bluuebunny/crossref_metadata_2025_split huggingface dataset:
Down-Modulation of TCR Expression by Salmonella enterica serovar Typhimurium
Authors: van der Velden Adrianus W. M. , Dougherty Jeffrey T. , Starnbach Michael N. 
Published: April 2014

Abstract
T cell-mediated adaptive immunity is required to help clear infection with the facultative intracellular bacterial pathogen Salmonella enterica serovar Typhimurium (S. Typhimurium), yet development of T cell-mediated adaptive immunity to S. Typhimurium has been described as slow and inefficient. A key step in inducing T cell-mediated adaptive immunity is T cell priming; the activation, proliferation, and differentiation of naive T cells following initial encounter with Ag. We previously demonstrated that S. Typhimurium had a direct inhibitory effect on naive T cells from mouse, blocking their proliferation. In this study, we show that S. Typhimurium down-modulates expression of the TCR β-chain, a molecule that is essential for Ag recognition and T cell function. Specifically, we demonstrate that reduced amounts of surface and intracellular TCR-β protein and decreased levels of tcrβ transcript are expressed by T cells cultured in the presence of S. Typhimurium. We further show that the down-modulation of TCR-β expression requires contact between S. Typhimurium and the T cells and that once contact occurs, a factor capable of reducing TCR-β expression is secreted. These results provide new insight into the mechanism by which S. Typhimurium may inhibit T cell priming and avoid clearance by the adaptive immune system.
HIV Envelope Suppresses CD4+ T Cell Activation Independent of T Regulatory Cells
Authors: Hu Haitao , Fernando Kathy , Ni Houping , Weissman Drew 
Published: April 2014

Abstract
We previously demonstrated that HIV envelope glycoprotein (Env), delivered in the form of a vaccine and expressed by dendritic cells or 293T cells, could suppress Ag-stimulated CD4+ T cell proliferation. The mechanism remains to be identified but is dependent on CD4 and independent of coreceptor binding. Recently, CD4+ regulatory T (Treg) cells were found to inhibit protective anti-HIV CD4+ and CD8+ T cell responses. However, the role of Tregs in HIV remains highly controversial. HIV Env is a potent immune inhibitory molecule that interacts with host CD4+ cells, including Treg cells. Using an in vitro model, we investigated whether Treg cells are involved in Env-induced suppression of CD4+ T cell proliferation, and whether Env directly affects the functional activity of Treg cells. Our data shows that exposure of human CD4+ T cells to Env neither induced a higher frequency nor a more activated phenotype of Treg cells. Depletion of CD25+ Treg cells from PBMC did not overcome the Env-induced suppression of CD4+ T cell proliferation, demonstrating that CD25+FoxP3+ Treg cells are not involved in Env-induced suppression of CD4+ T cell proliferation. In addition, we extend our observation that similar to Env expressed on cells, Env present on virions also suppresses CD4+ T cell proliferation.
Heme Oxygenase-1 Is a Critical Regulator of Nitric Oxide Production in Enterohemorrhagic Escherichia coli-Infected Human Enterocytes
Authors: Vareille Marjolaine , Rannou François , Thélier Natacha , Glasser Anne-Lise , de Sablet Thibaut , Martin Christine , Gobert Alain P. 
Published: April 2014

