.
Receptor for Advanced Glycation End Products Expression on T Cells Contributes to Antigen-Specific Cellular Expansion In Vivo
Authors: Moser Bernhard , Desai Dharmesh D. , Downie Matthew P. , Chen Yali , Yan Shi Fang , Herold Kevan , Schmidt Ann Marie , Clynes Raphael 
Published: April 2014

Abstract
Receptor for advanced glycation end products (RAGE) is an activation receptor triggered by inflammatory S100/calgranulins and high mobility group box-1 ligands. We have investigated the importance of RAGE on Ag priming of T cells in murine models in vivo. RAGE is inducibly up-regulated during T cell activation. Transfer of RAGE-deficient OT II T cells into OVA-immunized hosts resulted in reduced proliferative responses that were further diminished in RAGE-deficient recipients. Examination of RAGE-deficient dendritic cells did not reveal functional impairment in Ag presentation, maturation, or migratory capacities. However, RAGE-deficient T cells showed markedly impaired proliferative responses in vitro to nominal and alloantigens, in parallel with decreased production of IFN-γ and IL-2. These data indicate that RAGE expressed on T cells is required for efficient priming of T cells and elucidate critical roles for RAGE engagement during cognate dendritic cell-T cell interactions.
Chronic Antigen Stimulation In Vivo Induces a Distinct Population of Antigen-Specific Foxp3−CD25− Regulatory T Cells
Authors: Hansen Wiebke , Westendorf Astrid M. , Reinwald Simone , Bruder Dunja , Deppenmeier Stefanie , Groebe Lothar , Probst-Kepper Michael , Gruber Achim D. , Geffers Robert , Buer Jan 
Published: April 2014

Abstract
The concept of immune regulation/suppression has been well-established and, besides thymus-derived CD4+CD25+ regulatory T (TR) cells, it became clear that a variety of additional peripherally induced TR cells play vital roles in protection from many harmful immune responses including intestinal inflammation. In the present study, we have analyzed in vivo-induced Ag-specific CD4+ TR cells with respect to their molecular and functional phenotype. By comparative genomics we could show that these Ag-specific TR cells induced by chronic Ag stimulation in vivo clearly differ in their genetic program from naturally occurring thymus-derived CD4+CD25+ TR cells. This distinct population of induced TR cells express neither CD25 nor the TR-associated transcription factor Foxp3. Strikingly, CD25 is not even up-regulated upon stimulation. Despite the lack in Foxp3 expression, these in vivo-induced CD25− TR cells are able to interfere with an Ag-specific CD8+ T cell-mediated intestinal inflammation without significant increase in CD25 and Foxp3 expression. Thus, our results demonstrate that in vivo-induced Ag-specific TR cells represent a distinct population of Foxp3−CD25− TR cells with regulatory capacity both in vitro and in vivo.
IL-22 Is Expressed by Th17 Cells in an IL-23-Dependent Fashion, but Not Required for the Development of Autoimmune Encephalomyelitis
Authors: Kreymborg Katharina , Etzensperger Ruth , Dumoutier Laure , Haak Stefan , Rebollo Angelita , Buch Thorsten , Heppner Frank L. , Renauld Jean-Christophe , Becher Burkhard 
Published: April 2014

Abstract
Lately, IL-17-secreting Th cells have received an overwhelming amount of attention and are now widely held to be the major pathogenic population in autoimmune diseases. In particular, IL-22-secreting Th17 cells were shown to specifically mark the highly pathogenic population of self-reactive T cells in experimental autoimmune encephalomyelitis (EAE). As IL-17A itself was found to only play a minor role during the development of EAE, IL-22 is now postulated to contribute to the pathogenic function of Th17 cells. The goal of this study was to determine the role and function of IL-22 during the development of CNS autoimmunity in vivo. We found that CNS-invading encephalitogenic Th17 cells coexpress IL-22 and that IL-22 is specifically induced by IL-23 in autoimmune-pathogenic CD4+ T cells in a time- and dose-dependent manner. We next generated IL-22−/− mice, which—in contrast to the prediction that expression of inflammatory cytokines by CNS-invading T cells inevitably confers pathogenic function—turned out to be fully susceptible to EAE. Taken together, we show that self-reactive Th cells coexpress IL-17 and IL-22, but that the latter also does not appear to be directly involved in autoimmune pathogenesis of the CNS.
Anti-CD28 Antibodies Modify Regulatory Mechanisms and Reinforce Tolerance in CD40Ig-Treated Heart Allograft Recipients
Authors: Guillonneau Carole , Séveno Céline , Dugast Anne-Sophie , Li Xian-Liang , Renaudin Karine , Haspot Fabienne , Usal Claire , Veziers Joëlle , Anegon Ignacio , Vanhove Bernard 
Published: April 2014

