bluuebunny/crossref_metadata_2025_split huggingface dataset:
Rapid CD8+ T Cell Repertoire Focusing and Selection of High-Affinity Clones into Memory Following Primary Infection with a Persistent Human Virus: Human Cytomegalovirus
Authors: Day Elizabeth K. , Carmichael Andrew J. , ten Berge Ineke J. M. , Waller Edward C. P. , Sissons J. G. Patrick , Wills Mark R. 
Published: April 2014

Abstract
To investigate the mechanism of selection of individual human CD8+ T cell clones into long-term memory following primary infection with a persistent human virus (human CMV (HCMV)), we undertook a longitudinal analysis of the diversity of T cell clones directed toward an immunodominant viral epitope: we followed this longitudinally from early T cell expansion through the contraction phase and selection into the memory pool. We show that following initial HCMV infection, the early primary response against a defined epitope was composed of diverse clones possessing many different TCR Vβ segments. Longitudinal analysis showed that this usage rapidly focused predominantly on a single TCR Vβ segment within which dominant clones frequently had public TCR usage, in contrast to subdominant or contracted clones. Longitudinal clonotypic analysis showed evidence of disproportionate contraction of certain clones that were abundant in the primary response, and late expansion of clones that were subdominant in the primary response. All dominant clones selected into memory showed similar high functional avidity of their TCR, whereas two clones that greatly contracted showed substantially lower avidity. Expression of the IL-7R is required for survival of murine effector CD8+ T cells into memory, but in primary HCMV infection IL-7R was not detected on circulating Ag-specific cells until memory had been established. Thus, the oligoclonal T cell repertoire against an immunodominant persistent viral epitope is established early in primary infection by the rapid selection of public clonotypes, rather than being a stochastic process.
IL-18, but not IL-12, Regulates NK Cell Activity following Intranasal Herpes Simplex Virus Type 1 Infection
Authors: Reading Patrick C. , Whitney Paul G. , Barr Daniel P. , Wojtasiak Magdalena , Mintern Justine D. , Waithman Jason , Brooks Andrew G. 
Published: April 2014

Abstract
Infection of the respiratory tract with HSV type 1 (HSV-1) can have severe clinical complications, yet little is known of the immune mechanisms that control the replication and spread of HSV-1 in this site. The present study investigated the protective role of IL-12 and IL-18 in host defense against intranasal HSV-1 infection. Both IL-12 and IL-18 were detected in lung fluids following intranasal infection of C57BL/6 (B6) mice. IL-18-deficient (B6.IL-18−/−) mice were more susceptible to HSV-1 infection than wild-type B6 mice as evidenced by exacerbated weight loss and enhanced virus growth in the lung. IL-12-deficient (B6.IL-12−/−) mice behaved similarly to B6 controls. Enhanced susceptibility of B6.IL-18−/− mice to HSV-1 infection correlated with a profound impairment in the ability of NK cells recovered from the lungs to produce IFN-γ or to mediate cytotoxic activity ex vivo. The weak cytotoxic capacity of NK cells from the lungs of B6.IL-18−/− mice correlated with reduced expression of the cytolytic effector molecule granzyme B. Moreover, depletion of NK cells from B6 or B6.IL-12−/− mice led to enhanced viral growth in lungs by day 3 postinfection; however, this treatment had no effect on viral titers in lungs of B6.IL-18−/− mice. Together these studies demonstrate that IL-18, but not IL-12, plays a key role in the rapid activation of NK cells and therefore in control of early HSV-1 replication in the lung.
A Dual Role of Lipocalin 2 in the Apoptosis and Deramification of Activated Microglia
Authors: Lee Shinrye , Lee Jayoung , Kim Sangseop , Park Jae-Yong , Lee Won-Ha , Mori Kiyoshi , Kim Sang-Hyun , Kim In Kyeom , Suk Kyoungho 
Published: April 2014

