bluuebunny/crossref_metadata_2025_split huggingface dataset:
Tolerogenic APC Generate CD8+ T Regulatory Cells That Modulate Pulmonary Interstitial Fibrosis
Authors: Zhang-Hoover Jie , Stein-Streilein Joan 
Published: April 2014

Abstract
Transforming growth factor-β2-treated Ag-pulsed APC mimic APC from the immune privileged eye, and provide signals that generate regulatory T (Tr) cells and mediate peripheral tolerance. We postulated that TGF-β2-treated Ag-pulsed APC (tolerogenic APC (tol-APC)) might also orchestrate regulation of immune mediated pathogenesis in nonimmune privileged tissues such as the lung. We used an adoptive transfer model of autoimmune pulmonary interstitial fibrosis called hapten immune pulmonary interstitial fibrosis (ADT-HIPIF) in this study. Mice that received 2,4,6-trinitrobenzene sulfonic acid-sensitized cells and challenged (intratracheally) with the hapten developed pulmonary interstitial fibrosis. However, transfer (i.v.) of TGF-β2-treated 2,4,6-trinitrobenzene sulfonic acid-pulsed bone marrow-derived APC (tol-APC) to experimental mice 1 day after intratracheal challenge reduced the collagen deposition in the interstitium of the lung that usually follows challenge. Furthermore, ADT-HIPIF mice that received tol-APC developed Ag-specific efferent CD8+ Tr cells. Adoptive transfer of the Tr cells to another set of presensitized mice mediated suppression of the efferent phase of Th1 immune response and the subsequent immune dependent pulmonary interstitial fibrosis. Thus, tol-APC induced efferent CD8+ Tr cells in immune mice, and the regulation of the immune response limited the development of autoimmune pulmonary fibrosis in sensitized and pulmonary-challenged mice. Because ADT-HIPIF shares etiological and pathological characteristics with a variety of human immune inflammatory conditions in the lung that eventuate into interstitial fibrosis, these studies provide insight into potential therapy to alter the course of pulmonary fibrosis in humans.
Essential Contribution of Monocyte Chemoattractant Protein-1/C-C Chemokine Ligand-2 to Resolution and Repair Processes in Acute Bacterial Pneumonia
Authors: Amano Hideaki , Morimoto Kounosuke , Senba Masachika , Wang Hui , Ishida Yuko , Kumatori Atsushi , Yoshimine Hiroyuki , Oishi Kazunori , Mukaida Naofumi , Nagatake Tsuyoshi 
Published: April 2014

Abstract
Neutrophil infiltration is the first step in eradication of bacterial infection, but neutrophils rapidly die after killing bacteria. Subsequent accumulation of macrophage lineage cells, such as alveolar macrophages (AMs), is essential to remove dying neutrophils, which are a source of injurious substances. Macrophage lineage cells can promote tissue repair, by producing potential growth factors including hepatocyte growth factor (HGF). However, it remains elusive which factor activates macrophage in these processes. Intratracheal instillation of Pseudomonas aeruginosa caused neutrophil infiltration in the airspace; subsequently, the numbers of total AMs and neutrophil ingested AMs were increased. Bronchoalveolar lavage (BAL) fluid levels of monocyte chemoattractant protein (MCP)-1/CC chemokine ligand-2 (CCL2), a potent macrophage-activating factor, were increased before the increases in the number of AM ingesting neutrophils and HGF levels in BAL fluid. Immunoreactive MCP-1 proteins were detected in alveolar type II epithelial cells and AMs only after P. aeruginosa infection. The administration of anti-MCP-1/CCL2 Abs reduced the increases in the number of AM-ingesting neutrophils and HGF levels in BAL fluid, and eventually aggravated lung tissue injury. In contrast, the administration of MCP-1/CCL2 enhanced the increases in the number of AM ingesting neutrophils and HGF levels in BAL fluid, and eventually attenuated lung tissue injury. Furthermore, MCP-1/CCL2 enhanced the ingestion of apoptotic neutrophils and HGF production by a mouse macrophage cell line, RAW 267.4, in a dose-dependent manner. Collectively, MCP-1/CCL2 has a crucial role in the resolution and repair processes of acute bacterial pneumonia by enhancing the removal of dying neutrophils and HGF production by AMs
Cytoskeletal Reorganization Internalizes Multiple Transient Receptor Potential Channels and Blocks Calcium Entry into Human Neutrophils
Authors: Itagaki Kiyoshi , Kannan Kolenkode B. , Singh Brij B. , Hauser Carl J. 
Published: April 2014