Abstract
Blockade of CD40-CD40 ligand (CD40L) costimulation has been shown to synergize with that of CTLA4/CD28-B7 to promote transplant tolerance. To date, however, CD28-B7 interactions have been prevented using B7-blocking reagents like CTLA4-Ig that inhibit CD28-B7 together with CTLA4-B7 interactions. In this study, we have tested anti-CD28 Abs to prevent selectively CD28-B7 interactions while preserving CTLA4-B7 in addition to CD40-CD40L blockade. In the LEW.1W to LEW.1A rat combination, interfering with CD40-CD40L interactions by CD40Ig administration through gene transfer resulted in indefinite heart allograft survival due to the appearance of clonotypic CD8+CD45RClow regulatory T cells that were capable of transferring the tolerant state to naive animals. However, cardiac transplants in these recipients systematically developed chronic rejection lesions. Whereas anti-CD28 Ab monotherapy only delayed acute rejection and failed to induce tolerance, coadministration of anti-CD28 Abs and CD40Ig resulted in the long-term acceptation of allografts without chronic rejection lesions in 60% of the recipients, reduced the level of intragraft mRNA transcripts for cytokines and immune factors, and fully abrogated alloantibody production. In addition, the nature of regulatory cells was modified: the CD8+CD45RClow clonotypic T cells described in the CD40Ig-treated animals could not be found in cotreated animals, and the other CD8+CD45RClow cells had no regulatory activity and a different cytokine expression profile. Instead, in cotreated recipients we found IDO-dependent non-T cells with regulatory activity in vitro. Thus, the addition of a short-term anti-CD28 treatment with CD40Ig resulted in decreased heart allograft chronic rejection lesions, complete inhibition of Ab production, and modified regulatory mechanisms.
Death Receptor Ligation or Exposure to Perforin Trigger Rapid Egress of the Intracellular Parasite Toxoplasma gondii
Authors: Persson Emma K. , Agnarson Abela Mpobela , Lambert Henrik , Hitziger Niclas , Yagita Hideo , Chambers Benedict J. , Barragan Antonio , Grandien Alf 
Published: April 2014

Abstract
The obligate intracellular parasite Toxoplasma gondii chronically infects up to one-third of the global population, can result in severe disease in immunocompromised individuals, and can be teratogenic. In this study, we demonstrate that death receptor ligation in T. gondii-infected cells leads to rapid egress of infectious parasites and lytic necrosis of the host cell, an active process mediated through the release of intracellular calcium as a consequence of caspase activation early in the apoptotic cascade. Upon acting on infected cells via death receptor- or perforin-dependent pathways, T cells induce rapid egress of infectious parasites able to infect surrounding cells, including the Ag-specific effector cells.
NKT Cells Are Critical to Initiate an Inflammatory Response after Pseudomonas aeruginosa Ocular Infection in Susceptible Mice
Authors: Hazlett Linda D. , Li Qianqian , Liu Jianhua , McClellan Sharon , Du Wenjin , Barrett Ronald P. 
Published: April 2014

