bluuebunny/crossref_metadata_2025_split huggingface dataset:
Cutting Edge: Chromatin Remodeling as a Molecular Basis for the Enhanced Functionality of Memory CD8 T Cells
Authors: Northrop John K. , Wells Andrew D. , Shen Hao 
Published: April 2014

Abstract
Memory CD8 T cells, unlike their naive precursors, are capable of rapidly producing high levels of cytokines, killing target cells, and proliferating into numerous secondary effectors immediately upon Ag encounter. This ready-to-respond state contributes to their superior ability to confer protective immunity, yet the underlying molecular basis remains unknown. In this study, we show that memory CD8 T cells have increased histone acetylation compared with naive CD8 T cells; however, those activated without CD4 T cell help (“unhelped”) remain hypoacetylated and fail to develop into functional, protective memory. Treatment with a histone deacetylase inhibitor during activation results in increased histone acetylation in unhelped CD8 T cells and restores their ability to differentiate into functional memory cells capable of immediate cytokine production and providing protective immunity. These results demonstrate that CD4 T help-dependent chromatin remodeling provides a molecular basis for the enhanced responsiveness of memory CD8 T cells.
Impaired SLAM-SLAM Homotypic Interaction between Invariant NKT Cells and Dendritic Cells Affects Differentiation of IL-4/IL-10-Secreting NKT2 Cells in Nonobese Diabetic Mice
Authors: Baev Denis V. , Caielli Simone , Ronchi Francesca , Coccia Margherita , Facciotti Federica , Nichols Kim E. , Falcone Marika 
Published: April 2014

Abstract
The regulatory function of invariant NKT (iNKT) cells for tolerance induction and prevention of autoimmunity is linked to a specific cytokine profile that comprises the secretion of type 2 cytokines like IL-4 and IL-10 (NKT2 cytokine profile). The mechanism responsible for iNKT cell differentiation toward a type 2 phenotype is unknown. Herein we show that costimulatory signals provided by the surface receptor signaling lymphocytic activation molecule (SLAM) on myeloid dendritic cells (mDC) to iNKT cells is crucial for NKT2 orientation. Additionally, we demonstrate that the impaired acquisition of an NKT2 cytokine phenotype in nonobese diabetic (NOD) mice that spontaneously develop autoimmune diabetes is due to defective SLAM-induced signals generated by NOD mDC. Mature mDC of C57BL/6 mice express SLAM and induce C57BL/6 or NOD iNKT cells to acquire a predominant NKT2 cytokine phenotype in response to antigenic stimulation with the iNKT cell-specific Ag, the α-galactosylceramide. In contrast, mature NOD mDC express significantly lower levels of SLAM and are unable to promote GATA-3 (the SLAM-induced intracellular signal) up-regulation and IL-4/IL-10 production in iNKT cells from NOD or C57BL/6 mice. NOD mice carry a genetic defect of the Slamf1 gene that is associated with reduced SLAM expression on double-positive thymocytes and altered iNKT cell development in the thymus. Our data suggest that the genetic Slamf1 defect in NOD mice also affects SLAM expression on other immune cells such as the mDC, thus critically impairing the peripheral differentiation of iNKT cells toward a regulatory NKT2 type.
The Complement Inhibitor Low Molecular Weight Dextran Sulfate Prevents TLR4-Induced Phenotypic and Functional Maturation of Human Dendritic Cells
Authors: Spirig Rolf , van Kooten Cees , Obregon Carolina , Nicod Laurent , Daha Mohamed , Rieben Robert 
Published: April 2014

