bluuebunny/crossref_metadata_2025_split huggingface dataset:
Activating Fcγ Receptors Participate in the Development of Autoimmune Diabetes in NOD Mice
Authors: Inoue Yoshihiro , Kaifu Tomonori , Sugahara-Tobinai Akiko , Nakamura Akira , Miyazaki Jun-Ichi , Takai Toshiyuki 
Published: April 2014

Abstract
Type 1 diabetes mellitus (T1D) in humans is an organ-specific autoimmune disease in which pancreatic islet β cells are ruptured by autoreactive T cells. NOD mice, the most commonly used animal model of T1D, show early infiltration of leukocytes in the islets (insulitis), resulting in islet destruction and diabetes later. NOD mice produce various islet β cell-specific autoantibodies, although it remains a subject of debate regarding whether these autoantibodies contribute to the development of T1D. FcγRs are multipotent molecules that play important roles in Ab-mediated regulatory as well as effector functions in autoimmune diseases. To investigate the possible role of FcγRs in NOD mice, we generated several FcγR-less NOD lines, namely FcR common γ-chain (FcRγ)-deficient (NOD.γ−/−), FcγRIII-deficient (NOD.III−/−), FcγRIIB-deficient (NOD.IIB−/−), and both FcRγ and FcγRIIB-deficient NOD (NOD.null) mice. In this study, we show significant protection from diabetes in NOD.γ−/−, NOD.III−/−, and NOD.null, but not in NOD.IIB−/− mice even with grossly comparable production of autoantibodies among them. Insulitis in NOD.γ−/− mice was also alleviated. Adoptive transfer of bone marrow-derived dendritic cells or NK cells from NOD mice rendered NOD.γ−/− animals more susceptible to diabetes, suggesting a possible scenario in which activating FcγRs on dendritic cells enhance autoantigen presentation leading to the activation of autoreactive T cells, and FcγRIII on NK cells trigger Ab-dependent effector functions and inflammation. These findings highlight the critical roles of activating FcγRs in the development of T1D, and indicate that FcγRs are novel targets for therapies for T1D.
A Novel Alloantigen-Specific CD8+PD1+ Regulatory T Cell Induced by ICOS-B7h Blockade In Vivo
Authors: Izawa Atsushi , Yamaura Kazuhiro , Albin Monica J. , Jurewicz Mollie , Tanaka Katsunori , Clarkson Michael R. , Ueno Takuya , Habicht Antje , Freeman Gordon J. , Yagita Hideo , Abdi Reza , Pearson Todd , Greiner Dale L. , Sayegh Mohamed H. , Najafian Nader 
Published: April 2014

Abstract
Delayed ICOS-B7h signal blockade promotes significant prolongation of cardiac allograft survival in wild-type but not in CD8-deficient C57BL/6 recipients of fully MHC-mismatched BALB/c heart allografts, suggesting the possible generation of CD8+ regulatory T cells in vivo. We now show that the administration of a blocking anti-ICOS mAb results in the generation of regulatory CD8+ T cells. These cells can transfer protection and prolong the survival of donor-specific BALB/c, but not third party C3H, heart grafts in CD8-deficient C57BL/6 recipients. This is unique to ICOS-B7h blockade, because B7 blockade by CTLA4-Ig prolongs graft survival in CD8-deficient mice and does not result in the generation of regulatory CD8+ T cells. Those cells localize to the graft, produce both IFN-γ and IL-4 after allostimulation in vitro, prohibit the expansion of alloreactive CD4+ T cells, and appear to mediate a Th2 switch of recipient CD4+ T cells after adoptive transfer in vivo. Finally, these cells are not confined to the CD28-negative population but express programmed death 1, a molecule required for their regulatory function in vivo. CD8+PD1+ T cells suppress alloreactive CD4+ T cells but do not inhibit the functions by alloreactive CD8+ T cells in vitro. These results describe a novel allospecific regulatory CD8+PD1+ T cell induced by ICOS-B7h blockade in vivo.
Transcriptional Analysis of Clonal Deletion In Vivo
Authors: Baldwin Troy A. , Hogquist Kristin A. 
Published: April 2014