Abstract
Activated microglia are thought to undergo apoptosis as a self-regulatory mechanism. To better understand molecular mechanisms of the microglial apoptosis, apoptosis-resistant variants of microglial cells were selected and characterized. The expression of lipocalin 2 (lcn2) was significantly down-regulated in the microglial cells that were resistant to NO-induced apoptosis. lcn2 expression was increased by inflammatory stimuli in microglia. The stable expression of lcn2 as well as the addition of rLCN2 protein augmented the sensitivity of microglia to the NO-induced apoptosis, while knockdown of lcn2 expression using short hairpin RNA attenuated the cell death. Microglial cells with increased lcn2 expression were more sensitive to other cytotoxic agents as well. Thus, inflammatory activation of microglia may lead to up-regulation of lcn2 expression, which sensitizes microglia to the self-regulatory apoptosis. Additionally, the stable expression of lcn2 in BV-2 microglia cells induced a morphological change of the cells into the round shape with a loss of processes. Treatment of primary microglia cultures with the rLCN2 protein also induced the deramification of microglia. The deramification of microglia was closely related with the apoptosis-prone phenotype, because other deramification-inducing agents such as cAMP-elevating agent forskolin, ATP, and calcium ionophore also rendered microglia more sensitive to cell death. Taken together, our results suggest that activated microglia may secrete LCN2 protein, which act in an autocrine manner to sensitize microglia to the self-regulatory apoptosis and to endow microglia with an amoeboid form, a canonical morphology of activated microglia in vivo.
Genetic Control Directed toward Spontaneous IFN-α/IFN-β Responses and Downstream IFN-γ Expression Influences the Pathogenesis of a Murine Psoriasis-Like Skin Disease
Authors: Arakura Fuyuko , Hida Shigeaki , Ichikawa Eri , Yajima Chihiro , Nakajima Shinsuke , Saida Toshiaki , Taki Shinsuke 
Published: April 2014

Abstract
Psoriasis is an inflammatory skin disease, onset and severity of which are controlled by multiple genetic factors; aberrant expression of and responses to several cytokines including IFN-α/IFN-β and IFN-γ are associated with this “type 1” disease. However, it remains unclear whether genetic regulation influences these cytokine-related abnormalities. Mice deficient for IFN regulatory factor-2 (IRF-2) on the C57BL/6 background (IRF-2−/−BN mice) exhibited accelerated IFN-α/IFN-β responses leading to a psoriasis-like skin inflammation. In this study, we found that this skin phenotype disappeared in IRF-2−/− mice with the BALB/c or BALB/c × C57BL/6 F1 backgrounds. Genome-wide scan revealed two major quantitative trait loci controlled the skin disease severity. Interestingly, these loci were different from that for the defect in CD4+ dendritic cells, another IFN-α/IFN-β-dependent phenotype of the mice. Notably, IFN-γ expression as well as spontaneous IFN-α/IFN-β responses were up-regulated several fold spontaneously in the skin in IRF-2−/−BN mice but not in IRF-2−/− mice with “resistant” backgrounds. The absence of such IFN-γ up-regulation in IRF-2−/−BN mice lacking the IFN-α/IFN-β receptor or β2-microglobulin indicated that accelerated IFN-α/IFN-β signals augmented IFN-γ expression by CD8+ T cells in the skin. IFN-γ indeed played pathogenic roles as skin inflammation was delayed and was much more infrequent when IRF-2−/−BN mice lacked the IFN-γ receptor. Our current study thus revealed a novel genetic mechanism that kept the skin immune system under control and prevented skin inflammation through regulating the magnitude of IFN-α/IFN-β responses and downstream IFN-γ production, independently of CD4+ dendritic cells.
Suppressive Effect of IL-27 on Encephalitogenic Th17 Cells and the Effector Phase of Experimental Autoimmune Encephalomyelitis
Authors: Fitzgerald Denise C. , Ciric Bogoljub , Touil Tarik , Harle Heather , Grammatikopolou Julia , Sarma Jayasri Das , Gran Bruno , Zhang Guang-Xian , Rostami Abdolmohamad 
Published: April 2014