Abstract
Low molecular weight dextran sulfate (DXS) has been reported to inhibit the classical, alternative pathway as well as the mannan-binding lectin pathway of the complement system. Furthermore, it acts as an endothelial cell protectant inhibiting complement-mediated endothelial cell damage. Endothelial cells are covered with a layer of heparan sulfate (HS), which is rapidly released under conditions of inflammation and tissue injury. Soluble HS induces maturation of dendritic cells (DC) via TLR4. In this study, we show the inhibitory effect of DXS on human DC maturation. DXS significantly prevents phenotypic maturation of monocyte-derived DC and peripheral myeloid DC by inhibiting the up-regulation of CD40, CD80, CD83, CD86, ICAM-1, and HLA-DR and down-regulates DC-SIGN in response to HS or exogenous TLR ligands. DXS also inhibits the functional maturation of DC as demonstrated by reduced T cell proliferation, and strongly impairs secretion of the proinflammatory mediators IL-1β, IL-6, IL-12p70, and TNF-α. Exposure to DXS leads to a reduced production of the complement component C1q and a decreased phagocytic activity, whereas C3 secretion is increased. Moreover, DXS was found to inhibit phosphorylation of IκB-α and activation of NF-κB. These findings suggest that DXS prevents TLR-induced maturation of human DC and may therefore be a useful reagent to impede the link between innate and adaptive immunity.
Oral or Nasal Antigen Induces Regulatory T Cells That Suppress Arthritis and Proliferation of Arthritogenic T Cells in Joint Draining Lymph Nodes
Authors: Broere Femke , Wieten Lotte , Klein Koerkamp Elles I. , van Roon Joel A. G. , Guichelaar Teun , Lafeber Floris P. J. G. , van Eden Willem 
Published: April 2014

Abstract
The propagation of mucosal tolerance as a therapeutic approach in autoimmune diseases remains a difficult goal to achieve, and therefore further mechanistic studies are necessary to develop potential clinical protocols to induce mucosal regulatory T cells (Tr cells). In this study we addressed whether oral or nasal proteoglycan induced functional Tr cells in the cartilage proteoglycan-induced chronic arthritis model. Both nasal and oral application of human proteoglycan before induction of disease suppressed arthritis severity and incidence. Tolerized mice showed enhanced numbers of IL-10 producing CD4+ cells in the paw-draining lymph nodes. Furthermore, CD4+ spleen cells displayed enhanced expression of molecules associated with Tr cells, such as IL-10, Foxp3, and TGF-β. Transfer of CD4+ spleen cells from mucosally tolerized donors into proteoglycan-immunized mice abolished arthritis and reduced humoral responses, indicative of Tr cells with the capacity to inhibit already induced immune responses. Tr cells were activated upon transfer, because enhanced proliferation was observed in the joint draining lymph nodes compared with activated T cells from nontolerized donors. Upon cotransfer with naive proteoglycan-specific T cells, mucosally induced Tr cells inhibited proliferation of these arthritogenic T cells in vivo. Herein we show that both oral and nasal Ag application induced Tr cells, which had a direct inhibitory effect on already established pathogenic B and T cell responses.
Histone Acetylation and Flagellin Are Essential for Legionella pneumophila-Induced Cytokine Expression
Authors: Schmeck Bernd , Lorenz Janina , N′Guessan Philippe Dje , Opitz Bastian , van Laak Vincent , Zahlten Janine , Slevogt Hortense , Witzenrath Martin , Flieger Antje , Suttorp Norbert , Hippenstiel Stefan 
Published: April 2014