Abstract
Store-operated calcium entry (SOCE) is required for polymorphonuclear neutrophil (PMN) activation in response to G protein-coupled agonists. Some immunocytes express proteins homologous to the Drosophila transient receptor potential gene (trp) calcium channel. TRP proteins assemble into heterotetrameric ion channels and are known to support SOCE in overexpression systems, but the evidence that TRP proteins support SOCE and are functionally important in wild-type cells remains indirect. We therefore studied the expression and function of TRP proteins in primary human PMN. TRPC1, TRPC3, TRPC4, and TRPC6 were all expressed as mRNA as well as membrane proteins. Immunofluorescence microscopy demonstrated localization of TRPC1, TRPC3, and TRPC4 to the PMN cell membrane and their internalization after cytoskeletal reorganization by calyculin A (CalyA). Either TRPC internalization by CalyA or treatment with the inositol triphosphate receptor inhibitor 2-aminoethoxydiphenyl borane resulted in the loss of PMN SOCE. Cytochalasin D (CytoD) disrupts actin filaments, thus preventing cytoskeletal reorganization, and pretreatment with CytoD rescued PMN SOCE from inhibition by CalyA. Comparative studies of CytoD and 2-aminoethoxydiphenyl borane inhibition of PMN cationic entry after thapsigargin or platelet-activating factor suggested that SOCE occurs through both calcium-specific and nonspecific pathways. Taken together, these studies suggest that the multiple TRPC proteins expressed by human PMN participate in the formation of at least two store-operated calcium channels that have differing ionic permeabilities and regulatory characteristics.
Cutting Edge: C3d Functions as a Molecular Adjuvant in the Absence of CD21/35 Expression
Authors: Haas Karen M. , Toapanta Franklin R. , Oliver Julie A. , Poe Jonathan C. , Weis John H. , Karp David R. , Bower Joseph F. , Ross Ted M. , Tedder Thomas F. 
Published: April 2014

Abstract
Complement component C3 covalently attaches to Ags following activation, where the C3d cleavage fragment can function as a molecular adjuvant to augment humoral immune responses. C3d is proposed to exert its adjuvant-like activities by targeting Ags to the C3d receptor (CD21/35) expressed by B cells and follicular dendritic cells. To directly assess the importance of CD21/35 in mediating the immunostimulatory effects of C3d, CD21/35-deficient (CD21/35−/−) mice were immunized with streptavidin (SA), SA-C3dg tetramers, recombinant HIV gp120 (gp120), or gp120 fused with linear multimers of C3d. Remarkably, SA- and gp120-specific Ab responses were significantly augmented in CD21/35−/− mice when these Ags were complexed with C3d in comparison to Ag alone. In fact, primary and secondary Ab responses and Ab-forming cell responses of CD21/35−/− mice approached those of wild-type mice immunized with SA-C3dg and gp120-C3d. Thus, C3d can function as a molecular adjuvant in the absence of CD21/35 expression.
Depletion of CD8+ Cells Abolishes the Pregnancy Protective Effect of Progesterone Substitution with Dydrogesterone in Mice by Altering the Th1/Th2 Cytokine Profile
Authors: Blois Sandra M. , Joachim Ricarda , Kandil Judith , Margni Ricardo , Tometten Mareike , Klapp Burghard F. , Arck Petra C. 
Published: April 2014

