bluuebunny/crossref_metadata_2025_split huggingface dataset:
Repression of Bleomycin-Induced Pneumopathy by TNF
Authors: Kuroki Misuzu , Noguchi Yuji , Shimono Michihide , Tomono Kazunori , Tashiro Takayoshi , Obata Yuichi , Nakayama Eiichi , Kohno Shigeru 
Published: April 2014

Abstract
Idiopathic pulmonary fibrosis is a chronic inflammatory lung disease with interstitial fibrosis. As a potent proinflammatory cytokine, TNF has been suggested to play critical roles in the pathogenesis of the human disease and its animal model, bleomycin-induced pneumopathy. However, studies using TNF-deficient mice have demonstrated that TNF also has an anti-inflammatory function. To determine the role of TNF in pulmonary inflammation induced by bleomycin, we injected bleomycin intratracheally into TNF-deficient mice. In this study, we demonstrated persistent and intense inflammation in TNF-deficient mice due to reduced apoptosis of inflammatory cells. We also showed that in TNF-deficient mice, challenge via airways with murine, but not human rTNF, efficiently eliminated inflammatory cells from the bronchoalveolar space by apoptosis, and thus promoted tissue repair of damaged lungs. Contrary to previous reports that showed that TNF was a central mediator of pulmonary inflammation, we have demonstrated that TNF is essential for repressing pulmonary inflammation in bleomycin-induced pneumopathy.
By IL-1 Signaling, Monocyte-Derived Cells Dramatically Enhance the Epidermal Antimicrobial Response to Lipopolysaccharide
Authors: Liu Lide , Roberts Alice A. , Ganz Tomas 
Published: April 2014

Abstract
Epithelia react to microbial pathogens by mounting a defensive response that includes the production of antimicrobial peptides. In this study, we show that, in human epidermal cultures, Escherichia coli LPS was a very weak direct inducer of human β-defensin (HBD)-2 mRNA and peptide, but the induction was greatly amplified when monocyte-derived cells (MoDeC) acted as intermediaries between LPS and the epidermis. IL-1R antagonist largely reversed the effect of MoDeC on epidermal HBD-2, indicating that, from among the many products of MoDeC, IL-1 was the dominant inducer of HBD-2 synthesis. In normal fresh human skin, which contains Langerhans cells and other myeloid cell types, in addition to keratinocytes, LPS also induced HBD-2 in an IL-1-dependent manner. In DNA microarray expression studies, HBD-2 was one of the most abundant mRNAs induced in epidermis by LPS-treated MoDeC, and its induction was reversed by IL-1Ra. Thus, epidermal response to LPS is potently amplified by MoDeC through IL-1-mediated signaling, leading to a selective increase in the synthesis of the antimicrobial peptide HBD-2. This pattern of responses establishes a key role for both IL-1 and HBD-2 in the host defense reaction of the epidermis.
Absence of IL-4 Facilitates the Development of Chronic Autoimmune Myasthenia Gravis in C57BL/6 Mice
Authors: Ostlie Norma , Milani Monica , Wang Wei , Okita David , Conti-Fine Bianca M. 
Published: April 2014

Abstract
Myasthenia gravis (MG) is a T cell-dependent, Ab-mediated autoimmune disease. Ab against muscle acetylcholine receptor (AChR) cause the muscular weakness that characterizes MG and its animal model, experimental MG (EMG). EMG is induced in C57BL6 (B6) mice by three injections of Torpedo AChR (TAChR) in adjuvant. B6 mice develop anti-TAChR Ab that cross-react with mouse muscle AChR, but their CD4+ T cells do not cross-react with mouse AChR sequences. Moreover, murine EMG is not self-maintaining as is human MG, and it has limited duration. Several studies suggest that IL-4 has a protecting function in EMG. Here we show that B6 mice genetically deficient in IL-4 (IL-4−/−) develop long-lasting muscle weakness after a single immunization with TAChR. They develop chronic self-reactive Ab, and their CD4+ T cells respond not only to the TAChR and TAChR α subunit peptides, but also to several mouse AChR α subunit peptides. These results suggest that in B6 mice, regulatory mechanisms that involve IL-4 contribute to preventing the development of a chronic Ab-mediated autoimmune response to the AChR.
IL-4-Producing CD8+ T Cells with a CD62L++(bright) Phenotype Accumulate in a Subgroup of Older Adults and Are Associated with the Maintenance of Intact Humoral Immunity in Old Age
Authors: Schwaiger Susanne , Wolf Anna Maria , Robatscher Peter , Jenewein Brigitte , Grubeck-Loebenstein Beatrix 
Published: April 2014