Abstract
IL-27 has been shown to play a suppressive role in experimental autoimmune encephalomyelitis (EAE) as demonstrated by more severe disease in IL-27R-deficient (WSX-1−/−) mice. However, whether IL-27 influences the induction or effector phase of EAE is unknown. This is an important question as therapies for autoimmune diseases are generally started after autoreactive T cells have been primed. In this study, we demonstrate maximal gene expression of IL-27 subunits and its receptor in the CNS at the effector phases of relapsing-remitting EAE including disease peak and onset of relapse. We also show that activated astrocyte cultures secrete IL-27p28 protein which is augmented by the endogenous factor, IFN-γ. To investigate functional significance of a correlation between gene expression and disease activity, we examined the effect of IL-27 at the effector phase of disease using adoptive transfer EAE. Exogenous IL-27 potently suppressed the ability of encephalitogenic lymph node and spleen cells to transfer EAE. IL-27 significantly inhibited both nonpolarized and IL-23-driven IL-17 production by myelin-reactive T cells thereby suppressing their encephalitogenicity in adoptive transfer EAE. Furthermore, we demonstrate a strong suppressive effect of IL-27 on active EAE in vivo when delivered by s.c. osmotic pump. IL-27-treated mice had reduced CNS inflammatory infiltration and, notably, a lower proportion of Th17 cells. Together, these data demonstrate the suppressive effect of IL-27 on primed, autoreactive T cells, particularly, cells of the Th17 lineage. IL-27 can potently suppress the effector phase of EAE in vivo and, thus, may have therapeutic potential in autoimmune diseases such as multiple sclerosis.
Depletion of B Cells in Murine Lupus: Efficacy and Resistance
Authors: Ahuja Anupama , Shupe Jonathan , Dunn Robert , Kashgarian Michael , Kehry Marilyn R. , Shlomchik Mark J. 
Published: April 2014

Abstract
In mice, genetic deletion of B cells strongly suppresses systemic autoimmunity, providing a rationale for depleting B cells to treat autoimmunity. In fact, B cell depletion with rituximab is approved for rhematoid arthritis patients, and clinical trials are underway for systemic lupus erythematosus. Yet, basic questions concerning mechanism, pathologic effect, and extent of B cell depletion cannot be easily studied in humans. To better understand how B cell depletion affects autoimmunity, we have generated a transgenic mouse expressing human CD20 on B cells in an autoimmune-prone MRL/MpJ-Faslpr (MRL/lpr) background. Using high doses of a murine anti-human CD20 mAb, we were able to achieve significant depletion of B cells, which in turn markedly ameliorated clinical and histologic disease as well as antinuclear Ab and serum autoantibody levels. However, we also found that B cells were quite refractory to depletion in autoimmune-prone strains compared with nonautoimmune-prone strains. This was true with multiple anti-CD20 Abs, including a new anti-mouse CD20 Ab, and in several different autoimmune-prone strains. Thus, whereas successful B cell depletion is a promising therapy for lupus, at least some patients might be resistant to the therapy as a byproduct of the autoimmune condition itself.
Angiotensin Receptors, Autoimmunity, and Preeclampsia
Authors: Xia Yang , Zhou Cissy Chenyi , Ramin Susan M. , Kellems Rodney E. 
Published: April 2014