Abstract
Enterohemorrhagic Escherichia coli (EHEC) are the causative agent of hemolytic-uremic syndrome. In the first stage of the infection, EHEC interact with human enterocytes to modulate the innate immune response. Inducible NO synthase (iNOS)-derived NO is a critical mediator of the inflammatory response of the infected intestinal mucosa. We therefore aimed to analyze the role of EHEC on iNOS induction in human epithelial cell lines. In this regard, we show that EHEC down-regulate IFN-γ-induced iNOS mRNA expression and NO production in Hct-8, Caco-2, and T84 cells. This inhibitory effect occurs through the decrease of STAT-1 activation. In parallel, we demonstrate that EHEC stimulate the rapid inducible expression of the gene hmox-1 that encodes for the enzyme heme oxygenase-1 (HO-1). Knock-down of hmox-1 gene expression by small interfering RNA or the blockade of HO-1 activity by zinc protoporphyrin IX abrogated the EHEC-dependent inhibition of STAT-1 activation and iNOS mRNA expression in activated human enterocytes. These results highlight a new strategy elaborated by EHEC to control the host innate immune response.
NK Cells Expressing a Progesterone Receptor Are Susceptible to Progesterone-Induced Apoptosis
Authors: Arruvito Lourdes , Giulianelli Sebastián , Flores Ana C. , Paladino Natalia , Barboza Marcos , Lanari Claudia , Fainboim Leonardo 
Published: April 2014

Abstract
It has been proposed that progesterone (P4) induces the suppression of immune responses, particularly during pregnancy. However, knowledge about the mechanisms involved has remained largely elusive. We demonstrate herein that peripheral blood NK (PBNK) cells express both classical progesterone receptor (PR) isoforms and are specifically affected by the actions of P4 through two apparently independent mechanisms. Progesterone induces caspase-dependent PBNK cell death, which is reversed by two different anti-progestins, ZK 98.299 and RU 486, supporting the involvement of classical PR isoforms. It was suggested that CD56brightCD16− killer Ig-like receptor (KIR)− NK cells might represent precursor cells, which, upon activation, acquire the features of a more mature NK subset expressing KIR receptors. The present study demonstrates that PR expression seems to be restricted to more mature KIR+ PBNK cells. The expression of PR had a functional counterpart in the suppressive effect of P4 on IL-12-induced IFN-γ secretion. This cytokine suppression was mainly observed in KIR+ PBNK cells, without affecting the high secretion of IFN-γ by CD56bright PBNK cells. The lack of PR expression on CD56brightKIR− PBNK cells provides an additional phenotypic marker to test the idea that they might represent the PBNK precursors selectively recruited into the endometrium where they differentiate to become the uterine NK cells. Additionally, these findings may be relevant to NK cell function in viral immunity, human reproduction, and tumor immunity.
Stat6 Signaling Suppresses VLA-4 Expression by CD8+ T Cells and Limits Their Ability to Infiltrate Tumor Lesions In Vivo
Authors: Sasaki Kotaro , Zhao Xi , Pardee Angela D. , Ueda Ryo , Fujita Mitsugu , Sehra Sarita , Kaplan Mark H. , Kane Lawrence P. , Okada Hideho , Storkus Walter J. 
Published: April 2014

Abstract
VLA-4 plays a critical role in T cell trafficking into inflammatory sites. Our recent studies have suggested that VLA-4 expression on CD8+ T cells is negatively controlled by IL-4 and serves as a functionally distinguishing variable for why Type-1, but not Type-2, CD8+ T cells are able to traffic into tumors. In this study, using in vitro culture of murine CD8+ T cells under Type-1 and Type-2 cytokine conditions, we show that IL-4-mediated down-regulation of VLA-4 expression is completely abrogated in Stat6-deficient CD8+ T cells. Conversely, CD8+ T cells expressing a constitutively active mutant form Stat6 (Stat6VT) failed to express VLA-4 even in the absence of IL-4-stimulation. Notably, Type-2 CD8+ T cells developed from Stat6−/− but not wild-type mice were competent to migrate into tumor lesions in vivo. These results suggest that Stat6-signaling is necessary and sufficient to restrict CD8+ T cell expression of VLA-4 (by IL-4), thereby serving as a regulator for CD8+ T cell infiltration into tumors.
An Age-Old Paradigm Challenged: Old Baboons Generate Vigorous Humoral Immune Responses to LcrV, A Plague Antigen
Authors: Stacy Sue , Pasquali Amanda , Sexton Valerie L. , Cantwell Angelene M. , Kraig Ellen , Dube Peter H. 
Published: April 2014