Abstract
An increased production of proinflammatory cytokines occurs in a high percentage of elderly persons and is associated with an impaired humoral immune response. However, high IL-4 production has also been observed in old age. We now demonstrate an IL-4-producing subpopulation of CD8+ T cells in a subgroup of healthy older adults. This T cell subset is substantial in size and has a characteristic phenotype expressing CD45RO, CD28, CD62L, and CD25. IL-4-producing CD8+ T cells produce large amounts of IL-2 but not IFN-γ or perforin, and these cells do not have a regulatory suppressive effect on other T cells. In vivo IL-4-producing CD8+ T cells can be stably detected over a year. When put into culture they also have a stable cytokine production pattern but fail to produce perforin even in the presence of IL-12. This special T cell type does not occur in persons under the age of 40, but is present in 36% of the persons &gt;60 years of age. In this age group, IL-4-producing CD8+ T cells are more frequent in persons who are still capable of raising a humoral immune response following immunization than in others who fail to produce protective Abs after vaccination. Our results suggest that CD8+ T cells with a CD62L++(bright) phenotype accumulate in a subgroup of older adults. Due to their phenotype that enables them to migrate into lymphoid tissues and to their capacity to produce IL-4, these cells may counterbalance the overproduction of proinflammatory cytokines in old age.
Intracellular Calcium Waves Accompany Neutrophil Polarization, Formylmethionylleucylphenylalanine Stimulation, and Phagocytosis: A High Speed Microscopy Study
Authors: Kindzelskii Andrei L. , Petty Howard R. 
Published: April 2014

Abstract
Using high sensitivity fluorescence imaging with shutter speeds ∼600,000 times faster than those of video frames, we have characterized Ca2+ waves within cells in exquisite detail to reveal Ca2+ signaling routes. Polarized neutrophils exhibited a counterclockwise rotating ryanodine-sensitive juxtamembrane Ca2+ wave during temporal calcium spikes. During stimulation with fMLP, a chemotactic factor, two Ca2+ waves traveling in opposite directions around the perimeter of the cell emanated from sites of stimulation (the clockwise wave is verapamil sensitive). Phagocytosed targets exhibit counterclockwise Ca2+ waves traveling about their periphery originating from the plasma membrane. This study: 1) outlines the technology to observe Ca2+ signaling circuitry within small living cells; 2) shows that extracellular spatial information in the form of a chemotactic factor gradient is transduced into intracellular chemical patterns, which provides fresh insights in signaling; 3) suggests that a line of communication exits between the cell surface and phagosomes; and 4) suggests that spatiotemporal Ca2+ patterns contribute to drug actions.
Established T Cell-Driven Germinal Center B Cell Proliferation Is Independent of CD28 Signaling but Is Tightly Regulated Through CTLA-4
Authors: Walker Lucy S. K. , Wiggett Helen E. , Gaspal Fabrina M. C. , Raykundalia Chandra R. , Goodall Margaret D. , Toellner Kai-Michael , Lane Peter J. L. 
Published: April 2014

Abstract
CD4 T cell activation is positively (CD28) and negatively (CTLA-4) regulated by the costimulatory ligands CD80 and CD86. A central question is how the balance between these two opposing forces is controlled as T cells differentiate. We have previously shown that CD28 signaling is absolutely required to prime naive CD4 T cells to differentiate into effectors that provide help for germinal centers and class-switched Ab responses. In this study, we show that the requirement for CD28 signaling is transient and effector CD4 T cells do not require CD28 signals to sustain their function. The CD28 independence of effector T cells within germinal centers suggested that a key function for CD80/CD86 under these circumstances might be to provide negative regulatory signals via the CD28 homologue CTLA-4. By examining germinal center responses in mice where the ability to signal through T cell CTLA-4 was compromised, we provide data that supports a critical role for CTLA-4 in down-regulating T cell help for germinal center B cells.
Cutting Edge: The NK Cell Receptor 2B4 Augments Antigen-Specific T Cell Cytotoxicity Through CD48 Ligation on Neighboring T Cells
Authors: Lee Kyung-Mi , Bhawan Sadhna , Majima Takashi , Wei Hairong , Nishimura Michael I. , Yagita Hideo , Kumar Vinay 
Published: April 2014

