bluuebunny/crossref_metadata_2025_split huggingface dataset:
Cutting Edge: Foxp3+CD4+CD25+ Regulatory T Cells Induced by IL-2 and TGF-β Are Resistant to Th17 Conversion by IL-6
Authors: Zheng Song Guo , Wang Juhua , Horwitz David A. 
Published: April 2014

Abstract
TGF-β has pleiotropic effects on T cell differentiation that are determined by other cytokines in the local environment. Whereas IL-2 and TGF-β induce naive T cells to become forkhead/winged helix transcription factor (Foxp3) positive regulatory cells (iTregs), the combination of IL-6 and TGF-β induces IL-17-producing cells (Th17). Moreover, IL-6 can use TGF-β produced by thymus-derived natural regulatory T cells (nTregs) to convert them to Th17 cells. In this study, we report a major difference between iTregs and nTregs. Treatment of iTregs with IL-6 did not affect Foxp3 expression, and their suppressive activity in vitro and in vivo was intact. To explain this difference between nTregs and iTregs, we found that IL-2 and TGF-β down-regulate IL-6 receptor expression and IL-6 signaling. The resistance of iTregs to Th17 conversion suggests that they can function more effectively than nTregs in an inflammatory milieu and emphasizes the central role of IL-2 in combination with TGF-β to maintain immunologic homeostasis.
Plasticity of Regulatory T Cells: Subversion of Suppressive Function and Conversion to Enhancement of Lung Allergic Responses
Authors: Joetham Anthony , Matsubara Shigeki , Okamoto Masakazu , Takeda Katsuyuki , Miyahara Nobuaki , Dakhama Azzeddine , Gelfand Erwin W. 
Published: April 2014

Abstract
Activation of CD4+CD25+Foxp3+ naturally occurring regulatory T cells (nTregs) resulting in suppression of lung allergic responses requires interaction of MHC class I on nTregs and CD8. In the absence of CD8 (CD8−/− recipients), transferred nTregs restored airway hyperresponsiveness, eosinophilic inflammation, and IL-13 levels following allergen exposure. Enhancement of lung allergic responses was accompanied by reduced expression of Foxp3 and increased expression of IL-13 in the transferred nTregs. In CD8−/− recipients pretreated with glucocorticoid-induced TNFR-related protein-ligand Ab, the transferred nTregs maintained high levels of Foxp3 and did not result in altered lung responses. Thus, the regulatory function of nTregs can be subverted by reducing the expression of Foxp3 and following signaling through glucocorticoid-induced TNFR-related protein are converted nTregs into IL-13-producing CD4+ T cells mediating lung allergic responses.
TLR Ligand-Induced Type I IFNs Affect Thymopoiesis
Authors: Baron Marie-Laurence , Gauchat Dominique , La Motte-Mohs Ross , Kettaf Nadia , Abdallah Ali , Michiels Thomas , Zúñiga-Pflücker Juan-Carlos , Sékaly Rafick-Pierre 
Published: April 2014

Abstract
The interactions between TLRs and their ligands have profound immune modulation properties. Attention has focused mostly on the impact of TLR ligands on peripheral innate and adaptive immunity during viral infections, whereas little impact of TLR activation has been shown on thymic development. Here we show that treatment of murine fetal thymic organ cultures (FTOCs) with TLR3 or TLR7 ligands induced rapid expression of IFN-α and -β mRNA, hallmarks of acute and chronic viral infections. This resulted in an early developmental blockade, increased frequencies of apoptotic cells, and decreased proliferation of thymocytes, which led to an immediate decrease in cellularity. FTOCs infected with vesicular stomatitis virus, known to act through TLR7, were similarly affected. Down-regulation of IL-7R α-chain expression, together with an increased expression of suppressor of cytokine signaling-1 and a concomitant decreased expression of the transcriptional regulator growth factor independence 1 were observed in TLR ligands or IFN-treated FTOCs. This indicates a role for these pathways in the observed changes in thymocyte development. Taken together, our data demonstrate that TLR activation and ensuing type I IFN production exert a deleterious effect on T cell development. Because TLR ligands are widely used as vaccine adjuvants, their immunomodulatory actions mediated mainly by IFN-α suggested by our results should be taken in consideration.
Dissociation between Epitope Hierarchy and Immunoprevalence in CD8 Responses to Vaccinia Virus Western Reserve
Authors: Oseroff Carla , Peters Bjoern , Pasquetto Valerie , Moutaftsi Magdalini , Sidney John , Panchanathan Vijay , Tscharke David C. , Maillere Bernard , Grey Howard , Sette Alessandro 
Published: April 2014