Abstract
Legionella pneumophila causes severe pneumonia. Acetylation of histones is thought to be an important regulator of gene transcription, but its impact on L. pneumophila-induced expression of proinflammatory cytokines is unknown. L. pneumophila strain 130b induced the expression of the important chemoattractant IL-8 and genome-wide histone modifications in human lung epithelial A549 cells. We analyzed the IL-8-promoter and found that histone H4 was acetylated and H3 was phosphorylated at Ser10 and acetylated at Lys14, followed by transcription factor NF-κB. Recruitment of RNA polymerase II to the IL-8 promoter corresponded with increases in gene transcription. Histone modification and IL-8 release were dependent on p38 kinase and NF-κB pathways. Legionella-induced IL-8 expression was decreased by histone acetylase (HAT) inhibitor anacardic acid and enhanced by histone deacetylase (HDAC) inhibitor trichostatin A. After Legionella infection, HATs p300 and CREB-binding protein were time-dependently recruited to the IL-8 promoter, whereas HDAC1 and HDAC5 first decreased and later reappeared at the promoter. Legionella specifically induced expression of HDAC5 but not of other HDACs in lung epithelial cells, but knockdown of HDAC1 or 5 did not alter IL-8 release. Furthermore, Legionella-induced cytokine release, promoter-specific histone modifications, and RNA polymerase II recruitment were reduced in infection with flagellin-deletion mutants. Legionella-induced histone modification as well as HAT-/HDAC-dependent IL-8 release could also be shown in primary lung epithelial cells. In summary, histone acetylation seems to be important for the regulation of proinflammatory gene expression in L. pneumophila infected lung epithelial cells. These pathways may contribute to the host response in Legionnaires’ disease.
Transfusion of IgG-Opsonized Foreign Red Blood Cells Mediates Reduction of Antigen-Specific B Cell Priming in a Murine Model
Authors: Brinc Davor , Le-Tien Hoang , Crow Andrew R. , Siragam Vinayakumar , Freedman John , Lazarus Alan H. 
Published: April 2014

Abstract
Hemolytic disease of the fetus and newborn can be effectively prevented by administration of anti-D to the mother. The administered IgG results in the attenuation of RBC-specific Ab production, a process termed Ab-mediated immune suppression (AMIS). Because in animal models of AMIS no major effect on T cell priming occurs, we hypothesized that the effect of the IgG on the immune system under AMIS conditions may involve a deficiency in B cell priming. We therefore challenged mice with either untreated RBCs or IgG-opsonized RBCs (AMIS) and assessed B cell priming. B cells from mice transfused with untreated RBCs, but not from mice treated under AMIS conditions, were primed as assessed by their ability to function as Ag-specific APCs to appropriate T cells. To our knowledge, this is the first report demonstrating that AMIS inhibits the appearance of Ag-primed RBC-specific B cells.
IL-13 Production by Regulatory T Cells Protects against Experimental Autoimmune Encephalomyelitis Independently of Autoantigen
Authors: Ochoa-Repáraz Javier , Rynda Agnieszka , Ascón Miguel A. , Yang Xinghong , Kochetkova Irina , Riccardi Carol , Callis Gayle , Trunkle Theresa , Pascual David W. 
Published: April 2014

AbstractTreatment with an anti-inflammatory Salmonella vaccine expressing enterotoxigenic Escherichia coli colonization factor Ag 1 (CFA/I) proved effective in stimulating protective, potent CD25+CD4+ regulatory T (Treg) cells in susceptible mice challenged with experimental autoimmune encephalomyelitis (EAE). Because the Salmonella vector was considerably less protective, we questioned whether altering fimbrial subunit expression to resemble conventional Salmonella expression may impact Treg cell potency. The Salmonella-CFA/I vaccine was modified to limit fimbrial subunit expression to the intracellular compartment (Salmonella-CFA/IIC). SJL mice were challenged with proteolipid protein peptide 139–151 to induce EAE and orally treated with one of three Salmonella vaccines 6 days postchallenge. Treatment with Salmonella-CFA/IIC greatly reduced clinical disease, similarly as Salmonella-CFA/I, by subduing IL-17 and IL-21; however, mechanisms of protection differed as evident by increased IL-13 and IFN-γ but diminished TGF-β production by Treg cells from Salmonella-CFA/IIC-treated mice. Adoptive transfer of Treg cells from both CFA/I-expressing constructs was equivalent in protecting against EAE, showing minimal disease. Although not as potent in its protection, CD25−CD4+ T cells from Salmonella-CFA/IIC showed minimal Th2 cells, but vaccination did prime these Th2 cells rendering partial protection against EAE challenge. In vivo IL-13 but not IFN-γ neutralization compromised protection conferred by adoptive transfer with Salmonella-CFA/IIC-induced Treg cells. Thus, the Salmonella-CFA/IIC vaccine elicits Treg cells with attributes from both the Salmonella vector and Salmonella-CFA/I vaccines. Importantly, these Treg cells can be induced to high potency by simply vaccinating against irrelevant Ags, offering a novel approach to treat autoimmune diseases independently of the autoantigen.
Medroxyprogesterone Acetate Inhibits CD8+ T Cell Viral-Specific Effector Function and Induces Herpes Simplex Virus Type 1 Reactivation
Authors: Cherpes Thomas L. , Busch James L. , Sheridan Brian S. , Harvey Stephen A. K. , Hendricks Robert L. 
Published: April 2014