Abstract2B4 is expressed on all NK and a subset of memory/effector CD8+ T cells. 2B4 binds to CD48 and activates NK cytotoxicity, but its function on CD8+ T cells is not clear. Furthermore, two isoforms of 2B4 (2B4S and 2B4L) exist in mice but the role of individual isoforms is not known. To address these questions, we generated primary T cell cultures from Ld-specific 2C/Rag2−/− TCR transgenic mice and transduced them with 2B4S or 2B4L. 2B4S- or 2B4L-transduced T cells showed greater cytotoxicity over control cells against CD48+ and CD48− targets, suggesting that ligation of 2B4 by CD48 on target cells was not necessary for 2B4 function. Rather, 2B4/CD48 interaction on adjacent T cells appeared to be critical for cytotoxicity. Therefore, 2B4 functions as a costimulator of CD8+ T cells in MHC-restricted cytotoxicity. We conclude that 2B4/CD48 interactions among T cells themselves can augment CTL lysis of their specific targets.
Cutting Edge: Role of IL-27/WSX-1 Signaling for Induction of T-Bet Through Activation of STAT1 During Initial Th1 Commitment
Authors: Takeda Atsunobu , Hamano Shinjiro , Yamanaka Atsushi , Hanada Toshikatsu , Ishibashi Tatsuro , Mak Tak W. , Yoshimura Akihiko , Yoshida Hiroki 
Published: April 2014

Abstract
WSX-1 is a member of the class I cytokine receptor family with homology to IL-12Rβ2 and is essential for the initial mounting of Th1 responses. STAT1 interacts with tyrosine-phosphorylated WSX-1, and the conserved tyrosine residue of the cytoplasmic domain of WSX-1 is essential for transcriptional activation of STAT1. IL-27 stimulation induced STAT1 phosphorylation in wild-type but not in WSX-1-deficient naive CD4+ T cells. Although IL-27 did not directly induce IFN-γ production by wild-type CD4+ T cells, IL-12-dependent IFN-γ production was augmented by IL-27 stimulation in wild-type naive CD4+ T cells but was impaired in WSX-1-deficient naive CD4+ T cells. Additionally, IL-27 stimulation induced T-bet and IL-12Rβ2 expression in wild-type, but not in WSX-1-deficient, CD4+ T cells. Thus, during the initiation of Th1 differentiation, the IL-27/WSX-1 signaling system plays a pivotal role by STAT1-mediated T-bet induction before the IL-12R system.
Cutting Edge: Dependence of TCR Antagonism on Src Homology 2 Domain-Containing Protein Tyrosine Phosphatase Activity
Authors: Kilgore Neely E. , Carter Jenny D. , Lorenz Ulrike , Evavold Brian D. 
Published: April 2014

AbstractThe mechanism by which antagonist peptides inhibit T cell responses is unknown. Mice deficient in Src homology 2 domain-containing protein tyrosine phosphatase (SHP-1) have revealed its importance in the negative regulation of lymphocyte signaling. We investigated a possible role for SHP-1 in T cell antagonism and demonstrate, for the first time, a substantial increase in SHP-1 activity during antagonism of CD4+ T cells. Furthermore, the removal of functional SHP-1 prevents antagonism in these cells. Our data demonstrate that T cell antagonism occurs via a negative intracellular signal that is mediated by SHP-1.
Environmental Chemical-Induced Pro/Pre-B Cell Apoptosis: Analysis of c-Myc, p27Kip1, and p21WAF1 Reveals a Death Pathway Distinct from Clonal Deletion
Authors: Ryu Heui-Young , Mann Koren K. , Schlezinger Jennifer J. , Jensen Brenda , Sherr David H. 
Published: April 2014

Abstract
Polycyclic aromatic hydrocarbons (PAH) are common environmental pollutants that suppress the immune system in part by inducing pro/pre-B cell apoptosis. The PAH-induced death signaling pathway resembles the signaling cascade activated during clonal deletion and modeled by B cell receptor cross-linking or by dexamethasone exposure of immature surface Ig+ B cells in that apoptosis is mediated by NF-κB down-regulation. Because a PAH-induced, clonally nonrestricted deletion of B cells would have important implications for B cell repertoire development, the nature of the PAH-induced intracellular death signal was studied further. Particular emphasis was placed on the roles of growth arrest and c-Myc, p27Kip1, and p21WAF1 expression, because all of these elements contribute to clonal deletion. As in clonal deletion models, and as predicted by the down-regulation of NF-κB, PAH-induced death of pro/pre-B cells was at least partially dependent on c-Myc down-regulation. Furthermore, whereas dexamethasone induced a G0/G1 cell cycle arrest, PAH had no effect on pro/pre-B cell growth, indicating that growth arrest and apoptosis occur by separable signaling pathways in this early phase of B cell development. Finally, in contrast to clonal deletion, PAH-induced pro/pre-B cell death was not dependent on p27Kip1 or p21WAF1 up-regulation but did coincide with p53 induction. These results distinguish the PAH-induced apoptosis pathway from that activated during clonal deletion and indicate that signaling cascades leading to growth arrest and/or apoptosis in pro/pre-B cells differ from those active at later B cell developmental stages.
Induction of Tumor Cell Apoptosis In Vivo Increases Tumor Antigen Cross-Presentation, Cross-Priming Rather than Cross-Tolerizing Host Tumor-Specific CD8 T Cells
Authors: Nowak Anna K. , Lake Richard A. , Marzo Amanda L. , Scott Bernadette , Heath William R. , Collins Edward J. , Frelinger Jeffrey A. , Robinson Bruce W. S. 
Published: April 2014