Abstract
Understanding immunity to vaccinia virus (VACV) is important for the development of safer vaccines for smallpox- and poxvirus-vectored recombinant vaccines. VACV is also emerging as an outstanding model for studying CD8+ T cell immunodominance because of the large number of CD8+ T cell epitopes known for this virus in both mice and humans. In this study, we characterize the CD8+ T cell response in vaccinated BALB/c mice by a genome-wide mapping approach. Responses to each of 54 newly identified H-2d-restricted T cell epitopes could be detected after i.p. and dermal vaccination routes. Analysis of these new epitopes in the context of those already known for VACV in mice and humans revealed two important findings. First, CD8+ T cell epitopes are not randomly distributed across the VACV proteome, with some proteins being poorly or nonimmunogenic, while others are immunoprevalent, being frequently recognized across diverse MHC haplotypes. Second, some proteins constituted the major targets of the immune response by a specific haplotype as they recruited the majority of the specific CD8+ T cells but these proteins did not correspond to the immunoprevalent Ags. Thus, we found a dissociation between immunoprevalence and immunodominance, implying that different sets of rules govern these two phenomena. Together, these findings have clear implications for the design of CD8+ T cell subunit vaccines and in particular raise the exciting prospect of being able to choose subunits without reference to MHC restriction.
Human Tumor-Derived Exosomes Down-Modulate NKG2D Expression
Authors: Clayton Aled , Mitchell J. Paul , Court Jacquelyn , Linnane Seamus , Mason Malcolm D. , Tabi Zsuzsanna 
Published: April 2014

Abstract
NKG2D is an activating receptor for NK, NKT, CD8+, and γδ+ T cells, whose aberrant loss in cancer is a key mechanism of immune evasion. Soluble NKG2D ligands and growth factors, such as TGFβ1 emanating from tumors, are mechanisms for down-regulating NKG2D expression. Cancers thereby impair the capacity of lymphocytes to recognize and destroy them. In this study, we show that exosomes derived from cancer cells express ligands for NKG2D and express TGFβ1, and we investigate the impact of such exosomes on CD8+ T and NK cell NKG2D expression and on NKG2D-dependent functions. Exosomes produced by various cancer cell lines in vitro, or isolated from pleural effusions of mesothelioma patients triggered down-regulation of surface NKG2D expression by NK cells and CD8+ T cells. This decrease was rapid, sustained, and resulted from direct interactions between exosomes and NK cells or CD8+ T cells. Other markers (CD4, CD8, CD56, CD16, CD94, or CD69) remained unchanged, indicating the selectivity and nonactivatory nature of the response. Exosomal NKG2D ligands were partially responsible for this effect, as down-modulation of NKG2D was slightly attenuated in the presence of MICA-specific Ab. In contrast, TGFβ1-neutralizing Ab strongly abrogated NKG2D down-modulation, suggesting exosomally expressed TGFβ as the principal mechanism. Lymphocyte effector function was impaired by pretreatment with tumor exosomes, as these cells exhibited poor NKG2D-dependent production of IFN-γ and poor NKG2D-dependent killing function. This hyporesponsiveness was evident even in the presence of IL-15, a strong inducer of NKG2D. Our data show that NKG2D is a likely physiological target for exosome-mediated immune evasion in cancer.
IL-15 Expands Unconventional CD8ααNK1.1+ T Cells but Not Vα14Jα18+ NKT Cells
Authors: Terabe Masaki , Tagaya Yutaka , Zhu Qing , Granger Larry , Roederer Mario , Waldmann Thomas A. , Berzofsky Jay A. 
Published: April 2014