Abstract
CD4+ T cells produce IFN-γ contributing to corneal perforation in C57BL/6 (B6) mice after Pseudomonas aeruginosa infection. To determine the role of NK and NKT cells, infected corneas of B6 mice were dual immunolabeled. Initially, more NKT than NK cells were detected, but as disease progressed, NK cells increased, while NKT cells decreased. Therefore, B6 mice were depleted of NK/NKT cells with anti-asialo GM1 or anti-NK1.1 Ab. Either treatment accelerated time to perforation, increased bacterial load and polymorphonuclear neutrophils, but decreased IFN-γ and IL-12p40 mRNA expression vs controls. Next, RAG-1 knockout (−/−; no T/NKT cells), B6.TCR Jα281−/− (NKT cell deficient), α-galactosylceramide (αGalCer) (anergized NKT cells) injected and IL-12p40−/− vs B6 controls were tested. IFN-γ mRNA was undetectable in RAG-1−/−- and αGalCer-treated mice at 5 h and was significantly reduced vs controls at 1 day postinfection. It also was reduced significantly in B6.TCR Jα281−/−, αGalCer-treated, and IL-12p40−/− (activated CD4+ T cells also reduced) vs control mice at 5 days postinfection. In vitro studies tested whether endotoxin (LPS) stimulated Langerhans cells and macrophages (Mφ; from B6 mice) provided signals to activate NKT cells. LPS up-regulated mRNA expression for IL-12p40, costimulatory molecules CD80 and CD86, NF-κB, and CD1d, and addition of rIFN-γ potentiated Mφ CD1d levels. Together, these data suggest that Langerhans cell/Mφ recognition of microbial LPS regulates IL-12p40 (and CD1d) driven IFN-γ production by NKT cells, that IFN-γ is required to optimally activate NK cells to produce IFN-γ, and that depletion of both NKT/NK cells results in earlier corneal perforation.
Expression of CXC Chemokine Ligand 10 from the Mouse Hepatitis Virus Genome Results in Protection from Viral-Induced Neurological and Liver Disease
Authors: Walsh Kevin B. , Edwards Robert A. , Romero Kimberley M. , Kotlajich Matthew V. , Stohlman Stephen A. , Lane Thomas E. 
Published: April 2014

Abstract
Using the recombinant murine coronavirus mouse hepatitis virus (MHV) expressing the T cell-chemoattractant CXCL10 (MHV-CXCL10), we demonstrate a potent antiviral role for CXCL10 in host defense. Instillation of MHV-CXCL10 into the CNS of CXCL10-deficient (CXCL10−/−) mice resulted in viral infection and replication in both brain and liver. Expression of virally encoded CXCL10 within the brain protected mice from death and correlated with increased infiltration of T lymphocytes, enhanced IFN-γ secretion, and accelerated viral clearance when compared with mice infected with an isogenic control virus, MHV. Similarly, viral clearance from the livers of MHV-CXCL10-infected mice was accelerated in comparison to MHV-infected mice, yet was independent of enhanced infiltration of T lymphocytes and NK cells. Moreover, CXCL10−/− mice infected with MHV-CXCL10 were protected from severe hepatitis as evidenced by reduced pathology and serum alanine aminotransferase levels compared with MHV-infected mice. CXCL10-mediated protection within the liver was not dependent on CXC-chemokine receptor 2 (CXCR2) signaling as anti-CXCR2 treatment of MHV-CXCL10-infected mice did not modulate viral clearance or liver pathology. In contrast, treatment of MHV-CXCL10-infected CXCL10−/− mice with anti-CXCL10 Ab resulted in increased clinical disease correlating with enhanced viral recovery from the brain and liver as well as increased serum alanine aminotransferase levels. These studies highlight that CXCL10 expression promotes protection from coronavirus-induced neurological and liver disease.
Type I IFN Induction in Response to Listeria monocytogenes in Human Macrophages: Evidence for a Differential Activation of IFN Regulatory Factor 3 (IRF3)
Authors: Reimer Thornik , Schweizer Matthias , Jungi Thomas W. 
Published: April 2014