Abstract
Immune senescence in the elderly results in decreased immunity with a concomitant increase in susceptibility to infection and diminished efficacy of vaccination. Nonhuman primate models have proven critical for testing of vaccines and therapeutics in the general population, but a model using old animals has not been established. Toward that end, immunity to LcrV, a protective Ag from Yersinia pestis, was tested in young and old baboons. Surprisingly, there was no age-associated loss in immune competence; LcrV elicited high-titer, protective Ab responses in the older individuals. The primary responses in the younger baboons were lower, but they did show boosting upon secondary immunization to the levels achieved in the old animals. The LcrV Ag was also tested in mice and, as expected, age-associated loss of immunity was seen; older animals responded with lower-titer Abs and, as a result, were more susceptible to Yersinia challenge. Thus, although age-related loss in immune function has been observed in humans, rodents, and some nonhuman primates, baboons appear to be unusual; they age without losing immune competence.
Evidence That CD8+ Dendritic Cells Enable the Development of γδ T Cells That Modulate Airway Hyperresponsiveness
Authors: Cook Laura , Miyahara Nobuaki , Jin Niyun , Wands J. M. , Taube Christian , Roark Christina L. , Potter Terry A. , Gelfand Erwin W. , O'Brien Rebecca L. , Born Willi K. 
Published: April 2014

Abstract
Airway hyperresponsiveness (AHR), a hallmark of asthma and several other diseases, can be modulated by γδ T cells. In mice sensitized and challenged with OVA, AHR depends on allergen-specific αβ T cells; but Vγ1+ γδ T cells spontaneously enhance AHR, whereas Vγ4+ γδ T cells, after being induced by airway challenge, suppress AHR. The activity of these γδ T cell modulators is allergen nonspecific, and how they develop is unclear. We now show that CD8 is essential for the development of both the AHR suppressor and enhancer γδ T cells, although neither type needs to express CD8 itself. Both cell types encounter CD8-expressing non-T cells in the spleen, and their functional development in an otherwise CD8-negative environment can be restored with transferred spleen cell preparations containing CD8+ dendritic cells (DCs), but not CD8+ T cells or CD8− DCs. Our findings suggest that CD8+ DCs in the lymphoid tissues enable an early step in the development of γδ T cells through direct cell contact. DC-expressed CD8 might take part in this interaction.
Th1 and Th2 Cells Form Morphologically Distinct Immunological Synapses
Authors: Thauland Timothy J. , Koguchi Yoshinobu , Wetzel Scott A. , Dustin Michael L. , Parker David C. 
Published: April 2014

Abstract
The arrangement of molecules at the interface between T cells and APCs is known as the immunological synapse (IS). We conducted experiments with supported planar bilayers and transfected fibroblast APC to examine the IS formed by polarized Th1 and Th2 cells. Th1 cells formed typical “bull’s-eye” IS with a ring of adhesion molecules surrounding MHC/TCR interactions at all Ag concentrations tested, while Th2 cells formed multifocal IS at high concentrations of Ag. At low Ag concentrations, the majority of Th2 cells formed IS with a compact, central accumulation of MHC/TCR, but ICAM-1 was not excluded from the center of the IS. Additionally, CD45 was excluded from the center of the interface between Th1 cells and APC, while CD45 was found at the center of the multifocal IS formed by Th2 cells. Finally, phosphorylated signaling molecules colocalized with MHC/TCR to a greater extent in Th2 IS. Together, our results indicate that the IS formed by Th1 and Th2 cells are distinct in structure, with Th2 cells failing to form bull’s-eye IS.
Functional Analysis of Histone Methyltransferase G9a in B and T Lymphocytes
Authors: Thomas Lance R. , Miyashita Hiroki , Cobb Robin Milley , Pierce Steven , Tachibana Makoto , Hobeika Elias , Reth Michael , Shinkai Yoichi , Oltz Eugene M. 
Published: April 2014