Abstract
Preeclampsia is a pregnancy-induced hypertensive disorder that causes substantial maternal and fetal morbidity and mortality. Despite being a leading cause of maternal death and a major contributor to maternal and perinatal morbidity, the mechanisms responsible for the pathogenesis of preeclampsia are poorly understood. Recent studies indicate that women with preeclampsia have autoantibodies that activate the angiotensin receptor, AT1, and that autoantibody-mediated receptor activation contributes to pathophysiology associated with preeclampsia. The research reviewed here raises the intriguing possibility that preeclampsia may be a pregnancy-induced autoimmune disease.
Cutting Edge: Syntaxin 11 Regulates Lymphocyte-Mediated Secretion and Cytotoxicity
Authors: Arneson Laura N. , Brickshawana Adipong , Segovis Colin M. , Schoon Renee A. , Dick Christopher J. , Leibson Paul J. 
Published: April 2014

Abstract
Little is known about the regulatory roles of specific soluble N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE) proteins in cytotoxic lymphocytes. Recent information suggests that mutations in the SNARE protein syntaxin 11 result in a form of familial hemophagocytic lymphohistiocytosis (FHL). Because genetic abnormalities in key granule components (e.g., perforin) or in regulators of secretion (e.g., Munc13–4) underlie the other identified forms of FHL, we assessed whether syntaxin 11 might also serve a related regulatory role. We determined that syntaxin 11 is expressed in NK cells and activated CTLs and is located in discrete membrane-associated structures in the cytoplasm. Enhanced expression of syntaxin 11 augments the secretion and killing of tumor targets, and suppression of syntaxin 11 expression inhibits these functions. Our data identify and characterize a role for syntaxin 11 in granule exocytosis and in the generation of cell-mediated killing. These results also provide new insights on the mechanisms of hemopoietic dysregulation in FHL.
Cutting Edge: Size and Diversity of CD4+CD25high Foxp3+ Regulatory T Cell Repertoire in Humans: Evidence for Similarities and Partial Overlapping with CD4+CD25− T Cells
Authors: Fazilleau Nicolas , Bachelez Hervé , Gougeon Marie-Lise , Viguier Manuelle 
Published: April 2014

Abstract
Both differentiation and function of CD4+CD25high naturally arising regulatory T cells (Treg), which play a key role in the control of autoimmunity, are thought to depend on TCR specificity. In the present study, we comparatively measured the αβTCR repertoire sizes of human peripheral blood Treg and CD4+CD25− T cells by using a methodology based on PCR amplification and sequencing analysis. We show that Treg use a large unrestricted αβ TCR repertoire, the size and diversity of which are closely similar to those of CD4+CD25− T cells, with a mean estimated size of 3.5 × 106 distinct αβ TCR vs 4.7 × 106 distinct αβTCR for CD4+CD25− T cells. In addition, a 24% overlap between the repertoires of these two CD4+ subsets in the periphery is found. These data emphasize the intersection between naturally occurring Treg and effector T cell peripheral repertoires and provide new insights into the ontogeny of Treg in humans.
Bim and Bcl-2 Mutually Affect the Expression of the Other in T Cells
Authors: Jorgensen Trine N. , McKee Amy , Wang Michael , Kushnir Ella , White Janice , Refaeli Yosef , Kappler John W. , Marrack Philippa 
Published: April 2014

Abstract
The life and death of T cells is controlled to a large extent by the relative amounts of Bcl-2-related proteins they contain. The antiapoptotic protein Bcl-2 and the proapoptotic protein Bim are particularly important in this process with the amount of Bcl-2 per cell dropping by about one-half when T cells prepare to die. In this study we show that Bcl-2 and Bim each control the expression of the other. Absence of Bim leads to a drop in the amount of intracellular Bcl-2 protein, while having no effect on the amounts of mRNA for Bcl-2. Conversely, high amounts of Bcl-2 per cell allow high amounts of Bim, although in this case the effect involves increases in Bim mRNA. These mutual effects occur even if Bcl-2 is induced acutely. Thus these two proteins control the expression of the other, at either the protein or mRNA level.
IFN Regulatory Factor Family Members Differentially Regulate the Expression of Type III IFN (IFN-λ) Genes
Authors: Österlund Pamela I. , Pietilä Taija E. , Veckman Ville , Kotenko Sergei V. , Julkunen Ilkka 
Published: April 2014