Abstract
Engagement of the TCR on CD4+CD8+ thymocytes initiates either a program of survival and differentiation (positive selection) or death (clonal deletion), which is dictated in large part by the affinity of the TCR for self-peptide-MHC complexes. Although much is known about the factors involved in positive selection, little is understood about the molecular mechanism leading to clonal deletion. To gain further insight into this process, we used a highly physiological TCR transgenic mouse model to compare gene expression changes under conditions of nonselection, positive selection, and negative selection. We identified 388 genes that were differentially regulated in negative selection compared with either nonselection or positive selection. These regulated genes fall into many functional categories including cell surface and intracellular signal transduction, survival and apoptosis, transcription and translation, and adhesion and migration. Additionally, we have compared our transcriptional profile to profiles of negative selection in other model systems in an effort to identify those genes with a higher probability of being functionally relevant. These included three up-regulated genes, bim, nur77, and ian1, and one down-regulated gene, lip1. Collectively, these data provide a framework for understanding the molecular basis of clonal deletion.
Epidermal Langerhans Cells Are Dispensable for Humoral and Cell-Mediated Immunity Elicited by Gene Gun Immunization
Authors: Stoecklinger Angelika , Grieshuber Ines , Scheiblhofer Sandra , Weiss Richard , Ritter Uwe , Kissenpfennig Adrien , Malissen Bernard , Romani Nikolaus , Koch Franz , Ferreira Fatima , Thalhamer Josef , Hammerl Peter 
Published: April 2014

AbstractGene gun immunization, i.e., bombardment of skin with DNA-coated particles, is an efficient method for the administration of DNA vaccines. Direct transfection of APC or cross-presentation of exogenous Ag acquired from transfected nonimmune cells enables MHC-I-restricted activation of CD8+ T cells. Additionally, MHC-II-restricted presentation of exogenous Ag activates CD4+ Th cells. Being the principal APC in the epidermis, Langerhans cells (LC) seem ideal candidates to accomplish these functions. However, the dependence on LC of gene gun-induced immune reactions has not yet been demonstrated directly. This was primarily hampered by difficulties to discriminate the contributions of LC from those of other dermal dendritic cells. To address this problem, we have used Langerin-diphtheria toxin receptor knockin mice that allow for selective inducible ablation of LC. LC deficiency, even over the entire duration of experiments, did not affect any of the gene gun-induced immune functions examined, including proliferation of CD4+ and CD8+ T cells, IFN-γ secretion by spleen cells, Ab production, CTL activity, and development of protective antitumor immunity. Together, our data show that gene gun immunization is capable of inducing humoral and cell-mediated immune reactions independently of LC.
Blockade of IDO Inhibits Nasal Tolerance Induction
Authors: van der Marel Arnold P. J. , Samsom Janneke N. , Greuter Mascha , van Berkel Lisette A. , O’Toole Tom , Kraal Georg , Mebius Reina E. 
Published: April 2014

Abstract
The amino acid tryptophan is essential for the proliferation and survival of cells. Modulation of tryptophan metabolism has been described as an important regulatory mechanism for the control of immune responses. The enzyme IDO degrades the indole moiety of tryptophan, not only depleting tryptophan but also producing immunomodulatory metabolites called kynurenines, which have apoptosis-inducing capabilities. In this study, we show that IDO is more highly expressed in nonplasmacytoid dendritic cells of the nose draining lymph nodes (LNs), which form a unique environment to induce tolerance to inhaled Ags, when compared with other peripheral LNs. Upon blockade of IDO during intranasal OVA administration, Ag-specific immune tolerance was abrogated. Analysis of Ag-specific T cells in the LNs revealed that inhibition of IDO resulted in enhanced survival at 48 h after antigenic stimulation, although this result was not mediated through alterations in apoptosis or cell proliferation. Furthermore, no differences were found in CD4+ T cells expressing FoxP3. Our data suggest that the level of IDO expression in dendritic cells, present in nose draining LNs, allows for the generation of a sufficient number of regulatory T cells to control and balance effector T cells in such a way that immune tolerance is induced, whereas upon IDO blockade, effector T cells will outnumber regulatory T cells, leading to immunity.
Foxp3+CD25+ T Regulatory Cells Stimulate IFN-γ-Independent CD152-Mediated Activation of Tryptophan Catabolism That Provides Dendritic Cells with Immune Regulatory Activity in Mice Unresponsive to Staphylococcal Enterotoxin B
Authors: Feunou Pascal , Vanwetswinkel Sophie , Gaudray Florence , Goldman Michel , Matthys Patrick , Braun Michel Y. 
Published: April 2014