Abstract
Clinical research suggests hormonal contraceptive use is associated with increased frequencies of HSV reactivation and shedding. We examined the effects of medroxyprogesterone acetate (MPA), the compound most commonly used for injectable hormonal contraception, on HSV type 1 (HSV-1) reactivation and CD8+ T cell function in murine trigeminal ganglia (TG). In ex vivo TG cultures, MPA dramatically inhibited canonical CD8+ T cell effector functions, including IFN-γ production and lytic granule release, and increased HSV-1 reactivation from latency. In vivo, MPA treatment of latently infected ovariectomized mice inhibited IFN-γ production and lytic granule release by TG resident CD8+ T cells stimulated directly ex vivo. RNA specific for the essential immediate early viral gene ICP4 as well as viral genome DNA copy number were increased in mice that received MPA during latency, suggesting that treatment increased in vivo reactivation. The increase in HSV-1 copy number appeared to be the result of a two-tine effect, as MPA induced higher reactivation frequencies from latently infected explanted TG neurons in the presence or absence of CD45+ cells. Our data suggest hormonal contraceptives that contain MPA may promote increased frequency of HSV reactivation from latency through the combinatory effects of inhibiting protective CD8+ T cell responses and by a leukocyte-independent effect on infected neurons.
Increased Frequency of EBV-Specific Effector Memory CD8+ T Cells Correlates with Higher Viral Load in Rheumatoid Arthritis
Authors: Lünemann Jan D. , Frey Oliver , Eidner Thorsten , Baier Michael , Roberts Susanne , Sashihara Junji , Volkmer Rudolf , Cohen Jeffrey I. , Hein Gert , Kamradt Thomas , Münz Christian 
Published: April 2014

AbstractEBV is a candidate trigger of rheumatoid arthritis (RA). We determined both EBV-specific T cell and B cell responses and cell-associated EBV DNA copies in patients with RA and demographically matched healthy virus carriers. Patients with RA showed increased and broadened IgG responses to lytic and latent EBV-encoded Ags and 7-fold higher levels of EBV copy numbers in circulating blood cells. Additionally, patients with RA exhibited substantial expansions of CD8+ T cells specific for pooled EBV Ags expressed during both B cell transformation and productive viral replication and the frequency of CD8+ T cells specific for these Ags correlated with cellular EBV copy numbers. In contrast, CD4+ T cell responses to EBV and T cell responses to human CMV Ags were unchanged, altogether arguing against a defective control of latent EBV infection in RA. Our data show that the regulation of EBV infection is perturbed in RA and suggest that increased EBV-specific effector T cell and Ab responses are driven by an elevated EBV load in RA.
Auditing Protein Therapeutics Management by Professional APCs: Toward Prevention of Immune Responses against Therapeutic Proteins
Authors: Dasgupta Suryasarathi , Bayry Jagadeesh , André Sebastien , Dimitrov Jordan D. , Kaveri Srinivas V. , Lacroix-Desmazes Sebastien 
Published: April 2014