AbstractOne of the most remarkable immunological regulations is the maternal immune tolerance toward the fetal semiallograft during pregnancy, which has been referred to as immunity’s pregnant pause. Rejection of the semiallogeneic trophoblast cells must be selectively inhibited and pathways presumably include Th2 cytokines unopposed by Th1 cytokines. Steroid hormones, including progesterone, have similar effects. Low levels of progesterone and Th2 cytokines and high levels of Th1 cytokines are attributable for increased abortions in mammalians, which may be triggered by psychoemotional stress. Thus, the aim of the present study was to provide experimental evidence for the mechanism involved in the mediation of immune responses by endocrine signals during pregnancy and stress-triggered pregnancy failure. DBA/2J-mated CBA/J female mice were randomized in three groups: 1) control females, 2) mice exposed to stress on gestation day 5.5, and 3) mice exposed to stress and substituted with dydrogesterone, a progestogen with a binding profile highly selective for the progesterone receptor on gestation day 5.5. On gestation days 7.5, 9.5, and 10.5, mice of each group were sacrificed, and the frequency of CD8+ cells and cytokine expression (IL-4, IL-12, TNF-α, IFN-γ) in blood and uterus cells was evaluated by flow cytometry. Additionally, some mice were depleted of CD8 cells by injection of mAb. We observed that progesterone substitution abrogated the abortogenic effects of stress exposure by decreasing the frequency of abortogenic cytokines. This pathway was exceedingly CD8-dependent, because depletion of CD8 led to a termination of the pregnancy protective effect of progesterone substitution.
Heart, but Not Skin, Allografts from Donors Lacking Flt3 Ligand Exhibit Markedly Prolonged Survival Time
Authors: Wang Zhiliang , Castellaneta Antonino , De Creus An , Shufesky William J. , Morelli Adrian E. , Thomson Angus W. 
Published: April 2014

Abstract
Fms-like tyrosine kinase 3 ligand (Flt3L) administration leads to dramatic increases in dendritic cells (DC) in lymphoid and nonlymphoid tissues. Conversely, mice lacking Flt3L (Flt3L−/−) show severe reductions in both myeloid (CD11c+CD8α−) and lymphoid-related DC (CD11c+CD8α+) in the thymus and secondary lymphoid organs. In this study marked reductions in CD11c+ interstitial cardiac DC and in dermal, but not epidermal, DC (Langerhans cells) were also observed. CD11c+ cells that migrated from Flt3L−/− skin explants expressed lower surface MHC class II and costimulatory molecules and naive T cell allostimulatory activity than migratory wild-type (wt) C57BL/6 (B6) CD11c+ cells. We examined the survival of Flt3L−/− heart or tail skin grafts (H2b) in allogeneic wt (BALB/c; H2d) recipients. The outcome of transplantation of BALB/c organs into Flt3L−/− recipients was also determined. Flt3L−/− mice rejected BALB/c heart or skin grafts with similar kinetics as B6 wt recipients. Trafficking of donor DC into host spleens or draining lymph nodes was markedly reduced after transplantation of Flt3L−/− heart, but not skin grafts, respectively. Compared with wt hearts, survival of Flt3L−/− hearts was markedly prolonged in BALB/c recipients (median survival time, 37 and 15 days, respectively; p &lt; 0.001). Skin graft survival was unaffected. Rejection of Flt3L−/− hearts was precipitated by infusion of wt donor DC at the time of transplant. Thus, severe depletion of interstitial heart DC resulting from targeted gene disruption prolongs, but does not indefinitely extend, heart survival. Acute rejection of wt grafts in Flt3L−/− recipients reflects presumably an intact role of the direct pathway of allorecognition.
IL-10-Secreting Regulatory T Cells Do Not Express Foxp3 but Have Comparable Regulatory Function to Naturally Occurring CD4+CD25+ Regulatory T Cells
Authors: Vieira Pedro L. , Christensen Jillian R. , Minaee Sophie , O’Neill Emma J. , Barrat Franck J. , Boonstra André , Barthlott Thomas , Stockinger Brigitta , Wraith David C. , O’Garra Anne 
Published: April 2014