AbstractMice made unresponsive by repeated injection of staphylococcal enterotoxin B (SEB) contained SEB-specific CD25+CD4+TCRBV8+ T cells that were able to transfer their state of unresponsiveness to primary-stimulated T cells. About one-half of these cells stably up-regulated the expression of CD152. We undertook the present study to determine whether CD152high cells seen in this system were T regulatory cells responsible for suppression or whether they represented SEB-activated CD4+ T effector cells. Our results show that, among SEB-specific TCRBV8+ T cells isolated from unresponsive mice, all CD152highCD25+CD4+ T cells expressed Foxp3, the NF required for differentiation and function of natural T regulatory cells. Moreover, suppression by CD25+CD4+TCRBV8+ T cells was fully inhibited by anti-CD152 Abs. Following stimulation by soluble CD152-Ig, dendritic cells (DC) isolated from unresponsive mice strongly increased the expression and the function of indoleamine-2,3-dioxygenase (IDO), the enzyme responsible for the catabolism of tryptophan. This capacity to activate IDO was independent of IFN-γ production by DC because CD152-Ig stimulation of DC isolated from SEB-treated IFN-γ-deficient animals activated IDO expression and function. Finally, adding 1-methyl-tryptophan, an inhibitor of tryptophan catabolism, increased substantially the capacity of DC from unresponsive animals to stimulate primary T cell response toward SEB. Thus, we conclude that IFN-γ-independent CD152-mediated activation of tryptophan catabolism by Foxp3+CD25+ T regulatory cells provides DC with immune regulatory activity in mice unresponsive to SEB.
Tristetraprolin, a Negative Regulator of mRNA Stability, Is Increased in Old B Cells and Is Involved in the Degradation of E47 mRNA
Authors: Frasca Daniela , Landin Ana Marie , Alvarez Juan P. , Blackshear Perry J. , Riley Richard L. , Blomberg Bonnie B. 
Published: April 2014

Abstract
We have previously shown that the E2A-encoded transcription factor E47, which regulates class switch in splenic B cells, is down-regulated in old B cells, due to increased E47 mRNA decay. At least part of the decreased stability of E47 mRNA seen in aged B cells is mediated by proteins. We have herein looked at the specific proteins responsible for the degradation of the E47 mRNA and found that tristetraprolin (TTP), a physiological regulator of mRNA expression and stability, is involved in the degradation of the E47 mRNA. Although many studies have characterized TTP expression and function in macrophages, monocytes, mast cells, and T cells, little is known about the expression and function of TTP in primary B cells. We show herein that TTP mRNA and protein expression are induced by LPS in B cells from young and old mice, the levels of TTP in old B cells always being higher than those in young B cells. Although TTP mRNA is degraded at a significantly higher rate in old B cells, TTP mRNA expression is higher in old than in young, likely due to its increased transcription. Like in macrophages, TTP protein expression and function in B cells are dependent upon p38 MAPK. We found that there is less phospho-TTP (inactive form), as well as phospho-p38, in old than in young splenic-activated B cells. This is the first report showing that TTP is involved in the degradation of the E47 mRNA and is up-regulated in old B cells.
Cutting Edge: OX40 Inhibits TGF-β- and Antigen-Driven Conversion of Naive CD4 T Cells into CD25+Foxp3+ T cells
Authors: So Takanori , Croft Michael 
Published: April 2014

Abstract
Naive CD4 T cells can develop into regulatory T cells by acquiring the transcription factor Foxp3. Combined signals from the TCR, CD28, IL-2R, and TGF-βR promote Foxp3 expression in activated naive CD25− CD4 T cells. Here we show that OX40 (CD134) signaling inhibits TGF-β-driven Foxp3 mRNA and suppresses the conversion of naive Ag-specific transgenic CD4 T cells into CD25+Foxp3+ T cells. These data identify OX40 as a negative regulator of Foxp3 and suggest that OX40 can concomitantly promote effector T cell generation while antagonizing the differentiation of adaptive Foxp3+ regulatory T cells.
Controls for Lung Dendritic Cell Maturation and Migration during Respiratory Viral Infection
Authors: Grayson Mitchell H. , Ramos Madeleine S. , Rohlfing Michelle M. , Kitchens Robert , Wang Howard D. , Gould Aaron , Agapov Eugene , Holtzman Michael J. 
Published: April 2014