AbstractAlloimmunization is a crippling concern in the management of patients undergoing administration of protein therapeutics as evidenced in replacement therapy and other treatment procedures. Several issues in the genesis and modulation of such deleterious immune responses have been studied. While authors have focused on the downstream events of the specific immune response and suggested modification of protein therapeutics to eliminate epitopes that interact with B cell receptors, T cell receptors, or MHCII molecules, the mechanisms underlying Ag interaction with APCs, a step upstream of immune effectors, have been grossly neglected. We wish to emphasize that the recent knowledge in understanding the capacities of an APC to handle an Ag and the importance of the surrounding microenvironment in this process are crucial for designing novel protein therapeutics with reduced immunogenicity.
Cutting Edge: Multiple Sclerosis-Like Lesions Induced by Effector CD8 T Cells Recognizing a Sequestered Antigen on Oligodendrocytes
Authors: Saxena Amit , Bauer Jan , Scheikl Tanja , Zappulla Jacques , Audebert Marc , Desbois Sabine , Waisman Ari , Lassmann Hans , Liblau Roland S. , Mars Lennart T. 
Published: April 2014

Abstract
CD8 T cells are emerging as important players in multiple sclerosis (MS) pathogenesis, although their direct contribution to tissue damage is still debated. To assess whether autoreactive CD8 T cells can contribute to the pronounced loss of oligodendrocytes observed in MS plaques, we generated mice in which the model Ag influenza hemagglutinin is selectively expressed in oligodendrocytes. Transfer of preactivated hemagglutinin-specific CD8 T cells led to inflammatory lesions in the optic nerve, spinal cord, and brain. These lesions, associating CD8 T cell infiltration with focal loss of oligodendrocytes, demyelination, and microglia activation, were very reminiscent of active MS lesions. Thus, our study demonstrates the potential of CD8 T cells to induce oligodendrocyte lysis in vivo as a likely consequence of direct Ag-recognition. These results provide new insights with regard to CNS tissue damage mediated by CD8 T cells and for understanding the role of CD8 T cells in MS.
Cutting Edge: Priming of NK Cells by IL-18
Authors: Chaix Julie , Tessmer Marlowe S. , Hoebe Kasper , Fuséri Nicolas , Ryffel Bernhard , Dalod Marc , Alexopoulou Lena , Beutler Bruce , Brossay Laurent , Vivier Eric , Walzer Thierry 
Published: April 2014

Abstract
Recent evidence suggests that NK cells require priming to display full effector activity. In this study, we demonstrate that IL-18 contributed to this phenomenon. IL-18 signaling-deficient NK cells were found to be unable to secrete IFN-γ in response to ex vivo stimulation with IL-12. This was not due to a costimulatory role of IL-18, because blocking IL-18 signaling during the ex vivo stimulation with IL-12 did not alter IFN-γ production by wild-type NK cells. Rather, we demonstrate that IL-18 primes NK cells in vivo to produce IFN-γ upon subsequent stimulation with IL-12. Importantly, IL-12-induced IFN-γ transcription by NK cells was comparable in IL-18 signaling-deficient and -sufficient NK cells. This suggests that priming by IL-18 leads to an improved translation of IFN-γ mRNA. These results reveal a novel type of cooperation between IL-12 and IL-18 that requires the sequential action of these cytokines.
Type I IFN-Induced, NKT Cell-Mediated Negative Control of CD8 T Cell Priming by Dendritic Cells
Authors: Bochtler Petra , Kröger Andrea , Schirmbeck Reinhold , Reimann Jörg 
Published: April 2014

