bluuebunny/crossref_metadata_2025_split huggingface dataset:
Francisella tularensis-Infected Macrophages Release Prostaglandin E2 that Blocks T Cell Proliferation and Promotes a Th2-Like Response
Authors: Woolard Matthew D. , Wilson Justin E. , Hensley Lucinda L. , Jania Leigh A. , Kawula Thomas H. , Drake James R. , Frelinger Jeffrey A. 
Published: April 2014

Abstract
Francisella tularensis is a highly infectious bacterial pathogen, and is likely to have evolved strategies to evade and subvert the host immune response. In this study, we show that F. tularensis infection of macrophages alters T cell responses in vitro, by blocking T cell proliferation and promoting a Th2-like response. We demonstrate that a soluble mediator is responsible for this effect and identify it as PGE2. Supernatants from F. tularensis-infected macrophages inhibited IL-2 secretion from both MHC class I and MHC class II-restricted T cell hybridomas, as well as enhanced a Th2-like response by inducing increased production of IL-5. Furthermore, the soluble mediator blocked proliferation of naive MHC class I-restricted T cells when stimulated with cognate tetramer. Indomethacin treatment partially restored T cell proliferation and lowered IL-5 production to wild-type levels. Macrophages produced PGE2 when infected with F. tularensis, and treatment of infected macrophages with indomethacin, a cyclooxygenase-1/cyclooxygenase-2 inhibitor, blocked PGE2 production. To further demonstrate that PGE2 was responsible for skewing of T cell responses, we infected macrophages from membrane PGE synthase 1 knockout mice (mPGES1−/−) that cannot produce PGE2. Supernatants from F. tularensis-infected membrane PGE synthase 1−/− macrophages did not inhibit T cell proliferation. Furthermore, treatment of T cells with PGE2 recreated the effects seen with infected supernatant. From these data, we conclude that F. tularensis can alter host T cell responses by causing macrophages to produce PGE2. This study defines a previously unknown mechanism used by F. tularensis to modulate adaptive immunity.
Type I IFN-Producing CD4 Vα14i NKT Cells Facilitate Priming of IL-10-Producing CD8 T Cells by Hepatocytes
Authors: Wahl Christian , Bochtler Petra , Schirmbeck Reinhold , Reimann Jörg 
Published: April 2014

Abstract
Upon entering the liver CD8 T cells encounter large numbers of NKT cells patrolling the hepatocyte (HC) surface facing the perisinusoidal space. We asked whether hepatic NKT cells modulate the priming of CD8 T cells by HC. Hepatic (α-galactosyl-ceramide-loaded CD1d dimer binding) NKT cells produce predominantly IL-4 when stimulated with glycolipid-presenting HC but predominantly IFN-γ when stimulated with glycolipid-presenting dendritic cells. These NKT cells prime naive CD8 T cells to a (Kb-presented) peptide ligand if they simultaneously recognize a CD1d-binding glycolipid presented to them on the surface of the responding CD8 T cells that they prime. No IL-10-producing CD8 T cells are detected if these T cells are primed by either HC or NKT cells. In contrast, IL-10 is produced by HC-primed CD8 T cells if IFN-β-producing NKT cells are coactivated by the same HC presenting a glycolipid (in the context of CD1d) and an antigenic peptide (in the context of Kb). Hence, IL-10-producing CD8 T cells are generated in a type I IFN-dependent manner if the three cell types (CD8 T cells, NKT cells, and ligand-presenting HC) specifically and closely interact. IL-10-producing CD8 T cells generated under these conditions down-modulate IL-2 (and proliferative) responses of naive CD4 or CD8 T cells primed by DC. If in close proximity, NKT cells can thus locally modulate the phenotype of CD8 T cells during their priming by HC thereby limiting the local activation of proinflammatory immune effector cells and protecting the liver against immune injury.
CD18 Is Required for Intestinal T Cell Responses at Multiple Immune Checkpoints
Authors: Marski Marissa , Ye Alice L. , Abraham Clara 
Published: April 2014