Abstract
Dendritic cells are ideally suited to orchestrate the innate and adaptive immune responses to infection, but we know little about how these cells respond to infection with common respiratory viruses. Paramyxoviral infections are the most frequent cause of serious respiratory illness in childhood and are associated with an increased risk of asthma. We therefore used a high-fidelity mouse model of paramyxoviral respiratory infection triggered by Sendai virus to examine the response of conventional and plasmacytoid dendritic cells (cDCs and pDCs, respectively) in the lung. We found that pDCs are scarce at baseline but become the predominant population of lung dendritic cells during infection. This recruitment allows for a source of IFN-α locally at the site of infection. In contrast, cDCs rapidly differentiate into myeloid cDCs and begin to migrate from the lung to draining lymph nodes within 2 h after viral inoculation. These events cause the number of lung cDCs to decrease rapidly and remain decreased at the site of viral infection. Maturation and migration of lung cDCs depends on Ccl5 and Ccr5 signals because these events are significantly impaired in Ccl5−/− and Ccr5−/− mice. cDCs failure to migrate to draining lymph nodes in Ccl5−/− or Ccr5−/− mice is associated with impaired up-regulation of CCR7 that would normally direct this process. Our results indicate that pDCs and cDCs respond distinctly to respiratory paramyxoviral infection with patterns of movement that should serve to coordinate the innate and adaptive immune responses, respectively.
Steady State Dendritic Cells Present Parenchymal Self-Antigen and Contribute to, but Are Not Essential for, Tolerization of Naive and Th1 Effector CD4 Cells
Authors: Hagymasi Adam T. , Slaiby Aaron M. , Mihalyo Marianne A. , Qui Harry Z. , Zammit David J. , Lefrancois Leo , Adler Adam J. 
Published: April 2014

AbstractBone marrow-derived APC are critical for both priming effector/memory T cell responses to pathogens and inducing peripheral tolerance in self-reactive T cells. In particular, dendritic cells (DC) can acquire peripheral self-Ags under steady state conditions and are thought to present them to cognate T cells in a default tolerogenic manner, whereas exposure to pathogen-associated inflammatory mediators during the acquisition of pathogen-derived Ags appears to reprogram DCs to prime effector and memory T cell function. Recent studies have confirmed the critical role of DCs in priming CD8 cell effector responses to certain pathogens, although the necessity of steady state DCs in programming T cell tolerance to peripheral self-Ags has not been directly tested. In the current study, the role of steady state DCs in programming self-reactive CD4 cell peripheral tolerance was assessed by combining the CD11c-diphtheria toxin receptor transgenic system, in which DC can be depleted via treatment with diphtheria toxin, with a TCR-transgenic adoptive transfer system in which either naive or Th1 effector CD4 cells are induced to undergo tolerization after exposure to cognate parenchymally derived self-Ag. Although steady state DCs present parenchymal self-Ag and contribute to the tolerization of cognate naive and Th1 effector CD4 cells, they are not essential, indicating the involvement of a non-DC tolerogenic APC population(s). Tolerogenic APCs, however, do not require the cooperation of CD4+CD25+ regulatory T cells. Similarly, DC were required for maximal priming of naive CD4 cells to vaccinia viral-Ag, but priming could still occur in the absence of DC.
Listeriolysin O Expressed in a Bacterial Vaccine Suppresses CD4+CD25high Regulatory T Cell Function In Vivo
Authors: Nitcheu-Tefit Josianne , Dai Ming-Shen , Critchley-Thorne Rebecca J. , Ramirez-Jimenez Francisco , Xu Man , Conchon Sophie , Ferry Nicolas , Stauss Hans J. , Vassaux Georges 
Published: April 2014

Abstract
CD4+CD25high regulatory T cells (Treg) protect the host from autoimmune diseases but are also obstacles against cancer therapies. An ideal cancer vaccine would stimulate specific cytotoxic responses and reduce/suppress Treg function. In this study, we showed that Escherichia coli expressing listeriolysin O and OVA (E. coli LLO/OVA) demonstrated remarkable levels of protection against OVA-expressing tumor cells. By contrast, E. coli expressing OVA only (E. coli OVA) showed poor protection. High-avidity OVA-specific CTL were induced in E. coli LLO/OVA-vaccinated mice, and CD8+ depletion—but not NK cell depletion, abolished the antitumor activity of the E. coli LLO/OVA vaccine. Phenotypic analysis of T cells following vaccination with either vaccine revealed preferential generation of CD44highCD62Llow CD8+ effector memory T cells over CD44highCD62Lhigh central memory T cells. Unexpectedly, CD4+ depletion turned E. coli OVA into a vaccine as effective as E. coli LLO/OVA suggesting that a subset of CD4+ cells suppressed the CD8+ T cell-mediated antitumor response. Further depletion experiments demonstrated that these suppressive cells consisted of CD4+CD25high regulatory T cells. We therefore assessed these vaccines for Treg function and found that although CD4+CD25high expansion and Foxp3 expression within this population was similar in all groups of mice, Treg cells from E. coli LLO/OVA-vaccinated animals were unable to suppress conventional T cells proliferation. These findings provide the first evidence that LLO expression affects Treg cell function and may have important implications for enhancing antitumor vaccination strategies in humans.
Regulation of MHC Class II Expression and Antigen Processing in Murine and Human Mesenchymal Stromal Cells by IFN-γ, TGF-β, and Cell Density
Authors: Romieu-Mourez Raphaëlle , François Moïra , Boivin Marie-Noëlle , Stagg John , Galipeau Jacques 
Published: April 2014