Abstract
Virus replication induces the expression of antiviral type I (IFN-αβ) and type III (IFN-λ1–3 or IL-28A/B and IL-29) IFN genes via TLR-dependent and -independent pathways. Although type III IFNs differ genetically from type I IFNs, their similar biological antiviral functions suggest that their expression is regulated in a similar fashion. Structural and functional characterization of the IFN-λ1 and IFN-λ3 gene promoters revealed them to be similar to IFN-β and IFN-α genes, respectively. Both of these promoters had functional IFN-stimulated response element and NF-κB binding sites. The binding of IFN regulatory factors (IRF) to type III IFN promoter IFN-stimulated response element sites was the most important event regulating the expression of these genes. Ectopic expression of the components of TLR7 (MyD88 plus IRF1/IRF7), TLR3 (Toll/IL-1R domain-containing adapter-inducing factor), or retinoic acid-inducible gene I (RIG-I) signal transduction pathways induced the activation of IFN-λ1 promoter, whereas the IFN-λ3 promoter was efficiently activated only by overexpression of MyD88 and IRF7. The ectopic expression of Pin1, a recently identified suppressor for IRF3-dependent antiviral response, decreased the IFN promoter activation induced by any of these three signal transduction pathways, including the MyD88-dependent one. To conclude, the data suggest that the IFN-λ1 gene is regulated by virus-activated IRF3 and IRF7, thus resembling that of the IFN-β gene, whereas IFN-λ2/3 gene expression is mainly controlled by IRF7, thus resembling those of IFN-α genes.
Engagement of TLR3, TLR7, and NKG2D Regulate IFN-γ Secretion but Not NKG2D-Mediated Cytotoxicity by Human NK Cells Stimulated with Suboptimal Doses of IL-12
Authors: Girart María V. , Fuertes Mercedes B. , Domaica Carolina I. , Rossi Lucas E. , Zwirner Norberto W. 
Published: April 2014

Abstract
NK cells express different TLRs, such as TLR3, TLR7, and TLR9, but little is known about their role in NK cell stimulation. In this study, we used specific agonists (poly(I:C), loxoribine, and synthetic oligonucleotides containing unmethylated CpG sequences to stimulate human NK cells without or with suboptimal doses of IL-12, IL-15, or IFN-α, and investigated the secretion of IFN-γ, cytotoxicity, and expression of the activating receptor NKG2D. Poly(I:C) and loxoribine, in conjunction with IL-12, but not IL-15, triggered secretion of IFN-γ. Inhibition of IFN-γ secretion by chloroquine suggested that internalization of the TLR agonists was necessary. Also, secretion of IFN-γ was dependent on MEK1/ERK, p38 MAPK, p70S6 kinase, and NF-κB, but not on calcineurin. IFN-α induced a similar effect, but promoted lesser IFN-γ secretion. However, cytotoxicity (51Cr release assays) against MHC class I-chain related A (MICA)− and MICA+ tumor targets remained unchanged, as well as the expression of the NKG2D receptor. Excitingly, IFN-γ secretion was significantly increased when NK cells were stimulated with poly(I:C) or loxoribine and IL-12, and NKG2D engagement was induced by coculture with MICA+ tumor cells in a PI3K-dependent manner. We conclude that resting NK cells secrete high levels of IFN-γ in response to agonists of TLR3 or TLR7 and IL-12, and this effect can be further enhanced by costimulation through NKG2D. Hence, integration of the signaling cascades that involve TLR3, TLR7, IL-12, and NKG2D emerges as a critical step to promote IFN-γ-dependent NK cell-mediated effector functions, which could be a strategy to promote Th1-biased immune responses in pathological situations such as cancer.
Lung Macrophages Serve as Obligatory Intermediate between Blood Monocytes and Alveolar Macrophages
Authors: Landsman Limor , Jung Steffen 
Published: April 2014