AbstractThe intestinal immune response to oral Ags involves a complex multistep process. The requirements for optimal intestinal T cell responses in this process are unclear. LFA-1 plays a critical role in peripheral T cell trafficking and activation, however, its role in intestinal immune responses has not been precisely defined. To dissect the role of LFA-1 in intestinal immune responses, we used a system that allows for segregation of T cell migration and activation through the adoptive transfer of LFA-1-deficient (CD18−/−) CD4+ T cells from DO11.10 TCR transgenic mice into wild-type BALB/c mice. We find that wild-type mice adoptively transferred with CD18−/− DO11.10 CD4+ T cells demonstrate decreases in the numbers of Ag-specific T cells in the intestinal lamina propria after oral Ag administration. We also find that in addition to its role in trafficking to intestinal secondary lymphoid organs, LFA-1 is required for optimal CD4+ T cell proliferation in vivo upon oral Ag immunization. Furthermore, CD18−/− DO11.10 CD4+ T cells primed in the intestinal secondary lymphoid organs demonstrate defects in up-regulation of the intestinal-specific trafficking molecules, α4β7 and CCR9. Interestingly, the defect in trafficking of CD18−/− DO11.10 CD4+ T cells to the intestinal lamina propria persists even under conditions of equivalent activation and intestinal-tropic differentiation, implicating a role for CD18 in the trafficking of activated T cells into intestinal tissues independent of the earlier defects in the intestinal immune response. This argues for a complex role for CD18 in the early priming checkpoints and ultimately in the trafficking of T cells to the intestinal tissues during an intestinal immune response.
Peroxisome Proliferator-Activated Receptor γ Control of Dendritic Cell Function Contributes to Development of CD4+ T Cell Anergy
Authors: Klotz Luisa , Dani Indra , Edenhofer Frank , Nolden Lars , Evert Bernd , Paul Bianca , Kolanus Waldemar , Klockgether Thomas , Knolle Percy , Diehl Linda 
Published: April 2014

Abstract
There is increasing evidence that dendritic cell (DC) immunogenicity is not only positively regulated by ligands of pattern recognition receptors, but also negatively by signals that prevent DC activation and full functional maturation. Depending on their activation status, DCs can induce either immunity or tolerance. In this study, we provide molecular evidence that the transcription factor peroxisome proliferator-activated receptor γ (PPARγ) is a negative regulator of DC maturation and function. Sustained PPARγ activation in murine DCs reduced maturation-induced expression of costimulatory molecules and IL-12, and profoundly inhibited their capacity to prime naive CD4+ T cells in vitro. Using PPARγ-deficient DCs, generated by Cre-mediated ablation of the PPARγ gene, agonist-mediated suppression of maturation-induced functional changes were abrogated. Moreover, absence of PPARγ increased DC immunogenicity, suggesting a constitutive regulatory function of PPARγ in DCs. Adoptive transfer of PPARγ-activated Ag-presenting DCs induced CD4+ T cell anergy, characterized by impaired differentiation resulting in absent Th1 and Th2 cytokine production and failure of secondary clonal expansion upon restimulation. Collectively, our data support the notion that PPARγ is an efficient regulator of DC immunogenicity that may be exploited to deliberately target CD4+ T cell-mediated immune responses.
High IFN-γ Production of Individual CD8 T Lymphocytes Is Controlled by CD152 (CTLA-4)
Authors: Pandiyan Pushpa , Hegel J. Kolja E. , Krueger Manuela , Quandt Dagmar , Brunner-Weinzierl Monika C. 
Published: April 2014

Abstract
CD8 T cell expansion and cytokine production is needed to generate an effective defense against viral invasion of the host. These features of CD8 T lymphocytes are regulated, especially during primary responses, by positive and negative costimulation. We show in this study that surface expression of CD152 is highly up-regulated on activated CD8 T lymphocytes during primary immune responses, suggesting a prominent regulatory role. Indeed, production of the proinflammatory cytokine IFN-γ, but not TNF-α, by CD8 T cells was inhibited by CD152 engagement. The inhibition was regulated independent of proliferation and IL-2 production, but dependent on the quality of the TCR signaling. We show that signals induced by CD152 on activated CD8 T lymphocytes reduce the frequency of IFN-γhigh-expressing cells. Our data also show that in activated CD8 T cells, the CD152-mediated inhibition of cytokine production is more pronounced than inhibition of their proliferation.
NK3-Like NK Cells Are Involved in Protective Effect of Polyinosinic-Polycytidylic Acid on Type 1 Diabetes in Nonobese Diabetic Mice
Authors: Zhou Rongbin , Wei Haiming , Tian Zhigang 
Published: April 2014