Abstract
Lymphocyte development is controlled by dynamic repression and activation of gene expression. These developmental programs include the ordered, tissue-specific assembly of Ag receptor genes by V(D)J recombination. Changes in gene expression and the targeting of V(D)J recombination are largely controlled by patterns of epigenetic modifications imprinted on histones and DNA, which alter chromatin accessibility to nuclear factors. An important component of this epigenetic code is methylation of histone H3 at lysine 9 (H3K9me), which is catalyzed by histone methyltransferases and generally leads to gene repression. However, the function and genetic targets of H3K9 methyltransferases during lymphocyte development remain unknown. To elucidate the in vivo function of H3K9me, we generated mice lacking G9a, a major H3K9 histone methyltransferase, in lymphocytes. Surprisingly, lymphocyte development is unperturbed in G9a-deficient mice despite a significant loss of H3K9me2 in precursor B cells. G9a deficiency is manifest as modest defects in the proliferative capacity of mature B cells and their differentiation into plasma cells following stimulation with LPS and IL-4. Precursor lymphocytes from the mutant mice retain tissue- and stage-specific control over V(D)J recombination. However, G9a deficiency results in reduced usage of Igλ L chains and a corresponding inhibition of Igλ gene assembly in bone marrow precursors. These findings indicate that the H3K9me2 epigenetic mark affects a highly restricted set of processes during lymphocyte development and activation.
MEK1/2 Induces STAT5-Mediated Germline Transcription of the TCRγ Locus in Response to IL-7R Signaling
Authors: Maki Kazushige , Ikuta Koichi 
Published: April 2014

Abstract
The IL-7R plays an essential role in γδ T cell development by inducing V-J recombination of the TCRγ locus through STAT5. Although tyrosine residues in the intracellular domain of the mouse IL-7R α-chain (IL-7Rα) have been implicated in STAT5 activation, it is still unknown whether they are essential for γδ T cell development. In this study, we showed that those IL-7Rα tyrosine residues are not essential for γδ T cell development, because phenylalanine replacement of four intracellular tyrosine residues (IL-7R-FFFF) partially rescued γδ T cell development of IL-7Rα−/− progenitors. To examine signaling pathways activated by IL-7R-FFFF, we introduced a chimeric receptor consisting of the human IL-4R α-chain and mouse IL-7R-FFFF (4R/7R-FFFF) into an IL-7-dependent pre-B cell line and found that 4R/7R-FFFF induced TCRγ germline transcription and STAT5 activation. Treatment of cells with MEK1/2 inhibitors significantly decreased levels of TCRγ germline transcription and STAT5 tyrosine phosphorylation mediated by 4R/7R-FFFF, suggesting that MEK1/2 plays an alternative role in STAT5 activation by IL-7R. MEK1/2 associated with STAT5 and induced STAT5 tyrosine phosphorylation and DNA binding activity. Furthermore, MEK1 directly phosphorylated a STAT5 tyrosine residue in vitro. Finally, active MEK1 partially rescued TCRγ germline transcription by IL-7R in a pre-T cell line. These results demonstrate that MEK1/2 induces TCRγ germline transcription by phosphorylating STAT5 through IL-7R-FFFF and suggest a potential role for MAPK in IL-7R tyrosine-independent activation of STAT5.
The Anti-Apoptotic Bcl-2 Family Member Mcl-1 Promotes T Lymphocyte Survival at Multiple Stages
Authors: Dzhagalov Ivan , Dunkle Alexis , He You-Wen 
Published: April 2014