Abstract
Despite recent gains in knowledge regarding CD1d-restricted NKT cells, very little is understood of non-CD1d-restricted NKT cells such as CD8+NK1.1+ T cells, in part because of the very small proportion of these cells in the periphery. In this study we took advantage of the high number of CD8+NK1.1+ T cells in IL-15-transgenic mice to characterize this T cell population. In the IL-15-transgenic mice, the absolute number of CD1d-tetramer+ NKT cells did not increase, although IL-15 has been shown to play a critical role in the development and expansion of these cells. The CD8+NK1.1+ T cells in the IL-15-transgenic mice did not react with CD1d-tetramer. Approximately 50% of CD8+NK1.1+ T cells were CD8αα. In contrast to CD4+NK1.1+ T cells, which were mostly CD1d-restricted NKT cells and of which ∼70% were CD69+CD44+, ∼70% of CD8+NK1.1+ T cells were CD69−CD44+. We could also expand similar CD8ααNK1.1+ T cells but not CD4+ NKT cells from CD8α+β− bone marrow cells cultured ex vivo with IL-15. These results indicate that the increased CD8ααNK1.1+ T cells are not activated conventional CD8+ T cells and do not arise from conventional CD8αβ precursors. CD8ααNK1.1+ T cells produced very large amounts of IFN-γ and degranulated upon TCR activation. These results suggest that high levels of IL-15 induce expansion or differentiation of a novel NK1.1+ T cell subset, CD8ααNK1.1+ T cells, and that IL-15-transgenic mice may be a useful resource for studying the functional relevance of CD8+NK1.1+ T cells.
Latency-Associated Peptide Identifies a Novel CD4+CD25+ Regulatory T Cell Subset with TGFβ-Mediated Function and Enhanced Suppression of Experimental Autoimmune Encephalomyelitis
Authors: Chen Mei-Ling , Yan Bo-Shiun , Bando Yoshio , Kuchroo Vijay K. , Weiner Howard L. 
Published: April 2014

Abstract
CD4+CD25+ regulatory T cells (Tregs) are essential for maintaining self-tolerance and immune homeostasis. Here we characterize a novel subset of CD4+CD25+ Tregs that express latency-associated peptide (LAP) on their cell surface (CD4+CD25+LAP+ cells). CD4+CD25+LAP+ cells express elevated levels of Foxp3 and Treg-associated molecules (CTLA4, glucocorticoid-induced TNFR-related gene), secrete TGFβ, and express both cell surface TGFβ and surface receptors for TGFβ. In vitro, the suppressive function of CD4+CD25+LAP+ cells is both cell contact and soluble factor dependent; this contrasts with CD4+CD25+LAP− cells, which are mainly cell contact dependent. In a model of experimental autoimmune encephalomyelitis, CD4+CD25+LAP+ cells exhibit more potent suppressive activity than CD4+CD25+LAP− cells, and the suppression is TGFβ dependent. We further show that CD4+CD25+LAP+ cells suppress myelin oligodendrocyte glycoprotein-specific immune responses by inducing Foxp3 and by inhibiting IL-17 production. Our findings demonstrate that CD4+CD25+ Tregs are a heterogeneous population and that the CD4+CD25+ subset that expresses LAP functions in a TGFβ-dependent manner and has greater in vivo suppressive properties. Our work helps elucidate the ambiguity concerning the role of TGFβ in CD4+CD25+ Treg-mediated suppression and indicates that LAP is an authentic marker able to identify a TGFβ-expressing CD4+CD25+ Treg subset.
Macrophage Migration Inhibitory Factor Contributes to the Immune Escape of Ovarian Cancer by Down-Regulating NKG2D
Authors: Krockenberger Mathias , Dombrowski Yvonne , Weidler Claudia , Ossadnik Monika , Hönig Arnd , Häusler Sebastian , Voigt Heike , Becker Jürgen C. , Leng Lin , Steinle Alexander , Weller Michael , Bucala Richard , Dietl Johannes , Wischhusen Jörg 
Published: April 2014