AbstractCross-presentation of cell-bound Ags from established, solid tumors to CD8 cells is efficient and likely to have a role in determining host response to tumor. A number of investigators have predicted that when tumor Ags are derived from apoptotic cells either no response, due to Ag “sequestration,” or CD8 cross-tolerance would ensue. Because the crucial issue of whether this happens in vivo has never been addressed, we induced apoptosis of established hemagglutinin (HA)-transfected AB1 tumors in BALB/c mice using the apoptosis-inducing reagent gemcitabine. This shrank the tumor by ∼80%. This induction of apoptosis increased cross-presentation of HA to CD8 cells yet neither gross deletion nor functional tolerance of HA-specific CD8 cells were observed, based on tetramer analysis, proliferation of specific CD8 T cells, and in vivo CTL activity. Interestingly, apoptosis primed the host for a strong antitumor response to a second, virus-generated HA-specific signal in that administration of an HA-expressing virus after gemcitabine administration markedly decreased tumor growth compared with viral administration without gemcitabine. Thus tumor cell apoptosis in vivo neither sequesters tumor Ags nor cross-tolerizes tumor-specific CD8 cells. This observation has fundamental consequences for the development of tumor immunotherapy protocols and for understanding T cell reactivity to tumors and the in vivo immune responses to apoptotic cells.
Two Regions of Down-Regulation in the IgE-Mediated Signaling Pathway in Human Basophils
Authors: MacGlashan Donald 
Published: April 2014

AbstractPrevious studies demonstrated that after stimulation of human basophils with a polyclonal anti-IgE Ab, early signaling elements showed sustained phosphorylation, whereas later elements were transient, suggesting that a region of down-regulation involved inhibition of phosphatidylinositol (PI) 3 kinase or its products. However, the current studies show that under some conditions, syk phosphorylation is transient. Generally, stimulation with a variety of Ags makes this early form of down-regulation more apparent. An exploration of the conditions needed to induce early down-regulation indicates that both the nature of aggregation and the cell surface density of IgE play roles. It was also found that the previously described late form of down-regulation (PI3 kinase product transience) can occur in cells displaying early down-regulation (transient syk phosphorylation), but this phenomenon is revealed by testing for subsequent down-regulation of the response to non-cross-reacting stimuli, altering their ability to induce phosphorylation of Akt or extracellular signal-regulated kinase. In contrast, phosphorylation of syk kinase, in response to a non-cross-reacting stimulus, was relatively unaffected by prior stimulation. The magnitude of cross-desensitization of the Akt or extracellular signal-regulated kinase response was a function of the strength of the first stimulus. Mediator release showed a similar cross-desensitization effect. Therefore, stimulation induces two forms of down-regulation, one operating before or at the level of syk phosphorylation, possibly characterizing the process formerly known as specific desensitization, and one that operates in the region of PI3 kinase, accounting for the process formerly known as nonspecific desensitization, which is dependent on the strength of stimulus.
The Lymphoid Past of Mouse Plasmacytoid Cells and Thymic Dendritic Cells
Authors: Corcoran Lynn , Ferrero Isabel , Vremec David , Lucas Karen , Waithman Jason , O’Keeffe Meredith , Wu Li , Wilson Anne , Shortman Ken 
Published: April 2014