Abstract
T lymphocyte development and function are tightly regulated by the intrinsic death pathway through members of the Bcl-2 family. Genetic studies have demonstrated that the Bcl-2 family member Mcl-1 is an important anti-apoptotic protein in the development of multiple cell types including T lymphocytes. However, the expression pattern and anti-apoptotic roles of Mcl-1 in T lymphocytes at different developmental stages remain to be fully determined. In this study, we examined the expression pattern of Mcl-1 in different populations of T cells at the single-cell level and found that Mcl-1 protein is constitutively expressed in all T cell populations and up-regulated upon TCR stimulation. We then investigated the role of Mcl-1 in the survival of these different populations by conditionally deleting Mcl-1 at various T cell stages. Our results show that Mcl-1 is required for the survival of double-negative and single-positive thymocytes as well as naive and activated T cells. Furthermore, we demonstrate that Mcl-1 functions together with Bcl-xL to promote double-positive thymocyte survival. Thus, Mcl-1 is a critical anti-apoptotic factor for the survival of T cells at multiple stages in vivo.
IFN-α/β Signaling Is Required for Polarization of Cytokine Responses toward a Protective Type 1 Pattern during Experimental Cryptococcosis
Authors: Biondo Carmelo , Midiri Angelina , Gambuzza Maria , Gerace Elisabetta , Falduto Maria , Galbo Roberta , Bellantoni Antonella , Beninati Concetta , Teti Giuseppe , Leanderson Tomas , Mancuso Giuseppe 
Published: April 2014

Abstract
The antiviral activities of type I IFNs have long been established. However, comparatively little is known of their role in defenses against nonviral pathogens. We examined here the effects of type I IFNs on host resistance against the model pathogenic yeast Cryptococcus neoformans. After intratracheal or i.v. challenge with this fungus, most mice lacking either the IFN-α/β receptor (IFN-α/βR) or IFN-β died from unrestrained pneumonia and encephalitis, while all wild-type controls survived. The pulmonary immune response of IFN-α/βR−/− mice was characterized by increased expression of IL-4, IL-13, and IL-10, decreased expression of TNF-α, IFN-γ, inducible NO synthetase, and CXCL10, and similar levels of IL-12 mRNA, compared with wild-type controls. Histopathological analysis showed eosinophilic infiltrates in the lungs of IFN-α/βR−/− mice, although this change was less extensive than that observed in similarly infected IFN-γR-deficient animals. Type I IFN responses could not be detected in the lung after intratracheal challenge. However, small, but statistically significant, elevations in IFN-β levels were measured in the supernatants of bone marrow-derived macrophages or dendritic cells infected with C. neoformans. Our data demonstrate that type I IFN signaling is required for polarization of cytokine responses toward a protective type I pattern during cryptococcal infection.
IL-1β-Driven ST2L Expression Promotes Maturation Resistance in Rapamycin-Conditioned Dendritic Cells
Authors: Turnquist Hēth R. , Sumpter Tina L. , Tsung Allan , Zahorchak Alan F. , Nakao Atsunori , Nau Gerard J. , Liew Foo Y. , Geller David A. , Thomson Angus W. 
Published: April 2014

Abstract
Maturation resistance and tolerogenic properties can be conferred on human and murine dendritic cells (DC), crucial regulators of T cell responses, by exposure to rapamycin (RAPA), a “tolerance-sparing” immunosuppressive agent. Mechanisms underlying this acquired unresponsiveness, typified by diminished functional responses to TLR or CD40 ligation, have not been identified. We report that in vitro and in vivo conditioning of murine myeloid DC with RAPA elicits the de novo production of IL-1β by otherwise phenotypically immature DC. Interestingly, IL-1β production promotes overexpression of the transmembrane form of the IL-1R family member, IL-1R-like 1, also know as ST2 on RAPA-conditioned DC (RAPA-DC). ST2 is the recently identified receptor for IL-33, a cytokine favoring Th2 responses. In addition, transmembrane ST2, or ST2L, has been implicated as a potent negative regulator of TLR signaling. RAPA-DC generated from ST2−/− mice exhibited higher levels of costimulatory molecules (CD86) than wild-type RAPA-DC. Consistent with its regulatory function, IL-1β-induced ST2L expression suppressed the responsiveness of RAPA-DC to TLR or CD40 ligation. Thus, as a result of their de novo production of IL-1β, RAPA-DC up-regulate ST2L and become refractory to proinflammatory, maturation-inducing stimuli. This work identifies a novel mechanism through which a clinically important immunosuppressant impedes the capacity of DC to mature and consequently stimulate effector/adaptive T cell responses.
Macrophage Dysfunction and Susceptibility to Pulmonary Pseudomonas aeruginosa Infection in Surfactant Protein C-Deficient Mice
Authors: Glasser Stephan W. , Senft Albert P. , Whitsett Jeffrey A. , Maxfield Melissa D. , Ross Gary F. , Richardson Theresa R. , Prows Daniel R. , Xu Yan , Korfhagen Thomas R. 
Published: April 2014