Abstract
Alveolar macrophages are a unique type of mononuclear phagocytes that populate the external surface of the lung cavity. Early studies have suggested that alveolar macrophages originate from tissue-resident, local precursors, whereas others reported their derivation from blood-borne cells. However, the role of circulating monocytes as precursors of alveolar macrophages was never directly tested. In this study, we show through the combined use of conditional cell ablation and adoptive cell transfer that alveolar macrophages originate in vivo from blood monocytes. Interestingly, this process requires an obligate intermediate stage, the differentiation of blood monocytes into parenchymal lung macrophages, which subsequently migrate into the alveolar space. We also provide direct evidence for the ability of both lung and alveolar macrophages to proliferate.
In Vitro Induction of Mucosa-Type Dendritic Cells by All-Trans Retinoic Acid
Authors: Saurer Leslie , McCullough Kenneth C. , Summerfield Artur 
Published: April 2014

Abstract
Efficient induction of mucosal immunity usually employs nasal or oral vaccination while parenteral immunization generally is ineffective at generating mucosal immune responses. This relates to the unique ability of resident mucosal dendritic cells (DC) to induce IgA switching and to imprint mucosa-specific homing receptors on lymphocytes. Based on the well-established plasticity of the DC system, this study sought to investigate whether peripheral DC could be modulated toward “mucosa-type” DC by treatment with immunomodulatory, and therefore potentially adjuvant-like, factors. In this study, we show that monocyte-derived DCs pretreated with the vitamin A derivative all-trans retinoic acid (RA) indeed acquired several attributes characteristic of mucosal DC: secretion of TGF-β and IL-6 and the capacity to augment mucosal homing receptor expression and IgA responses in cocultured lymphocytes. Addition of a TGF-β-neutralizing Ab to cocultures significantly inhibited α4β7 integrin, but not CCR9 mRNA expression by the lymphocytes. Both α4β7 integrin and CCR9 mRNA expression, but not IgA production, were suppressed in the presence of a RA receptor antagonist. None of the observed effects on the lymphocytes were influenced by citral, a retinal dehydrogenase inhibitor, arguing against a role for de novo-synthesized RA. Collectively, our findings identified a novel role for RA as a mucosal immune modulator targeting DC. Our results further demonstrate that DC can act as efficient carriers of RA at least in vitro. Consequently, RA targeting of DC shows potential for promoting vaccine-induced mucosal immune responses via a parenteral route of immunization.
Dendritic Cell Expression of OX40 Ligand Acts as a Costimulatory, Not Polarizing, Signal for Optimal Th2 Priming and Memory Induction In Vivo
Authors: Jenkins Stephen J. , Perona-Wright Georgia , Worsley Alan G. F. , Ishii Naoto , MacDonald Andrew S. 
Published: April 2014

Abstract
Costimulatory cross-talk can occur at multiple cellular levels to potentiate expansion and polarization of Th responses. Although OX40L ligand (OX40L) is thought to play a key role in Th2 development, the critical cellular source of this molecule has yet to be identified. In this study, we demonstrate that OX40L expression by the initiating dendritic cell (DC) is a fundamental requirement for optimal induction of primary and memory Th2 responses in vivo. Analysis of the kinetics of the residual Th2 response primed by OX40L-deficient DC suggested a failure to stimulate appropriate expansion and/or survival of T cells, rather than an inability to polarize per se. The dependence upon OX40L was predominantly due to the provision of signaling through OX40 rather than retrograde signaling to the DC. Mechanistically, impaired Th2 priming in the absence of OX40L was not due to exaggerated regulation because there was no evidence of increased expansion or function of regulatory cell populations, suppression through IL-10 production, or hyporesponsiveness to secondary challenge. These data define a critical role for DC-derived OX40L in the induction and development of Th2 responses in vivo.