bluuebunny/crossref_metadata_2025_split huggingface dataset:
Epigenetic and Transcriptional Programs Lead to Default IFN-γ Production by γδ T Cells
Authors: Chen Liang , He Weifeng , Kim Sean T. , Tao Jian , Gao Yunfei , Chi Hongbo , Intlekofer Andrew M. , Harvey Bohdan , Reiner Steven L. , Yin Zhinan , Flavell Richard A. , Craft Joe 
Published: April 2014

Abstractγδ T cells have unique features and functions compared with αβ T cells and have been proposed to bridge the innate and adaptive immune responses. Our earlier studies demonstrated that splenic γδ T cells predominantly produce IFN-γ upon activation in vitro, which is partially due to the expression of the Th1-specific transcription factor T-bet. In this study we have explored the epigenetic and transcriptional programs that underlie default IFN-γ production by γδ T cells. We show that the kinetics of IFN-γ transcription is faster in γδ T cells compared with CD4+ and CD8+ T cells and that γδ T cells produce significantly greater amounts of IFN-γ in a proliferation-independent manner when compared with other T cell subsets. By analyzing the methylation pattern of intron 1 of the ifn-γ locus, we demonstrate that this region in naive γδ T cells is hypomethylated relative to the same element in naive CD4+ and CD8+ T cells. Furthermore, naive γδ T cells constitutively express eomesodermin (Eomes), a transcription factor important for IFN-γ production in CD8+ T cells, and Eomes expression levels are enhanced upon activation. Retroviral transduction of activated γδ T cells from both wild-type and T-bet-deficient mice with a dominant negative form of Eomes significantly reduced IFN-γ production, indicating a critical role for this transcription factor in mediating IFN-γ production by γδ T cells in a T-bet-independent manner. Our results demonstrate that both epigenetic and transcriptional programs contribute to the early vigorous IFN-γ production by γδ T cells.
Gag-Specific CD8+ T Lymphocytes Recognize Infected Cells before AIDS-Virus Integration and Viral Protein Expression
Authors: Sacha Jonah B. , Chung Chungwon , Rakasz Eva G. , Spencer Sean P. , Jonas Anna K. , Bean Alexander T. , Lee Wonhee , Burwitz Benjamin J. , Stephany Jason J. , Loffredo John T. , Allison David B. , Adnan Sama , Hoji Akihiko , Wilson Nancy A. , Friedrich Thomas C. , Lifson Jeffrey D. , Yang Otto O. , Watkins David I. 
Published: April 2014

Abstract
CD8+ T cells are a key focus of vaccine development efforts for HIV. However, there is no clear consensus as to which of the nine HIV proteins should be used for vaccination. The early proteins Tat, Rev, and Nef may be better CD8+ T cell targets than the late-expressed structural proteins Gag, Pol, and Env. In this study, we show that Gag-specific CD8+ T cells recognize infected CD4+ T lymphocytes as early as 2 h postinfection, before proviral DNA integration, viral protein synthesis, and Nef-mediated MHC class I down-regulation. Additionally, the number of Gag epitopes recognized by CD8+ T cells was significantly associated with lower viremia (p = 0.0017) in SIV-infected rhesus macaques. These results suggest that HIV vaccines should focus CD8+ T cell responses on Gag.
Efficient Activation of Vα14 Invariant NKT Cells by Foreign Lipid Antigen Is Associated with Concurrent Dendritic Cell-Specific Self Recognition
Authors: Cheng Lu , Ueno Aito , Cho Suzanne , Im Jin S. , Golby Susanne , Hou Sheng , Porcelli Steven A. , Yang Yang 
Published: April 2014

Abstract
A burst release of cytokines by Vα14 invariant NKT (iNKT) cells upon their TCR engagement critically regulates innate and adaptive immune responses. However, it remains unclear in vivo why iNKT cells respond efficiently to microbial or intracellular lipid Ags that are at low levels or that possess suboptimal antigenicity. We found that dendritic cells (DCs) potentiated iNKT cells to respond to a minimal amount of ligand α-galactosylceramide (αGalCer) through CD1d-dependent autoreactive responses that require endosomal processing and CD1d trafficking. The ability of potentiation of NKT cells was DC specific and did not depend on costimulatory signals and IL-12 production by DCs. However, DCs that failed to synthesize a major endogenous lipid Ag isoglobotrihexosylceramide were unable to potentiate NKT cells for efficient activation. Further analysis showed that differences in the level and pattern of endogenous lipid Ag presentation differentiate DCs and B cells for effective potentiation and subsequent activation of iNKT cells in the presence of an exogenous Ag. Thus, CD1d-dependent potentiation by DCs may be crucial for iNKT cell-mediated immunity against infectious agents.
Dendritic Cells Infiltrating Human Non-Small Cell Lung Cancer Are Blocked at Immature Stage
Authors: Perrot Ivan , Blanchard Dominique , Freymond Nathalie , Isaac Sylvie , Guibert Benoît , Pachéco Yves , Lebecque Serge 
Published: April 2014