Abstract
We investigated the negative effect of type I IFN (IFN-I) on the priming of specific CD8 T cell immunity. Priming of murine CD8 T cells is down-modulated if Ag is codelivered with IFN-I-inducing polyinosinic:polycytidylic acid (pI/C) that induces (NK cell- and T/B cell-independent) acute changes in the composition and surface phenotype of dendritic cells (DC). In wild-type but not IFN-I receptor-deficient mice, pI/C reduces the plasmacytoid DC but expands the CD8+ conventional DC (cDC) population and up-regulates surface expression of activation-associated (CD69, BST2), MHC (class I/II), costimulator (CD40, CD80/CD86), and coinhibitor (PD-L1/L2) molecules by cDC. Naive T cells are efficiently primed in vitro by IFN-I-stimulated CD8 cDC (the key APC involved in CD8 T cell priming) although these DC produced less IL-12 p40 and IL-6. pI/C (IFN-I)-mediated down modulation of CD8 T cell priming in vivo was not observed in NKT cell-deficient CD1d−/− mice. CD8 cDC from pI/C-treated mice inefficiently stimulated IFN-γ, IL-4, and IL-2 responses of NKT cells. In vitro, CD8 cDC that had activated NKT cells in the presence of IFN-I primed CD8 T cells that produced less IFN-γ but more IL-10. The described immunosuppressive effect of IFN-I thus involves an NKT cell-mediated change in the phenotype of CD8 cDC that favors priming of IL-10-producing CD8 T cells. In the presence of IFN-I, NKT cells hence impair the competence of CD8 cDC to prime proinflammatory CD8 T cell responses.
The Transcription Factor Fli-1 Modulates Marginal Zone and Follicular B Cell Development in Mice
Authors: Zhang Xian K. , Moussa Omar , LaRue Amanda , Bradshaw Sarah , Molano Ivan , Spyropoulos Demetri D. , Gilkeson Gary S. , Watson Dennis K. 
Published: April 2014

Abstract
Fli-1 belongs to the Ets transcription factor family and is expressed primarily in hematopoietic cells, including most cells active in immunity. To assess the role of Fli-1 in lymphocyte development in vivo, we generated mice that express a truncated Fli-1 protein, lacking the C-terminal transcriptional activation domain (Fli-1ΔCTA). Fli-1ΔCTA/Fli-1ΔCTA mice had significantly fewer splenic follicular B cells, and an increased number of transitional and marginal zone B cells, compared with wild-type controls. Bone marrow reconstitution studies demonstrated that this phenotype is the result of lymphocyte intrinsic effects. Expression of Igα and other genes implicated in B cell development, including Pax-5, E2A, and Egr-1, are reduced, while Id1 and Id2 are increased in Fli-1ΔCTA/Fli-1ΔCTA mice. Proliferation of B cells from Fli-1ΔCTA/Fli-1ΔCTA mice was diminished, although intracellular Ca2+ flux in B cells from Fli-1ΔCTA/Fli-1ΔCTA mice was similar to that of wild-type controls after anti-IgM stimulation. Immune responses and in vitro class switch recombination were also altered in Fli-1ΔCTA/Fli-1ΔCTA mice. Thus, Fli-1 modulates B cell development both centrally and peripherally, resulting in a significant impact on the in vivo immune response.
Allele-Selective Effect of PA28 in MHC Class I Antigen Processing
Authors: Yamano Taketoshi , Sugahara Hidetoshi , Mizukami Shusaku , Murata Shigeo , Chiba Tomoki , Tanaka Keiji , Yui Katsuyuki , Udono Heiichiro 
Published: April 2014

Abstract
PA28 is an IFN-γ-inducible proteasome activator and its genetic ablation causes complete loss of processing of certain Ags, but not all of them. The reason why this occurs and how PA28 influences the formation of peptide repertoires for MHC class I molecules remains unknown. In this study, we show the allele-specific role of PA28 in Ag processing. Retrovirus-transduced overexpression of PA28α decreased expression of Kd (Dd) while it increased Kb and Ld on the cell surface. By contrast, overexpression of PA28αΔC5, a mutant carrying a deletion of its five C-terminal residues and capable of attenuating the activity of endogenous PA28, produced the opposite effect on expression of those MHC class I molecules. Moreover, knockdown of both PA28α and β by small-interfering RNA profoundly augmented expression of Kd and Dd, but not of Ld, on the cell surface. Finally, we found that PA28-associated proteasome preferentially digested within epitopic sequences of Kd, although correct C-terminal flankings were removed, which in turn hampered production of Kd ligands. Our results indicate that whereas PA28 negatively influences processing of Kd (Dd) ligands, thereby, down-regulating Ag presentation by those MHC class I molecules, it also efficiently produces Kb (Ld) epitopes, leading to up-regulation of the MHC molecules.