Abstract
Type 1 diabetes in NOD mice is characterized by the uncontrolled Th1 immune responses and deficiency of regulatory or suppressor cells. Previous study has shown that NOD mice treated with polyinosinic-polycytidylic acid (poly(I:C)) have a markedly reduced incidence of diabetes, but the underlying mechanisms remain unclear. In this study, we report that the prevention of diabetes by poly(I:C) is associated with the formation of Th2-enriched environment in spleen and pancreas. We further show that the prevention of diabetes and the formation of Th2-enriched environment depend on the presence of NK cells. Long-term poly(I:C)-treated NK cells exhibit a NK3-like phenotype, and are involved in the induction of Th2 bias of spleen cells in response to islet autoantigens via TGF-β-dependent manner. Therefore, NK cells mediate the protective effect of poly(I:C) possibly through the promotion of Th2 bias of immune responses. These findings suggest that NK cells can participate in the regulation of autoimmune diabetes.
Selective Use of TRAM in Lipopolysaccharide (LPS) and Lipoteichoic Acid (LTA) Induced NF-κB Activation and Cytokine Production in Primary Human Cells: TRAM Is an Adaptor for LPS and LTA Signaling
Authors: Sacre Sandra M. , Lundberg Anna M. C. , Andreakos Evangelos , Taylor Corinne , Feldmann Marc , Foxwell Brian M. 
Published: April 2014

Abstract
TLR signal via Toll-IL-1R (TIR) homology domain-containing adaptor proteins. One of these adaptors, Toll-IL-1R domain-containing adaptor inducing IFN-β-related adaptor molecule (TRAM), has been shown to be essential for TLR4 signaling in TRAM−/− mice and cell lines. Previously, we showed that MyD88 or Mal dominant-negative constructs did not inhibit LPS induction of cytokines in primary human M-CSF-derived macrophages. A possible explanation was redundancy of the adaptors during LPS signaling. TRAM is a suitable candidate to compensate for these adaptors. To investigate a potential role for TRAM in LPS signaling in human M-CSF-derived macrophages, we engineered an adenoviral construct expressing dominant-negative TRAM-C117H (AdTRAMdn). Synovial fibroblasts (SF) and human umbilical endothelial cells (HUVECs) were used as a nonmyeloid comparison. AdTRAMdn inhibited LPS-induced signaling in SFs and HUVECs, reducing NF-κB activation and cytokine production, but did not inhibit LPS signaling in M-CSF-derived human macrophages. Further investigation of other TLR ligands showed that AdTRAMdn was also able to inhibit signaling initiated by lipoteichoic acid, a TLR2 ligand, in SFs and HUVECs and lipoteichoic acid and macrophage-activating lipopeptide 2 signaling was also inhibited in TRAM−/− murine embryonic fibroblasts. We conclude that TRAM is an adaptor protein for both TLR4 and TLR2/6 signaling in SFs, HUVECs, and murine embryonic fibroblasts, but cannot demonstrate a role in human macrophages.
A Role for Mammalian Target of Rapamycin in Regulating T Cell Activation versus Anergy
Authors: Zheng Yan , Collins Samuel L. , Lutz Michael A. , Allen Amy N. , Kole Thomas P. , Zarek Paul E. , Powell Jonathan D. 
Published: April 2014

Abstract
Whether TCR engagement leads to activation or tolerance is determined by the concomitant delivery of multiple accessory signals, cytokines, and environmental cues. In this study, we demonstrate that the mammalian target of rapamycin (mTOR) integrates these signals and determines the outcome of TCR engagement with regard to activation or anergy. In vitro, Ag recognition in the setting of mTOR activation leads to full immune responses, whereas recognition in the setting of mTOR inhibition results in anergy. Full T cell activation is associated with an increase in the phosphorylation of the downstream mTOR target S6 kinase 1 at Thr421/Ser424 and an increase in the mTOR-dependent cell surface expression of transferrin receptor (CD71). Alternatively, the induction of anergy results in markedly less S6 kinase 1 Thr421/Ser424 phosphorylation and CD71 surface expression. Likewise, the reversal of anergy is associated not with proliferation, but rather the specific activation of mTOR. Importantly, T cells engineered to express a rapamycin-resistant mTOR construct are resistant to anergy induction caused by rapamycin. In vivo, mTOR inhibition promotes T cell anergy under conditions that would normally induce priming. Furthermore, by examining CD71 surface expression, we are able to distinguish and differentially isolate anergic and activated T cells in vivo. Overall, our data suggest that by integrating environmental cues, mTOR plays a central role in determining the outcome of Ag recognition.
TLR Signaling Fine-Tunes Anti-Influenza B Cell Responses without Regulating Effector T Cell Responses
Authors: Heer Alex K. , Shamshiev Abdijapar , Donda Alena , Uematsu Satoshi , Akira Shizuo , Kopf Manfred , Marsland Benjamin J. 
Published: April 2014