Abstract
There has been controversy over the possible lymphoid origin of certain dendritic cell (DC) subtypes. To resolve this issue, DC and plasmacytoid pre-DC isolated from normal mouse tissues were analyzed for transient (mRNA) and permanent (DNA rearrangement) markers of early stages of lymphoid development. About 27% of the DNA of CD8+ DC from thymus, and 22–35% of the DNA of plasmacytoid pre-DC from spleen and thymus, was found to contain IgH gene D-J rearrangements, compared with 40% for T cells. However, the DC DNA did not contain IgH gene V-D-J rearrangements nor T cell Ag receptor β gene D-J rearrangements. The same DC lineage populations containing IgH D-J rearrangements expressed mRNA for CD3 chains, and for pre-Tα. In contrast, little of the DNA of the conventional DC derived from spleen, lymph nodes, or skin, whether CD8+ or CD8−, contained IgH D-J rearrangements and splenic conventional DC expressed very little CD3ε or pre-Tα mRNA. Therefore, many plasmacytoid pre-DC and thymic CD8+ DC have shared early steps of development with the lymphoid lineages, and differ in origin from conventional peripheral DC.
Regulation of CD8+ T Cells Undergoing Primary and Secondary Responses to Infection in the Same Host
Authors: Badovinac Vladimir P. , Messingham Kelly A. Nordyke , Hamilton Sara E. , Harty John T. 
Published: April 2014

Abstract
Naive Ag-specific CD8+ T cells expand, contract, and become memory cells after infection and/or vaccination. Memory CD8+ T cells provide faster, more effective secondary responses against repeated exposure to the same pathogen. Using an adoptive transfer system with low numbers of trackable nontransgenic memory CD8+ T cells, we showed that secondary responses can be comprised of both primary (naive) and secondary (memory) CD8+ T cells after bacterial (Listeria monocytogenes) and/or viral (lymphocytic choriomeningitis virus) infections. The level of memory CD8+ T cells present at the time of infection inversely correlated with the magnitude of primary CD8+ T cell responses against the same epitope but directly correlated with the level of protection against infection. However, similar numbers of Ag-specific CD8+ T cells were found 8 days postinfection no matter how many memory cells were present at the time of infection. Rapid contraction of primary CD8+ T cell responses was not influenced by the presence of memory CD8+ T cells. However, contraction of secondary CD8+ T cell responses was markedly prolonged compared with primary responses in the same host mice. This situation occurred in response to lymphocytic choriomeningitis virus or L. monocytogenes infection and for CD8+ T cell responses against multiple epitopes. The delayed contraction of secondary CD8+ T cells was also observed after immunization with peptide-coated dendritic cells. Together, the results show that the level of memory CD8+ T cells influences protective immunity and activation of naive precursors specific for the same epitope but has little impact on the magnitude or program of the CD8+ T cell response.
Prostaglandin D2 Affects the Maturation of Human Monocyte-Derived Dendritic Cells: Consequence on the Polarization of Naive Th Cells
Authors: Gosset Philippe , Bureau Fabrice , Angeli Veronique , Pichavant Muriel , Faveeuw Christelle , Tonnel André-Bernard , Trottein François 
Published: April 2014

AbstractAmong the factors produced at inflammatory sites and those capable of modulating dendritic cell (DC) functions, PGD2 may be important in the outcome of immune responses. The biological roles for PGD2 are in part effected through two plasma membrane G protein-coupled receptors: the D prostanoid (DP) receptor and the chemoattractant receptor-homologous molecule expressed on Th2 lymphocytes (CRTH2). In this report, we studied the effects of PGD2 and of its major physiological metabolite, 15-deoxy-Δ12,14-PGJ2 (15d-PGJ2), on the functions of human monocyte-derived DC. First, we show that PGD2 exerts in vitro chemotactic effects on monocytes via CRTH2 activation while it inhibits the chemokine-driven migration of monocyte-derived DC through DP. We also report that PGD2 and 15d-PGJ2 alter the LPS- and allergen-induced DC maturation and enhance the CD80/CD86 ratio on mature DC in a DP- and CRTH2-independent manner. Moreover, PGD2 and 15d-PGJ2 strongly reduce the secretion of the Th1 promoting cytokine IL-12 and affect the synthesis of chemokines involved in Th1 cell chemotaxis, particularly CXCL10. Inhibition of cytokine/chemokine secretion implicates at least in part DP, but not CRTH2. The effects exerted by PGD2 are associated with the phosphorylation of CREB, but do not parallel with the deactivation of the NF-κB and mitogen-activated protein kinase pathways. In contrast, 15d-PGJ2 seems to target other cellular proteins. Finally, in a model of Th CD45RA+ differentiation induced by allergen- and superantigen-pulsed DC, PGD2 impacts on the orientation of the immune response by favoring a Th2 response.