Abstract
Listeria monocytogenes is a prototypic bacterium for studying innate and adaptive cellular immunity as well as host defense. Using human monocyte-derived macrophages, we report that an infection with a wild-type strain, but not a listeriolysin O-deficient strain, of the Gram-positive bacterium L. monocytogenes induces expression of IFN-β and a bioactive type I IFN response. Investigating the activation of signaling pathways in human macrophages after infection revealed that a wild-type strain and a hemolysin-deficient strain of L. monocytogenes activated the NF-κB pathway and induced a comparable TNF response. p38 MAPK and activating transcription factor 2 were phosphorylated following infection with either strain, and IFN-β gene expression induced by wild-type L. monocytogenes was reduced when p38 was inhibited. However, neither IFN regulatory factor (IRF) 3 translocation to the nucleus nor posttranslational modifications and dimerizations were observed after L. monocytogenes infection. In contrast, vesicular stomatitis virus and LPS triggered IRF3 activation and signaling. When IRF3 was knocked down using small interfering RNA, a L. monocytogenes-induced IFN-β response remained unaffected whereas a vesicular stomatitis virus-triggered response was reduced. Evidence against the possibility that IRF7 acts in place of IRF3 is provided. Thus, we show that wild-type L. monocytogenes induced an IFN-β response in human macrophages and propose that this response involves p38 MAPK and activating transcription factor 2. Using various stimuli, we show that IRF3 is differentially activated during type I IFN responses in human macrophages.
Direct Interferon-γ Signaling Dramatically Enhances CD4+ and CD8+ T Cell Memory
Authors: Whitmire Jason K. , Eam Boreth , Benning Nicola , Whitton J. Lindsay 
Published: April 2014

Abstract
Studies in IFN-γ-deficient mice suggest that the delivery of IFN-γ to CD8+ T cells early in virus infection programs their eventual contraction, thereby reducing the abundance of CD8+ memory T cells. In this study, we show that such mice fail to completely eliminate virus infection and that, when evaluated without the confounding factor of persisting Ag, both CD4+ and CD8+ T cells undergo profound contraction when they are unable to receive IFN-γ signals. Furthermore, the abundance of CD4+ and CD8+ memory cells that express the IFN-γ receptor is ∼100-fold higher than cells lacking this molecule. Thus, direct IFN-γ signaling is not required for T cell contraction during virus infection, and it enhances, rather than suppresses, the development of virus-specific CD4+ and CD8+ T cell memory.
Human Cytotoxic CD4+ T Cells Recognize HLA-DR1-Restricted Epitopes on Vaccinia Virus Proteins A24R and D1R Conserved among Poxviruses
Authors: Mitra-Kaushik Shibani , Cruz John , Stern Lawrence J. , Ennis Francis A. , Terajima Masanori 
Published: April 2014

Abstract
We previously demonstrated that vaccinia virus (VV)-specific CD4+ cytolytic T cells can persist for &gt;50 years after immunization against smallpox in the absence of re-exposure to VV. Nevertheless, there have been few studies focusing on CD4+ T cell responses to smallpox vaccination. To ensure successful vaccination, a candidate vaccine should contain immunodominant CD4+ T cell epitopes as well as CD8+ T and B cell epitopes. In the present study, we established cytotoxic CD4+ T cell lines from VV-immune donors, which recognize epitopes in VV proteins D1R and A24R in association with HLA-DR1 Ags. Comparisons of sequences between different members of the poxvirus family show that both epitopes are completely conserved among VV, variola viruses, and most mammalian poxviruses, including monkeypox, cowpox, and ectromelia. The CD4+ T cell lines lysed VV-infected, Ag- and peptide-pulsed targets, and the lysis was inhibited by concanamycin A. We also detected these peptide-specific cytolytic and IFN-γ-producing CD4+ T cells in short-term bulk cultures of PBMC from each of the three VV-immune donors tested. These are the first VV-specific CD4+ T cell epitopes identified in humans restricted by one of the most common MHC class II molecules, HLA-DR1, and this information may be useful in analyzing CD4+ T cell responses to pre-existing or new generation VV vaccines against smallpox.
Immunomodulatory Dendritic Cells Inhibit Th1 Responses and Arthritis via Different Mechanisms
Authors: van Duivenvoorde Leonie M. , Han Wanda G. H. , Bakker Aleida M. , Louis-Plence Pascale , Charbonnier Louis-Marie , Apparailly Florence , van der Voort Ellen I. H. , Jorgensen Christian , Huizinga Tom W. J. , Toes René E. M. 
Published: April 2014