Abstract
To determine the role of surfactant protein C (SP-C) in host defense, SP-C-deficient (Sftpc−/−) mice were infected with the pulmonary pathogen Pseudomonas aeruginosa by intratracheal injection. Survival of young, postnatal day 14 Sftpc−/− mice was decreased in comparison to Sftpc+/+ mice. The sensitivity to Pseudomonas bacteria was specific to the 129S6 strain of Sftpc−/− mice, a strain that spontaneously develops interstitial lung disease-like lung pathology with age. Pulmonary bacterial load and leukocyte infiltration were increased in the lungs of Sftpc−/− mice 24 h after infection. Early influx of polymorphonuclear leukocytes in the lungs of uninfected newborn Sftpc−/− mice relative to Sftpc+/+ mice indicate that the lack of SP-C promotes proinflammatory responses in the lung. Mucin expression, as indicated by Alcian blue staining, was increased in the airways of Sftpc−/− mice following infection. Phagocytic activity of alveolar macrophages from Sftpc−/− mice was reduced. The uptake of fluorescent beads in vitro and the number of bacteria phagocytosed by alveolar macrophages in vivo was decreased in the Sftpc−/− mice. Alveolar macrophages from Sftpc−/− mice expressed markers of alternative activation that are associated with diminished pathogen response and advancing pulmonary fibrosis. These findings implicate SP-C as a modifier of alveolar homeostasis. SP-C plays an important role in innate host defense of the lung, enhancing macrophage-mediated Pseudomonas phagocytosis, clearance and limiting pulmonary inflammatory responses.
IL-8 as Antibody Therapeutic Target in Inflammatory Diseases: Reduction of Clinical Activity in Palmoplantar Pustulosis
Authors: Skov Lone , Beurskens Frank J. , Zachariae Claus O. C. , Reitamo Sakari , Teeling Jessica , Satijn David , Knudsen Kim M. , Boot Elmieke P. J. , Hudson Debra , Baadsgaard Ole , Parren Paul W. H. I. , van de Winkel Jan G. J. 
Published: April 2014

Abstract
IL-8 is a chemokine that has been implicated in a number of inflammatory diseases involving neutrophil activation. HuMab 10F8 is a novel fully human mAb against IL-8, which binds a discontinuous epitope on IL-8 overlapping the receptor binding site, and which effectively neutralizes IL-8-dependent human neutrophil activation and migration. We investigated whether interference in the cytokine network by HuMab 10F8 might benefit patients suffering from palmoplantar pustulosis, a chronic inflammatory skin disease. Treatment of patients with HuMab 10F8 was well tolerated and significantly reduced clinical disease activity at all five endpoints, which included a ≥50% reduction in the formation of fresh pustules. IL-8 neutralization was monitored at the site of inflammation by assessing exudates of palmoplantar pustulosis lesions. HuMab 10F8 sequestered IL-8 in situ, as observed by rapid dose-dependent decreases of IL-8 concentrations immediately following Ab infusion. These data demonstrate a critical role for IL-8 in the pathophysiology of palmoplantar pustulosis. HuMab 10F8 is capable of interrupting IL-8 activity in vivo and represents a candidate for treatment of inflammatory diseases and other pathological conditions associated with IL-8 overproduction.