Abstract
Mesenchymal stromal cells (MSC) possess immunosuppressive properties, yet when treated with IFN-γ they acquire APC functions. To gain insight into MSC immune plasticity, we explored signaling pathways induced by IFN-γ required for MHC class II (MHC II)-dependent Ag presentation. IFN-γ-induced MHC II expression in mouse MSC was enhanced by high cell density or serum deprivation and suppressed by TGF-β. This process was regulated by the activity of the type IV CIITA promoter independently of STAT1 activation and the induction of the IFN regulatory factor 1-dependent B7H1/PD-L1 encoding gene. The absence of direct correlation with the cell cycle suggested that cellular connectivity modulates IFN-γ responsiveness for MHC II expression in mouse MSC. TGF-β signaling in mouse MSC involved ALK5 and ALK1 TGF-βRI, leading to the phosphorylation of Smad2/Smad3 and Smad1/Smad5/Smad8. An opposite effect was observed in human MSC where IFN-γ-induced MHC II expression occurred at the highest levels in low-density cultures; however, TGF-β reduced IFN-γ-induced MHC II expression and its signaling was similar as in mouse MSC. This suggests that the IFN-γ-induced APC features of MSC can be modulated by TGF-β, serum factors, and cell density in vitro, although not in the same way in mouse and human MSC, via their convergent effects on CIITA expression.
Ca2+ Signals in CD4+ T Cells during Early Contacts with Antigen-Bearing Dendritic Cells in Lymph Node
Authors: Wei Sindy H. , Safrina Olga , Yu Ying , Garrod Kym R. , Cahalan Michael D. , Parker Ian 
Published: April 2014

Abstract
T cell activation by APC requires cytosolic Ca2+ ([Ca2+]i) elevation. Using two-photon microscopy, we visualized Ca2+ signaling and motility of murine CD4+ T cells within lymph node (LN) explants under control, inflammatory, and immunizing conditions. Without Ag under basal noninflammatory conditions, T cells showed infrequent Ca2+ spikes associated with sustained slowing. Inflammation reduced velocities and Ca2+ spiking in the absence of specific Ag. During early Ag encounter, most T cells engaged Ag-presenting dendritic cells in clusters, and showed increased Ca2+ spike frequency and elevated basal [Ca2+]i. These Ca2+ signals persisted for hours, irrespective of whether T cells were in contact with visualized dendritic cells. We propose that sustained increases in basal [Ca2+]i and spiking frequency constitute a Ca2+ signaling modality that, integrated over hours, distinguishes immunogenic from basal state in the native lymphoid environment.
IFN-γ and Fas Ligand Are Required for Graft-versus-Tumor Activity against Renal Cell Carcinoma in the Absence of Lethal Graft-versus-Host Disease
Authors: Ramirez-Montagut Teresa , Chow Andrew , Kochman Adam A. , Smith Odette M. , Suh David , Sindhi Hamad , Lu Sydney , Borsotti Chiara , Grubin Jeremy , Patel Neel , Terwey Theis H. , Kim Theo D. , Heller Glenn , Murphy George F. , Liu Chen , Alpdogan Onder , van den Brink Marcel R. M. 
Published: April 2014

Abstract
To determine the mechanisms of graft-versus-tumor (GVT) activity in the absence of graft-versus-host disease (GVHD) against a solid tumor, we established two allogeneic bone marrow transplantation models with a murine renal cell carcinoma (RENCA). The addition of 0.3 × 106 donor CD8+ T cells to the allograft increased the survival of tumor-bearing mice without causing GVHD. The analysis of CD8+ T cells deficient in cytotoxic molecules demonstrated that anti-RENCA activity is dependent on IFN-γ and Fas ligand (FasL), but does not require soluble or membrane-bound TNF-α, perforin, or TRAIL. Recipients of IFN-γ−/− CD8+ T cells are unable to reject RENCA compared with recipients of wild-type CD8+ T cells and, importantly, neither group develops severe GVHD. IFN-γ−/− CD8+ T cells derived from transplanted mice are less able to kill RENCA cells in vitro, while pretreatment of RENCA cells with IFN-γ enhances class I and FasL expression and rescues the lytic capacity of IFN-γ−/− CD8+ T cells. These results demonstrate that the addition of low numbers of selected donor CD8+ T cells to the allograft can mediate GVT activity without lethal GVHD against murine renal cell carcinoma, and this GVT activity is dependent on IFN-γ and FasL.