Abstract
Dendritic cells (DCs) are professional APCs which have the unique ability to present both foreign and self-Ags to T cells and steer the outcome of immune responses. Because of these characteristics, DCs are attractive vehicles for the delivery of therapeutic vaccines. Fully matured DCs are relatively well-defined and even used in clinical trials in cancer. DCs also have the potential to influence the outcome of autoimmunity by modulating the underlying autoimmune response. To gain a better appreciation of the abilities and mechanisms by which immunomodulatory DCs influence the outcome of T cell responses, we studied several immunomodulatory DCs (TNF-, IL-10-, or dexamethasone-stimulated bone marrow-derived DCs) side by side for their ability to modulate T cell responses and autoimmune diseases. Our data show that these differentially modulated DCs display a different composition of molecules involved in T cell activation. Although, all DC subsets analyzed were able to inhibit the induction of collagen-induced arthritis, the modulation of the underlying immune response was different. Vaccination with TNF- or IL-10-modulated DCs altered the Th1/Th2 balance as evidenced by the induction of IL-5- and IL-10-secreting T cells and the concomitant reduction of the IgG2a-IgG1 ratio against the immunizing Ag. In contrast, DCs modulated with dexamethasone did not affect the ratio of IL-5-producing vs IFN-γ-producing T cells and tended to affect the Ab response in a nonspecific manner. These data indicate that distinct mechanisms can be used by distinct DC subsets to change the outcome of autoimmunity.
Cross-Talk between T Cells and Innate Immune Cells Is Crucial for IFN-γ-Dependent Tumor Rejection
Authors: Li Zhiguang , Pradera Felicia , Kammertoens Thomas , Li Bing , Liu Shubai , Qin Zhihai 
Published: April 2014

AbstractThough the importance of IFN-γ in tumor immunity has been well-demonstrated, little is known about its source and how it is induced. By using various bone marrow chimeric mice, we show here that IFN-γ essential for tumor immunity is solely produced by hemopoietic cells. Surprisingly, IFN-γ derived from T cells was not necessary for tumor immunity in this model. In the immunized mice, in which only innate immune cells have the IFN-γ-producing potential, tumors were efficiently rejected. The innate immune cells, such as NK1.1+ cells and CD11b+ cells, can provide sufficient amounts of IFN-γ which requires, however, the help of T cells. The close cooperation between T cells and innate immune cells during tumor regression is likely mediated by IL-2. Together, our results clearly illustrate how T cells cooperate with innate immune cells for IFN-γ-mediated tumor rejection and this may have important indications for clinical trials of tumor immunotherapy.
Noninvasive Intravital Imaging of Thymocyte Dynamics in Medaka
Authors: Li Jie , Iwanami Norimasa , Hoa Vu Quynh , Furutani-Seiki Makoto , Takahama Yousuke 
Published: April 2014

Abstract
In vivo imaging of thymocytes has not been accomplished due to their localization deep within opaque body and high susceptibility to surgical stress. To overcome these problems, medaka is useful because of transparency and ex-uterine development. We report the noninvasive detection of thymocytes in transgenic medaka that express fluorescent protein under the control of immature-lymphocyte-specific rag1. We show that lymphoid progenitor cells colonize the thymus primordium in an anterior-to-posterior orientation-specific manner, revealing that extrathymic anterior components guide prevascular thymus colonization. We also show that developing thymocytes acquire “random walk motility” along with the expression of Ag receptors and coreceptors, suggesting that thymocyte walking is initiated at the developmental stage for repertoire selection. Thus, transgenic medaka enables real-time intravital imaging of thymocytes without surgical invasion.