Abstract
The proinflammatory cytokine macrophage migration inhibitory factor (MIF) stimulates tumor cell proliferation, migration, and metastasis; promotes tumor angiogenesis; suppresses p53-mediated apoptosis; and inhibits antitumor immunity by largely unknown mechanisms. We here describe an overexpression of MIF in ovarian cancer that correlates with malignancy and the presence of ascites. Functionally, we find that MIF may contribute to the immune escape of ovarian carcinoma by transcriptionally down-regulating NKG2D in vitro and in vivo which impairs NK cell cytotoxicity toward tumor cells. Together with the additional tumorigenic properties of MIF, this finding provides a rationale for novel small-molecule inhibitors of MIF to be used for the treatment of MIF-secreting cancers.
Bacillus Calmette-Guérin and TLR4 Agonist Prevent Cardiovascular Hypertrophy and Fibrosis by Regulating Immune Microenvironment
Authors: Liu Yu-Ying , Cai Wen-Feng , Yang Hong-Zhen , Cui Bing , Chen Zhi-Rong , Liu Han-Zhi , Yan Jun , Jin Wen , Yan Hui-Min , Xin Bing-Mu , Yuan Bin , Hua Fang , Hu Zhuo-Wei 
Published: April 2014

Abstract
Hypertension-induced cardiovascular hypertrophy and fibrosis are critical in the development of heart failure. The activity of TLRs has been found to be involved in the development of pressure overload-induced myocardial hypertrophy and cardiac fibrosis. We wondered whether vaccine bacillus Calmette-Guérin (BCG), which activated TLR4 to elicit immune responses, modulated the pressure overload-stimulated cardiovascular hypertrophy and cardiac fibrosis in the murine models of abdominal aortic constriction (AAC)-induced hypertension. Before or after AAC, animals received BCG, TLR4 agonist, IFN-γ, or TLR4 antagonist i.p. BCG and TLR4 agonist significantly prevented AAC-induced cardiovascular hypertrophy and reactive cardiac fibrosis with no changes in hemodynamics. Moreover, TLR4 antagonist reversed the BCG- and TLR4 agonist-induced actions of anti-cardiovascular hypertrophy and cardiac fibrosis. BCG decreased the expression of TLR2 or TLR4 on the heart tissue but TLR4 agonist increased the expression of TLR2 or TLR4 on the immune cells that infiltrate into the heart tissue. This led to an increased expression ratio of IFN-γ/TGF-β in the heart. The cardiac protective effects of BCG and TLR4 agonist are related to their regulation of ERK-Akt and p38-NF-κB signal pathways in the heart. In conclusion, the activity of TLR4 plays a critical role in the mediation of pressure overload-induced myocardial hypertrophy and fibrosis. The regulation of immune responses by BCG and TLR4 agonist has a great potential for the prevention and treatment of hypertension-induced myocardial hypertrophy and cardiac fibrosis.
Human Flt3 Is Expressed at the Hematopoietic Stem Cell and the Granulocyte/Macrophage Progenitor Stages to Maintain Cell Survival
Authors: Kikushige Yoshikane , Yoshimoto Goichi , Miyamoto Toshihiro , Iino Tadafumi , Mori Yasuo , Iwasaki Hiromi , Niiro Hiroaki , Takenaka Katsuto , Nagafuji Koji , Harada Mine , Ishikawa Fumihiko , Akashi Koichi 
Published: April 2014