Abstract
Regulatory T cells (TReg) control immune responses to self and nonself Ags. The relationship between Ag-driven IL-10-secreting TReg (IL-10-TReg) and naturally occurring CD4+CD25+ TReg is as yet unclear. We show that mouse IL-10-TReg obtained using either in vitro or in vivo regimens of antigenic stimulation did not express the CD4+CD25+ TReg-associated transcription factor Foxp3. However, despite the absence of Foxp3 expression, homogeneous populations of IL-10-TReg inhibited the in vitro proliferation of CD4+CD25− T cells with a similar efficiency to that of CD4+CD25+ TReg. This inhibition of T cell proliferation by IL-10-TReg was achieved through an IL-10-independent mechanism as seen for CD4+CD25+ TReg and was overcome by exogenous IL-2. Both IL-10-TReg and CD4+CD25+ TReg were similar in that they produced little to no IL-2. These data show that Foxp3 expression is not a prerequisite for IL-10-TReg activity in vitro or in vivo, and suggest that IL-10-TReg and naturally occurring CD4+CD25+ TReg may have distinct origins.
The Serotoninergic Receptors of Human Dendritic Cells: Identification and Coupling to Cytokine Release
Authors: Idzko Marco , Panther Elisabeth , Stratz Christian , Müller Tobias , Bayer Hannes , Zissel Gernot , Dürk Thorsten , Sorichter Stephan , Di Virgilio Francesco , Geissler Michael , Fiebich Bernd , Herouy Yared , Elsner Peter , Norgauer Johannes , Ferrari Davide 
Published: April 2014

Abstract
The neurotransmitter 5-hydroxytryptamine (5-HT), commonly known as serotonin, is stored at peripheral sites in mast cells and released from this peripheral source upon IgE cross-linking. In this study, we investigated the expression of serotoninergic receptors (5-HTR), the signaling pathway, and biological activity of 5-HT on human dendritic cells (DC), showing that immature and mature DC expressed mRNA for different serotoninergic receptors. Thereby, the mRNA of 5-HTR1B, 5-HTR1E, 5-HTR2A, 5-HTR2B, one splicing variant of the 5-HTR3, 5-HTR4, and 5-HTR7 receptors were detected. Immature DC preferentially expressed mRNA for the heptahelical 5-HTR1B, 5-HTR1E, and 5-HTR2B receptors, while mature DC mostly expressed 5-HTR4 and 5-HTR7. The mRNA expression level of the ligand-gated cation channel 5-HTR3 and the heptahelical 5-HTR2A did not significantly change during maturation. Isotype-selective receptor agonists allowed us to show that 5-HT stimulated 5-HTR3-dependent Ca2+ influx in immature and mature DC. Moreover, we revealed that 5-HTR1 and 5-HTR2 receptor stimulation induced intracellular Ca2+ mobilization via Gi/o proteins in immature, but not mature, DC. Activation of 5-HTR4 and 5-HTR7 induced cAMP elevation in mature DC. Functional studies indicated that activation of 5-HTR4 and 5-HTR7 enhanced the release of the cytokines IL-1β and IL-8, while reducing the secretion of IL-12 and TNF-α in mature DC. In summary, our study shows that 5-HT stimulated, in a maturation-dependent manner, different signaling pathways in DC. These data point to a role for 5-HT in regulating the immune response at peripheral sites.
The Role of the p38 Mitogen-Activated Protein Kinase, Extracellular Signal-Regulated Kinase, and Phosphoinositide-3-OH Kinase Signal Transduction Pathways in CD40 Ligand-Induced Dendritic Cell Activation and Expansion of Virus-Specific CD8+ T Cell Memory Responses
Authors: Yu Qigui , Kovacs Colin , Yue Feng Yun , Ostrowski Mario A. 
Published: April 2014