Abstract
Influenza is a ssRNA virus that has been responsible for widespread morbidity and mortality; however, the innate immunological mechanisms that drive the adaptive anti-influenza immune response in vivo are yet to be fully elucidated. TLRs are pattern recognition receptors that bind evolutionarily conserved pathogen-associated molecular patterns, induce dendritic cell maturation, and consequently aid the development of effective immune responses. We have examined the role of TLRs in driving effective T and B cell responses against influenza virus. We found TLR3 and its associated adapter molecule, Toll/IL-R domain-containing adaptor-inducing IFN-β, did not play a role in the development of CD4+ or CD8+ T cell responses against influenza virus, nor did they influence influenza-specific B cell responses. Surprisingly, TLR7 and MyD88 also played negligible roles in T cell activation and effector function upon infection with influenza virus; however, their signaling was critical for regulating anti-influenza B cell Ab isotype switching. The induction of appropriate anti-influenza humoral responses involved stimulation of TLRs on B cells directly and TLR-induced production of IFN-α, which acted to reduce IgG1 and increase IgG2a/c class switching. Notably, direct TLR signaling on B cells or T cell help through the CD40-CD40L interaction was sufficient to support B cell proliferation and IgG1 production, whereas IFN-α was critical for fine-tuning the nature of the isotype switch. Taken together, these data reveal that TLR signaling is not required for anti-influenza T cell responses, but through both direct and indirect means orchestrates appropriate anti-influenza B cell responses.
AID−/−μs−/− Mice Are Agammaglobulinemic and Fail to Maintain B220−CD138+ Plasma Cells
Authors: Kumazaki Kaori , Tirosh Boaz , Maehr René , Boes Marianne , Honjo Tasuku , Ploegh Hidde L. 
Published: April 2014

Abstract
The terminal stage of B cell differentiation culminates in the formation of plasma cells (PC), which secrete large quantities of Igs. Despite recent progress in understanding the molecular aspect of PC differentiation and maintenance, the requirement for the synthesis of secretory Igs as a contributing factor has not been explored. To address this issue, we generated activation-induced cytidine deaminase (AID)/secretory μ-chain (μs) double-knockout mice, in which a normally diverse repertoire of B cell receptors is retained, yet B cells are unable to synthesize secretory Igs. These mice possess polyclonal B cells but have no serum Igs. Following immunization in vivo, PCs, identified by CD138 expression and loss of the B220 marker, were starkly reduced in number in spleen and bone marrow of AID−/−μs−/− agammaglobulinemic mice compared with wild-type mice. Upon mitogenic stimulation in vitro, AID−/−μs−/− B cells differentiated into plasmablasts to some extent, but showed reduced survival compared with wild-type B cells. We found no evidence that this reduced survival was attributable to accumulation of membrane IgM. Our results indicate that the synthesis of secretory Igs is a requirement for maintenance of B220−CD138+ PCs.
Abrogation of Antibody-Mediated Allograft Rejection by Regulatory CD4 T Cells with Indirect Allospecificity
Authors: Callaghan Chris J. , Rouhani Foad J. , Negus Margaret C. , Curry Allison J. , Bolton Eleanor M. , Bradley J. Andrew , Pettigrew Gavin J. 
Published: April 2014

Abstract
Alloantibody is an important effector mechanism for allograft rejection. In this study, we tested the hypothesis that regulatory T cells with indirect allospecificity can prevent humoral rejection by using a rat transplant model in which acute rejection of MHC class I-disparate PVG.R8 heart grafts by PVG.RT1u recipients is mediated by alloantibody and is dependent upon help from CD4 T cells that can recognize the disparate MHC alloantigen only via the indirect pathway. Pretransplant treatment of PVG.RT1u recipients with anti-CD4 mAb plus donor-specific transfusion abrogated alloantibody production and prolonged PVG.R8 graft survival indefinitely. Naive syngeneic splenocytes injected into tolerant animals did not effect heart graft rejection, suggesting the presence of regulatory mechanisms. Adoptive transfer experiments into CD4 T cell-reconstituted, congenitally athymic recipients confirmed that regulation was mediated by CD4 T cells and was alloantigen-specific. CD4 T cell regulation could be broken in tolerant animals either by immunizing with an immunodominant linear allopeptide or by depleting tolerant CD4 T cells, but surprisingly this resulted in neither alloantibody generation nor graft rejection. These findings demonstrate that anti-CD4 plus donor-specific transfusion treatment results in the development of CD4 regulatory T cells that recognize alloantigens via the indirect pathway and act in an Ag-specific manner to prevent alloantibody-mediated rejection. Their development is associated with intrinsic tolerance within the alloantigen-specific B cell compartment that persists after T cell help is made available.
The Effects of IL-20 Subfamily Cytokines on Reconstituted Human Epidermis Suggest Potential Roles in Cutaneous Innate Defense and Pathogenic Adaptive Immunity in Psoriasis
Authors: Sa Susan M. , Valdez Patricia A. , Wu Jianfeng , Jung Kenneth , Zhong Fiona , Hall Linda , Kasman Ian , Winer Jane , Modrusan Zora , Danilenko Dimitry M. , Ouyang Wenjun 
Published: April 2014