Abstract
FLT3/FLK2, a member of the receptor tyrosine kinase family, plays a critical role in maintenance of hematopoietic homeostasis, and the constitutively active form of the FLT3 mutation is one of the most common genetic abnormalities in acute myelogenous leukemia. In murine hematopoiesis, Flt3 is not expressed in self-renewing hematopoietic stem cells, but its expression is restricted to the multipotent and the lymphoid progenitor stages at which cells are incapable of self-renewal. We extensively analyzed the expression of Flt3 in human (h) hematopoiesis. Strikingly, in both the bone marrow and the cord blood, the human hematopoietic stem cell population capable of long-term reconstitution in xenogeneic hosts uniformly expressed Flt3. Furthermore, human Flt3 is expressed not only in early lymphoid progenitors, but also in progenitors continuously along the granulocyte/macrophage pathway, including the common myeloid progenitor and the granulocyte/macrophage progenitor. We further found that human Flt3 signaling prevents stem and progenitors from spontaneous apoptotic cell death at least through up-regulating Mcl-1, an indispensable survival factor for hematopoiesis. Thus, the distribution of Flt3 expression is considerably different in human and mouse hematopoiesis, and human FLT3 signaling might play an important role in cell survival, especially at stem and progenitor cells that are critical cellular targets for acute myelogenous leukemia transformation.
C5a and TNF-α Up-Regulate the Expression of Tissue Factor in Intra-Alveolar Neutrophils of Patients with the Acute Respiratory Distress Syndrome
Authors: Kambas Konstantinos , Markiewski Maciej M. , Pneumatikos Ioannis A. , Rafail Stavros S. , Theodorou Vassiliki , Konstantonis Dimitrios , Kourtzelis Ioannis , Doumas Michael N. , Magotti Paola , DeAngelis Robert A. , Lambris John D. , Ritis Konstantinos D. 
Published: April 2014

Abstract
Acute respiratory distress syndrome (ARDS) is characterized by the presence of fibrin-rich inflammatory exudates in the intra-alveolar spaces and the extensive migration of neutrophils into alveoli of the lungs. Tissue factor (TF)-dependent procoagulant properties of bronchoalveaolar lavage fluid (BALF) obtained from ARDS patients favor fibrin deposition, and are likely the result of cross-talk between inflammatory mediators and hemostatic mechanisms. However, the regulation of these interactions remains elusive. Prompted by previous findings suggesting that neutrophils, under certain inflammatory conditions, can express functional TF, we investigated the contribution of intra-alveolar neutrophils to the procoagulant properties of BALF from patients with ARDS. Our results confirm that the procoagulant properties of BALF from ARDS patients are the result of TF induction, and further indicate that BALF neutrophils are a main source of TF in intra-alveolar fluid. We also found that BALF neutrophils in these patients express significantly higher levels of TF than peripheral blood neutrophils. These results suggest that the alveolar microenvironment contributes to TF induction in ARDS. Additional experiments indicated that the ability of BALF to induce TF expression in neutrophils from healthy donors can be abolished by inhibiting C5a or TNF-α signaling, suggesting a primary role for these inflammatory mediators in the up-regulation of TF in alveolar neutrophils in ARDS. This cross-talk between inflammatory mediators and the induction of TF expression in intra-alveolar neutrophils may be a potential target for novel therapeutic strategies to limit ARDS-associated disturbances of coagulation.
Production of CCL2 by Central Nervous System Cells Regulates Development of Murine Experimental Autoimmune Encephalomyelitis through the Recruitment of TNF- and iNOS-Expressing Macrophages and Myeloid Dendritic Cells
Authors: Dogan Rukiye-Nazan E. , Elhofy Adam , Karpus William J. 
Published: April 2014