AbstractMature dendritic cells (DCs) are central to the development of optimal T cell immune responses. CD40 ligand (CD40L, CD154) is one of the most potent maturation stimuli for immature DCs. We studied the role of three signaling pathways, p38 mitogen-activated protein kinase (MAPK), extracellular signal-regulated kinase (ERK), and phosphoinositide-3-OH kinase (PI3K), in CD40L-induced monocyte-derived DC activation, survival, and expansion of virus-specific CD8+ T cell responses. p38 MAPK pathway was critical for CD40L-mediated up-regulation of CD83, a marker of DC maturation. CD40L-induced monocyte-derived DC IL-12 production was mediated by both the p38 MAPK and PI3K pathways. CD40L-mediated DC survival was mostly mediated by the PI3K pathway, with smaller contributions by p38 MAPK and ERK pathways. Finally, the p38 MAPK pathway was most important in mediating CD40L-stimulated DCs to induce strong allogeneic responses as well as expanding virus-specific memory CD8+ T cell responses. Thus, although the p38 MAPK, PI3K, and ERK pathways independently affect various parameters of DC maturation induced by CD40L, the p38 MAPK pathway within CD40L-conditioned DCs is the most important pathway to maximally elicit T cell immune responses. This pathway should be exploited in vivo to either completely suppress or enhance CD8+ T cell immune responses.
Restoration of NK T Cell Development infyn-Mutant Mice by a TCR Reveals a Requirement for Fyn During Early NK T Cell Ontogeny
Authors: Gadue Paul , Yin Liqun , Jain Sumesh , Stein Paul L. 
Published: April 2014

AbstractNK T cells are a unique lymphocyte population that have developmental requirements distinct from conventional T cells. Mice lacking the tyrosine kinase Fyn have 5- to 10-fold fewer mature NK T cells. This study shows that Fyn-deficient mice have decreased numbers of NK1.1− NK T cell progenitors as well. 5-Bromo-2′-deoxyuridine-labeling studies indicate that the NK T cells remaining in fyn−/− mice exhibit a similar turnover rate as wild-type cells. The fyn−/− NK T cells respond to α-galactosylceramide, a ligand recognized by NK T cells, and produce cytokines, but have depressed proliferative capacity. Transgenic expression of the NK T cell-specific TCR α-chain Vα14Jα18 leads to a complete restoration of NK T cell numbers in fyn−/− mice. Together, these results suggest that Fyn may have a role before α-chain rearrangement rather than for positive selection or the peripheral upkeep of cell number. NK T cells can activate other lymphoid lineages via cytokine secretion. These secondary responses are impaired in Fyn-deficient mice, but occur normally in fyn mutants expressing the Vα14Jα18 transgene. Because this transgene restores NK T cell numbers, the lack of secondary lymphocyte activation in the fyn-mutant mice is due to the decreased numbers of NK T cells present in the mutant, rather than an intrinsic defect in the ability of the other fyn−/− lymphoid populations to respond.
The Size and Phenotype of Virus-Specific T Cell Populations Is Determined by Repetitive Antigenic Stimulation and Environmental Cytokines
Authors: Gamadia Laila E. , van Leeuwen Ester M. M. , Remmerswaal Ester B. M. , Yong Si-La , Surachno Sugianto , Wertheim-van Dillen Pauline M. E. , ten Berge Ineke J. M. , van Lier René A. W. 
Published: April 2014