Abstract
The efficacy of immune response to control human cancer remains controversial. It is particularly debated whether and to what extent the capacity of tumor-infiltrating dendritic cells (DC) to drive immunization can be turned off by transformed cells, leading to tumor-specific tolerance rather than immunization. To address this issue, we have characterized the DC isolated from human non-small cell lung cancer (NSCLC). These biopsy specimens contained CD11chigh myeloid DC (mDC), but also CD11c− plasmacytoid DC (pDC) and a third DC subset expressing intermediate level of CD11c. Compared with peripheral blood, CD11chigh tumor-infiltrating DC (TIDC) displayed a “semi-mature” phenotype, and TLR4 or TLR8 stimulation drove them to mature partially and to secrete limited amounts of cytokines. In contrast, most tumor-infiltrating pDC were immature but underwent partial maturation after TLR7 activation, whereas TLR9 ligation triggered low secretion of IFN-α. CD11cint mDC represented ∼25% of total DC in tumoral and peritumoral tissues and expressed low levels of costimulatory molecules contrasting with high levels of the immunoinhibitory molecule B7-H1. Finally, the poor APC function of total TIDC even after TLR stimulation and the migratory response of both tumor-infiltrating mDC and pDC toward CCL21 and SDF-1 in vitro suggested their ability to compromise the tumor-specific immune response in draining lymph nodes in vivo. Further studies will be required to establish the specific role of the three TIDC subsets in tumor immunity and to draw conclusions for the design of therapeutic strategies.
Regulation of Suppressor of Cytokine Signaling 3 (SOCS3) mRNA Stability by TNF-α Involves Activation of the MKK6/p38MAPK/MK2 Cascade
Authors: Ehlting Christian , Lai Wi S. , Schaper Fred , Brenndörfer Erwin D. , Matthes Raphaela-Jessica , Heinrich Peter C. , Ludwig Stephan , Blackshear Perry J. , Gaestel Matthias , Häussinger Dieter , Bode Johannes G. 
Published: April 2014

Abstract
The potential of some proinflammatory mediators to inhibit gp130-dependent STAT3 activation by enhancing suppressor of cytokine signaling (SOCS) 3 expression represents an important molecular mechanism admitting the modulation of the cellular response toward gp130-mediated signals. Thus, it is necessary to understand the mechanisms involved in the regulation of SOCS3 expression by proinflammatory mediators. In this study, we investigate SOCS3 expression initiated by the proinflammatory cytokine TNF-α. In contrast to IL-6, TNF-α increases SOCS3 expression by stabilizing SOCS3 mRNA. Activation of the MAPK kinase 6 (MKK6)/p38MAPK-cascade is required for TNF-α-mediated stabilization of SOCS3 mRNA and results in enhanced SOCS3 protein expression. In fibroblasts or macrophages deficient for MAPK-activated protein kinase 2 (MK2), a downstream target of the MKK6/p38MAPK cascade, basal SOCS3-expression is strongly reduced and TNF-α-induced SOCS3-mRNA stabilization is impaired, indicating that MK2 is crucial for the control of SOCS3 expression by p38MAPK-dependent signals. As a target for SOCS3 mRNA stability-regulating signals, a region containing three copies of a pentameric AUUUA motif in close proximity to a U-rich region located between positions 2422 and 2541 of the 3′ untranslated region of SOCS3 is identified. One factor that could target this region is the zinc finger protein tristetraprolin (TTP), which is shown to be capable of destabilizing SOCS3 mRNA via this region. However, data from TTP-deficient cells suggest that TTP does not play an irreplaceable role in the regulation of SOCS3 mRNA stability by TNF-α. In summary, these data indicate that TNF-α regulates SOCS3 expression on the level of mRNA stability via activation of the MKK6/p38MAPK cascade and that the activation of MK2, a downstream target of p38MAPK, is important for the regulation of SOCS3 expression.
IL-21 Is Produced by NKT Cells and Modulates NKT Cell Activation and Cytokine Production
Authors: Coquet Jonathan M. , Kyparissoudis Konstantinos , Pellicci Daniel G. , Besra Gurdyal , Berzins Stuart P. , Smyth Mark J. , Godfrey Dale I. 
Published: April 2014