Abstract
IL-19, IL-20, IL-22, IL-24, and IL-26 are members of the IL-10 family of cytokines that have been shown to be up-regulated in psoriatic skin. Contrary to IL-10, these cytokines signal using receptor complex R1 subunits that are preferentially expressed on cells of epithelial origin; thus, we henceforth refer to them as the IL-20 subfamily cytokines. In this study, we show that primary human keratinocytes (KCs) express receptors for these cytokines and that IL-19, IL-20, IL-22, and IL-24 induce acanthosis in reconstituted human epidermis (RHE) in a dose-dependent manner. These cytokines also induce expression of the psoriasis-associated protein S100A7 and keratin 16 in RHE and cause persistent activation of Stat3 with nuclear localization. IL-22 had the most pronounced effects on KC proliferation and on the differentiation of KCs in RHE, inducing a decrease in the granular cell layer (hypogranulosis). Furthermore, gene expression analysis performed on cultured RHE treated with these cytokines showed that IL-19, IL-20, IL-22, and IL-24 regulate many of these same genes to variable degrees, inducing a gene expression profile consistent with inflammatory responses, wound healing re-epithelialization, and altered differentiation. Many of these genes have also been found to be up-regulated in psoriatic skin, including several chemokines, β-defensins, S100 family proteins, and kallikreins. These results confirm that IL-20 subfamily cytokines are important regulators of epidermal KC biology with potentially pivotal roles in the immunopathology of psoriasis.
Epitope-Dependent Effect of Anti-Murine TIM-1 Monoclonal Antibodies on T Cell Activity and Lung Immune Responses
Authors: Sizing Irene D. , Bailly Véronique , McCoon Patricia , Chang Wenjie , Rao Sambasiva , Pablo Lourdes , Rennard Rachel , Walsh Meghan , Li Zhifang , Zafari Mohammad , Dobles Max , Tarilonte Leticia , Miklasz Steven , Majeau Gerard , Godbout Kevin , Scott Martin L. , Rennert Paul D. 
Published: April 2014

Abstract
The TAPR locus containing the TIM gene family is implicated in the development of atopic inflammation in mouse, and TIM-1 allelic variation has been associated with the incidence of atopy in human patient populations. In this study, we show that manipulation of the TIM-1 pathway influences airway inflammation and pathology. Anti-TIM-1 mAbs recognizing distinct epitopes differentially modulated OVA-induced lung inflammation in the mouse. The epitopes recognized by these Abs were mapped, revealing that mAbs to both the IgV and stalk domains of TIM-1 have therapeutic activity. Unexpectedly, mAbs recognizing unique epitopes spanning exon 4 of the mucin/stalk domains exacerbated immune responses. Using Ag recall response studies, we demonstrate that the TIM-1 pathway acts primarily by modulating the production of TH2 cytokines. Furthermore, ex vivo cellular experiments indicate that TIM-1 activity controls CD4+ T cell activity. These studies validate the genetic hypothesis that the TIM-1 locus is linked to the development of atopic disease and suggest novel therapeutic strategies for targeting asthma and other atopic disorders.
Dendritic Cells Sensitize TCRs through Self-MHC-Mediated Src Family Kinase Activation
Authors: Meraner Paul , Horejsí Václav , Wolpl Alois , Fischer Gottfried F. , Stingl Georg , Maurer Dieter 
Published: April 2014

Abstract
It is unclear whether peptide-MHC class II (pMHC) complexes on distinct types of APCs differ in their capacity to trigger TCRs. In this study, we show that individual cognate pMHC complexes displayed by dendritic cells (DCs), as compared with nonprofessional APCs, are far better in productively triggering Ag-specific TCRs independently of conventional costimulation. As we further show, this is accomplished by the unique ability of DCs to robustly activate the Src family kinases (SFKs) Lck and Fyn in T cells even in the absence of cognate peptide. Instead, this form of SFK activation depends on interactions of DC-displayed MHC with TCRs of appropriate restriction, suggesting a central role of self-pMHC recognition. DC-mediated SFK activation leads to “TCR licensing,” a process that dramatically increases sensitivity and magnitude of the TCR response to cognate pMHC. Thus, TCR licensing, besides costimulation, is a main mechanism of DCs to present Ag effectively.