Abstract
Based on the expression of the TNFR SFP CD27, two Ag-primed CD8+ T cell subsets can be discerned in the circulation of healthy individuals: CD27+ T cells that produce a variety of cytokines but do not display immediate cytolytic activity; and cytotoxic CD27− T cells, which secrete only IFN-γ and TNF-α. The mechanism that controls the generation of these different phenotypes is unknown. We show that CMV reactivation not only increases the number of virus-specific T cells but also induces their transition from a CD27+ to a CD27− phenotype. In support of a relation between pool size and phenotype in a cohort of latently infected individuals, the number of Ag-specific CD27− CD8+ T cells was found to be linearly related to the total number of CMV-specific CD8+ T cells. In vitro studies revealed that the acquisition of the CD27− phenotype on CMV-specific T cells depended on the interaction of CD27 with its cellular ligand, CD70. Expression of CD70 was proportional to the amount of antigenic stimulation and blocked by the CD4+ T cell-derived cytokine IL-21. Thus, induction of CD70, which may vary in distinct viral infections, appears to be a key factor in determining the size and phenotype of the CMV-specific T cell population in latently infected individuals.
IL-4-Induced GATA-3 Expression Is a Time-Restricted Instruction Switch for Th2 Cell Differentiation
Authors: Seki Noriyasu , Miyazaki Mayumi , Suzuki Wataru , Hayashi Katsuhiko , Arima Kazuhiko , Myburgh Elmarie , Izuhara Kenji , Brombacher Frank , Kubo Masato 
Published: April 2014

AbstractAn initial activation signal via the TCR in a restricted cytokine environment is critical for the onset of Th cell development. Cytokines regulate the expression of key transcriptional factors, T-bet and GATA-3, which instruct the direction of Th1 and Th2 differentiation, through changes in chromatin conformation. In this study, we investigated the kinetics of IL-4-mediated signaling in a transgenic mouse, expressing human IL-4R on a mouse IL-4αR-deficient background. These experiments, allowing induction with human IL-4 at defined times, demonstrated that an IL-4 signal was required at the early stage of TCR-mediated T cell activation for lineage commitment to Th2, along with structural changes in chromatin, which take place in the conserved noncoding sequence-1 and -2 within the IL-4 locus. At later times, however, IL-4 failed to promote efficient Th2 differentiation and decondensation of chromatin, even though GATA-3 was clearly induced in the nuclei by IL-4 stimulation. Moreover, IL-4-mediated Th2 instruction was independent from cell division mediated by initial TCR stimulation. The role of IL-4 signaling may have a time restriction during Th2 differentiation. In late stages of initial T cell activation, the chromatin structure of the IL-4 locus retains condensation state. These results demonstrate that IL-4-induced GATA-3 expression is time-restriction switch for Th2 differentiation.
Mycobacterium tuberculosisInhibits Macrophage Responses to IFN-γ through Myeloid Differentiation Factor 88-Dependent and -Independent Mechanisms
Authors: Fortune Sarah M. , Solache Alejandra , Jaeger Alejandra , Hill Preston J. , Belisle John T. , Bloom Barry R. , Rubin Eric J. , Ernst Joel D. 
Published: April 2014

AbstractMycobacterium tuberculosis overcomes macrophage bactericidal activities and persists intracellularly. One mechanism by which M. tuberculosis avoids macrophage killing might be through inhibition of IFN-γ-mediated signaling. In this study we provide evidence that at least two distinct components of M. tuberculosis, the 19-kDa lipoprotein and cell wall peptidoglycan (contained in the mycolylarabinogalactan peptidoglycan (mAGP) complex), inhibit macrophage responses to IFN-γ at a transcriptional level. Moreover, these components engage distinct proximal signaling pathways to inhibit responses to IFN-γ: the 19-kDa lipoprotein inhibits IFN-γ signaling in a Toll-like receptor (TLR)2-dependent and myeloid differentiation factor 88-dependent fashion whereas mAGP inhibits independently of TLR2, TLR4, and myeloid differentiation factor 88. In addition to inhibiting the induction of specific IFN-γ responsive genes, the 19-kDa lipoprotein and mAGP inhibit the ability of IFN-γ to activate murine macrophages to kill virulent M. tuberculosis without inhibiting production of NO. These results imply that inhibition of macrophage responses to IFN-γ may contribute to the inability of an apparently effective immune response to eradicate M. tuberculosis.