Abstract
The common γ-chain cytokine, IL-21, is produced by CD4+ T cells and mediates potent effects on a variety of immune cells including NK, T, and B cells. NKT cells express the receptor for IL-21; however, the effect of this cytokine on NKT cell function has not been studied. We show that IL-21 on its own enhances survival of NKT cells in vitro, and IL-21 increases the proliferation of NKT cells in combination with IL-2 or IL-15, and particularly with the CD1d-restricted glycosphingolipid Ag α-galactosylceramide. Similar to its effects on NK cells, IL-21 enhances NKT cell granular morphology, including granzyme B expression, and some inhibitory NK receptors, including Ly49C/I and CD94. IL-21 also enhanced NKT cell cytokine production in response to anti-CD3/CD28 in vitro. Furthermore, NKT cells may be subject to autocrine IL-21-mediated stimulation because they are potent producers of this cytokine following in vitro stimulation via CD3 and CD28, particularly in conjunction with IL-12 or following in vivo stimulation with α-galactosylceramide. Indeed, NKT cells produced much higher levels of IL-21 than conventional CD4 T cells in this assay. This study demonstrates that NKT cells are potentially a major source of IL-21, and that IL-21 may be an important factor in NKT cell-mediated immune regulation, both in its effects on NK, T, and B cells, as well as direct effects on NKT cells themselves. The influence of IL-21 in NKT cell-dependent models of tumor rejection, microbial clearance, autoimmunity, and allergy should be the subject of future investigations.
Tumor Evasion of the Immune System by Converting CD4+CD25− T Cells into CD4+CD25+ T Regulatory Cells: Role of Tumor-Derived TGF-β
Authors: Liu Victoria C. , Wong Larry Y. , Jang Thomas , Shah Ali H. , Park Irwin , Yang Ximing , Zhang Qiang , Lonning Scott , Teicher Beverly A. , Lee Chung 
Published: April 2014

Abstract
CD4+CD25+ T regulatory (Treg) cells were initially described for their ability to suppress autoimmune diseases in animal models. An emerging interest is the potential role of Treg cells in cancer development and progression because they have been shown to suppress antitumor immunity. In this study, CD4+CD25− T cells cultured in conditioned medium (CM) derived from tumor cells, RENCA or TRAMP-C2, possess similar characteristics as those of naturally occurring Treg cells, including expression of Foxp3, a crucial transcription factor of Treg cells, production of low levels of IL-2, high levels of IL-10 and TGF-β, and the ability to suppress CD4+CD25− T cell proliferation. Further investigation revealed a critical role of tumor-derived TGF-β in converting CD4+CD25− T cells into Treg cells because a neutralizing Ab against TGF-β, 1D11, completely abrogated the induction of Treg cells. CM from a nontumorigenic cell line, NRP-152, or irradiated tumor cells did not convert CD4+CD25− T cells to Treg cells because they produce low levels of TGF-β in CM. Finally, we observed a reduced tumor burden in animals receiving 1D11. The reduction in tumor burden correlated with a decrease in tumor-derived TGF-β. Treatment of 1D11 also reduced the conversion of CD4+ T cells into Treg cells and subsequent Treg cell-mediated suppression of antitumor immunity. In summary, we have demonstrated that tumor cells directly convert CD4+CD25− T cells to Treg cells through production of high levels of TGF-β, suggesting a possible mechanism through which tumor cells evade the immune system.
Augmentation of Signaling through BCR Containing IgE but not That Containing IgA Due to Lack of CD22-Mediated Signal Regulation
Authors: Sato Motohiko , Adachi Takahiro , Tsubata Takeshi 
Published: April 2014

Abstract
The B cell membrane molecules CD22 and CD72 contain ITIMs in their cytoplasmic portion, and negatively regulate signaling through BCR. Various lines of evidence suggest that ligation of BCR containing IgG (IgG-BCR) transmits augmented signaling due to lack of CD22-mediated signal regulation. However, the signaling capacities of BCR containing IgA and IgE remain largely undefined. In this study, we demonstrate that both IgE-BCR and IgG-BCR, but not IgA-BCR, transmit augmented signaling compared with IgM-BCR. Ligation of IgE-BCR does not induce signaling events required for CD22-mediated signal inhibition, and restoration of these signaling events by coligation of CD22 with BCR abrogates signal augmentation. Furthermore, the cytoplasmic portion of IgE but not that of IgA is sufficient for suppressing CD22-mediated signal inhibition. These findings strongly suggest that the cytoplasmic portion of IgE but not that of IgA reverses CD22-mediated signal inhibition, leading to augmentation of signaling through IgE-BCR but not IgA-BCR. Augmented IgE-BCR signaling appears to play a role in production of large amounts of IgE during helminth infection, whereas regulated signaling through IgA-BCR may be crucial for constitutive production of IgA for mucosal immunity.
Fitness of Cell-Mediated Immunity Independent of Repertoire Diversity
Authors: AbuAttieh Mouhammed , Rebrovich Michelle , Wettstein Peter J. , Vuk-Pavlovic Zvezdana , Limper Andrew H. , Platt Jeffrey L. , Cascalho Marilia 
Published: April 2014