Abstract
Experimental autoimmune encephalomyelitis is a T cell-mediated demyelinating disease of the CNS that serves as a model for the human disease multiple sclerosis. Increased expression of the chemokine CCL2 in the CNS has been demonstrated to be important in the development of demyelinating disease presumably by attracting inflammatory cells. However, the mechanism of how CCL2 regulates disease pathogenesis has not been fully elucidated. Using radiation bone marrow chimeric mice we demonstrated that optimum disease was achieved when CCL2 was glia derived. Furthermore, CNS production of CCL2 resulted in the accumulation of iNOS-producing CD11b+CD11c+ dendritic cells and TNF-producing macrophages important for demyelination. Lack of glial-derived CCL2 production did not influence experimental autoimmune encephalomyelitis by altering either Th1 or Th17 cells, as there were no differences in these populations in the CNS or periphery between groups. These results demonstrate that the glial-derived CCL2 is important for the attraction of TNF- and iNOS-producing dendritic cells and effector macrophages to the CNS for development of subsequent autoimmune disease.
Requirement for Enhancer Specificity in Immunoglobulin Heavy Chain Locus Regulation
Authors: Kuzin Igor I. , Bagaeva Ludmila , Young Faith M. , Bottaro Andrea 
Published: April 2014

Abstract
The intronic Eμ enhancer has been implicated in IgH locus transcription, VDJ recombination, class switch recombination, and somatic hypermutation. How Eμ controls these diverse mechanisms is still largely unclear, but transcriptional enhancer activity is thought to play a central role. In this study we compare the phenotype of mice lacking the Eμ element (ΔEμ) with that of mice in which Eμ was replaced with the ubiquitous SV40 transcriptional enhancer (SV40eR mutation) and show that SV40e cannot functionally complement Eμ loss in pro-B cells. Surprisingly, in fact, the SV40eR mutation yields a more profound defect than ΔEμ, with an almost complete block in μ0 germline transcription in pro-B cells. This active transcriptional suppression caused by enhancer replacement appears to be specific to the early stages of B cell development, as mature SV40eR B cells express μ0 transcripts at higher levels than ΔEμ mice and undergo complete DNA demethylation at the IgH locus. These results indicate an unexpectedly stringent, developmentally restricted requirement for enhancer specificity in regulating IgH function during the early phases of B cell differentiation, consistent with the view that coordination of multiple independent regulatory mechanisms and elements is essential for locus activation and VDJ recombination.
The Evolution of Multiple Isotypic IgM Heavy Chain Genes in the Shark
Authors: Lee Victor , Huang Jing Li , Lui Ming Fai , Malecek Karolina , Ohta Yuko , Mooers Arne , Hsu Ellen 
Published: April 2014

Abstract
The IgM H chain gene organization of cartilaginous fishes consists of 15–200 miniloci, each with a few gene segments (VH-D1-D2-JH) and one C gene. This is a gene arrangement ancestral to the complex IgH locus that exists in all other vertebrate classes. To understand the molecular evolution of this system, we studied the nurse shark, which has relatively fewer loci, and characterized the IgH isotypes for organization, functionality, and the somatic diversification mechanisms that act upon them. Gene numbers differ slightly between individuals (∼15), but five active IgM subclasses are always present. Each gene undergoes rearrangement that is strictly confined within the minilocus; in B cells there is no interaction between adjacent loci located ≥120 kb apart. Without combinatorial events, the shark IgM H chain repertoire is based on junctional diversity and, subsequently, somatic hypermutation. We suggest that the significant contribution by junctional diversification reflects the selected novelty introduced by RAG in the early vertebrate ancestor, whereas combinatorial diversity coevolved with the complex translocon organization. Moreover, unlike other cartilaginous fishes, there are no germline-joined VDJ at any nurse shark μ locus, and we suggest that such genes, when functional, are species-specific and may have specialized roles. With an entire complement of IgM genes available for the first time, phylogenetic analyses were performed to examine how the multiple Ig loci evolved. We found that all domains changed at comparable rates, but VH appears to be under strong positive selection for increased amino acid sequence diversity, and surprisingly, so does Cμ2.