Abstract
Fitness of cell-mediated immunity is thought to depend on TCR diversity; however, this concept has not been tested formally. We tested the concept using JH−/− mice that lack B cells and have TCR Vβ diversity &lt;1% that of wild-type mice and quasimonoclonal (QM) mice with oligoclonal B cells and TCR Vβ diversity 7% that of wild-type mice. Despite having a TCR repertoire contracted &gt;99% and defective lymphoid organogenesis, JH−/− mice rejected H-Y-incompatible skin grafts as rapidly as wild-type mice. JH−/− mice exhibited T cell priming by peptide and delayed-type hypersensitivity, although these responses were less than normal owing either to TCR repertoire contraction or defective lymphoid organogenesis. QM mice with TCR diversity contracted &gt;90%, and normal lymphoid organs rejected H-Y incompatible skin grafts as rapidly as wild type mice and exhibited normal T cell priming and normal delayed-type hypersensitivity reactions. QM mice also resisted Pneumocystis murina like wild-type mice. Thus, cell-mediated immunity can function normally despite contractions of TCR diversity &gt;90% and possibly &gt;99%.
Targeting of Antigen to Dendritic Cells with Poly(γ-Glutamic Acid) Nanoparticles Induces Antigen-Specific Humoral and Cellular Immunity
Authors: Uto Tomofumi , Wang Xin , Sato Katsuaki , Haraguchi Misako , Akagi Takami , Akashi Mitsuru , Baba Masanori 
Published: April 2014

Abstract
Nanoparticles are considered to be efficient tools for inducing potent immune responses by an Ag carrier. In this study, we examined the effect of Ag-carrying biodegradable poly(γ-glutamic acid) (γ-PGA) nanoparticles (NPs) on the induction of immune responses in mice. The NPs were efficiently taken up by dendritic cells (DCs) and subsequently localized in the lysosomal compartments. γ-PGA NPs strongly induced cytokine production, up-regulation of costimulatory molecules, and the enhancement of T cell stimulatory capacity in DCs. These maturational changes of DCs involved the MyD88-mediated NF-κB signaling pathway. In vivo, γ-PGA NPs were preferentially internalized by APCs (DCs and macrophages) and induced the production of IL-12p40 and IL-6. The immunization of mice with OVA-carrying NPs induced Ag-specific CTL activity and Ag-specific production of IFN-γ in splenocytes as well as potent production of Ag-specific IgG1 and IgG2a Abs in serum. Furthermore, immunization with NPs carrying a CD8+ T cell epitope peptide of Listeria monocytogenes significantly protected the infected mice from death. These results suggest that Ag-carrying γ-PGA NPs are capable of inducing strong cellular and humoral immune responses and might be potentially useful as effective vaccine adjuvants for the therapy of infectious diseases.
Anti-Nuclear Antibody Production and Autoimmunity in Transgenic Mice That Overexpress the Transcription Factor Bright
Authors: Shankar Malini , Nixon Jamee C. , Maier Shannon , Workman Jennifer , Farris A. Darise , Webb Carol F. 
Published: April 2014

Abstract
The B cell-restricted transcription factor, B cell regulator of IgH transcription (Bright), up-regulates Ig H chain transcription 3- to 7-fold in activated B cells in vitro. Bright function is dependent upon both active Bruton’s tyrosine kinase and its substrate, the transcription factor, TFII-I. In mouse and human B lymphocytes, Bright transcription is down-regulated in mature B cells, and its expression is tightly regulated during B cell differentiation. To determine how Bright expression affects B cell development, transgenic mice were generated that express Bright constitutively in all B lineage cells. These mice exhibited increases in total B220+ B lymphocyte lineage cells in the bone marrow, but the relative percentages of the individual subpopulations were not altered. Splenic immature transitional B cells were significantly expanded both in total cell numbers and as increased percentages of cells relative to other B cell subpopulations. Serum Ig levels, particularly IgG isotypes, were increased slightly in the Bright-transgenic mice compared with littermate controls. However, immunization studies suggest that responses to all foreign Ags were not increased globally. Moreover, 4-wk-old Bright-transgenic mice produced anti-nuclear Abs. Older animals developed Ab deposits in the kidney glomeruli, but did not succumb to further autoimmune sequelae. These data indicate that enhanced Bright expression results in failure to maintain B cell tolerance and suggest a previously unappreciated role for Bright regulation in immature B cells. Bright is the first B cell-restricted transcription factor demonstrated to induce autoimmunity. Therefore, the Bright transgenics provide a novel model system for future analyses of B cell autoreactivity.
Aire-Dependent Alterations in Medullary Thymic Epithelium Indicate a Role for Aire in Thymic Epithelial Differentiation
Authors: Gillard Geoffrey O. , Dooley James , Erickson Matthew , Peltonen Leena , Farr Andrew G. 
Published: April 2014

Abstract
The prevalent view of thymic epithelial differentiation and Aire activity holds that Aire functions in terminally differentiated medullary thymic epithelial cells (MTECs) to derepress the expression of structural tissue-restricted Ags, including pancreatic endocrine hormones. An alternative view of these processes has proposed that Aire functions to regulate the differentiation of immature thymic epithelial cells, thereby affecting tissue-restricted Ag expression and negative selection. In this study, we demonstrate that Aire impacts several aspects of murine MTECs and provide support for this second model. Expression of transcription factors associated with developmental plasticity of progenitor cells, Nanog, Oct4, and Sox2, by MTECs was Aire dependent. Similarly, the transcription factors that regulate pancreatic development and the expression of pancreatic hormones are also expressed by wild-type MTECs in an Aire-dependent manner. The altered transcriptional profiles in Aire-deficient MTECs were accompanied by changes in the organization and composition of the medullary epithelial compartment, including a reduction in the medullary compartment defined by keratin (K) 14 expression, altered patterns of K5 and K8 expression, and more prominent epithelial cysts. These findings implicate Aire in the regulation of MTEC differentiation and the organization of the medullary thymic compartment and are compatible with a role for Aire in thymic epithelium differentiation.
Genomic Organization of the Chicken CD8 Locus Reveals a Novel Family of Immunoreceptor Genes
Authors: Liaw Hung-Jiun , Chen Wei-Ru , Huang Yu-Chia , Tsai Chung-Wei , Chang King-Chan , Kuo Chia-Lam 
Published: April 2014

Abstract
The genomic organization of the chicken CD8α gene was investigated to determine the basis of its polymorphism. Contiguous to the CD8α gene we identified multiple DNA blocks possessing sequences homologous to CD8α. Gene conversions and recombination over evolutionary time among CD8α and these CD8α homologous genes seem to account for the observed polymorphism. Furthermore, these CD8α-like DNAs encode a distinct multigene family of immunoreceptors that have a charged or polar residue in place of the interspecies-conserved CD8α transmembrane proline residue and a short cytoplasmic tail nonhomologous to CD8α. The identification of this novel multigene family with an organization reminiscent of human killer Ig-like receptors raises compelling questions on their evolutionary relationship among immunoreceptors.
Early Growth Response Transcriptional Regulators Are Dispensable for Macrophage Differentiation
Authors: Carter John H. , Tourtellotte Warren G. 
Published: April 2014

Abstract
Early growth response (Egr) proteins comprise a family of transcriptional regulators (Egr1–4) that modulate gene expression involved in the growth and differentiation of many cell types. In particular, Egr1 is widely believed to have an essential role in regulating monocyte/macrophage differentiation. However, Egr1-deficient mice have normal numbers of functional macrophages, an observation that has led to the hypothesis that other Egr proteins may compensate for Egr1 function in vivo. We examined whether other Egr transcription factors have a functionally redundant role in monocyte/macrophage differentiation. Egr1 and Egr3 expression was found to be induced in myeloid cells when they were differentiated into macrophages by treatment with M-CSF, whereas Egr2 was minimally induced and Egr4 was not detected. In either Egr1/Egr3 or Egr1/Egr2 double homozygous mutant mice, macrophage differentiation and function remained unimpaired. Additionally, the expression of molecules that broadly inhibit Egr function failed to block commitment to the monocytic lineage or inhibit the maturation of monocyte precursors. Finally, several hemopoietic growth factors were found to induce Egr gene expression, indicating that Egr gene expression is not cell lineage specific. Taken together, these results demonstrate that Egr transcription factors are neither essential for nor specific to monocyte/macrophage differentiation.