bluuebunny/crossref_metadata_2025_split huggingface dataset:
T Cells in G1 Provide a Memory-Like Response to Secondary Stimulation
Authors: Munitic Ivana , Ryan Philip E. , Ashwell Jonathan D. 
Published: April 2014

Abstract
The commitment of naive T cells to proliferate is a function of the strength and duration of stimuli mediated by the TCR and coreceptors. Ranges of 2–20 h of stimulation have been reported as necessary in vitro. Whether T cells actually experience uninterrupted stimulation for such long periods under physiological conditions is controversial. Here we ask whether commitment to proliferate requires continuous stimulation, or can T cells integrate intermittent periods of stimulation. T cells were stimulated for two short-term (subthreshold) periods (5–7 h) either sequentially or separated by an interval of rest. Naive lymph node T cells were able to integrate interrupted stimulation, even when the duration of rest was as long as 2 days. Furthermore, when short-term-stimulated T cells were separated by density, three populations were observed: low density blasts, intermediate density G1 cells, and high density G0 cells. Low density cells progressed to division without further stimulation, whereas G0 and G1 cells remained undivided. However, after a period of rest, a second subthreshold stimulation caused the G1 but not the G0 fraction to quickly proceed through the cell cycle. We conclude that noncycling T cells in the G1 phase of the cell cycle remain in a state of readiness for prolonged periods of time, and may represent a population of memory-like effectors capable of responding rapidly to antigenic challenge.
IL-15 Activates Telomerase and Minimizes Telomere Loss and May Preserve the Replicative Life Span of Memory CD8+ T Cells In Vitro
Authors: Li Yu , Zhi Wang , Wareski Przemyslaw , Weng Nan-ping 
Published: April 2014

Abstract
The preservation of the replicative life span of memory CD8+ T cells is vital for long-term immune protection. Although IL-15 plays a key role in the homeostasis of memory CD8+ T cells, it is unknown whether IL-15 regulates the replicative life span of memory CD8+ T cells. In this study, we report an analysis of telomerase expression and telomere length in human memory phenotype CD8+ T cells maintained by IL-15 in vitro. We demonstrate that IL-15 is capable of activating telomerase in memory CD8+ T cells via Jak3 and PI3K signaling pathways. Furthermore, IL-15 induces a sustained level of telomerase activity over long periods of time, and in turn minimizes telomere loss in memory CD8+ T cells after substantial cell divisions. These findings suggest that IL-15 activates stable telomerase expression and compensates telomere loss in memory phenotype CD8+ T cells, and that telomerase may play an important role in memory CD8+ T cell homeostasis.
Increased Expression of CD27 on Activated Human Memory B Cells Correlates with Their Commitment to the Plasma Cell Lineage
Authors: Avery Danielle T. , Ellyard Julia I. , Mackay Fabienne , Corcoran Lynn M. , Hodgkin Philip D. , Tangye Stuart G. 
Published: April 2014

AbstractPlasma cells (PC) or Ig-secreting cells (ISC) are terminally differentiated B cells responsible for the production of protective Ig. ISC can be generated in vitro by culturing human B cells with the T cell-derived stimuli CD40L, IL-2, and IL-10. ISC have traditionally been identified by the increased expression of CD38, analogous to primary human PC, and the acquired ability to secrete Ig. By tracking the proliferation history of activated B cells, we previously reported that the differentiation of memory B cells into CD38+ B cells is IL-10 dependent, and increases in frequency with cell division. However, &lt;50% of CD38+ cells secreted Ig, and there was a population of CD38− ISC. Thus, the PC phenotype of CD38+ cells generated in vitro did not correlate with PC function. To address this, we have examined cultures of activated memory B cells to accurately identify the phenotype of ISC generated in vitro. We found that CD27 is also up-regulated on memory B cells in an IL-10-dependent and division-dependent manner, and that ISC segregated into the CD27high subset of activated memory B cells irrespective of the acquired expression of CD38. The ISC generated in these cultures expressed elevated levels of the transcription factors Blimp-1 and X box-binding protein-1 and reduced levels of Pax-5, and exhibited selective migration toward CXCL12, similar to primary PC. We propose that the differentiation of memory B cells into PC involves a transitional stage characterized by a CD27highCD38− phenotype with the acquired ability to secrete high levels of Ig.
An Alternate Core 2 β1,6-N-Acetylglucosaminyltransferase Selectively Contributes to P-Selectin Ligand Formation in Activated CD8 T Cells
Authors: Merzaban Jasmeen S. , Zuccolo Jonathan , Corbel Stéphane Y. , Williams Michael J. , Ziltener Hermann J. 
Published: April 2014

AbstractCore 2 β1,6-N-acetylglucosaminyltransferase (C2GlcNAcT) synthesizes essential core 2 O-glycans on selectin ligands, which mediate cell-cell adhesion required for lymphocyte trafficking. Although gene-deletion studies have implicated C2GlcNAcT-I in controlling selectin ligand-mediated cell trafficking, little is known about the role of the two other core 2 isoenzymes, C2GlcNAcT-II and C2GlcNAcT-III. We show that C2GlcNAcT-I-independent P-selectin ligand formation occurs in activated C2GlcNAcT-Inull CD8 T cells. These CD8 T cells were capable of rolling under shear flow on immobilized P-selectin in a P-selectin glycoprotein ligand 1-dependent manner. RT-PCR analysis identified significant levels of C2GlcNAcT-III RNA, identifying this enzyme as a possible source of core 2 enzyme activity. Up-regulation of P-selectin ligand correlated with altered cell surface binding of the core 2-sensitive mAb 1B11, indicating that CD43 and CD45 are also physiological targets for this alternate C2GlcNAcT enzyme. Furthermore, C2GlcNAcT-I-independent P-selectin ligand induction was observed in an in vivo model. HYtg CD8 T cells from C2GlcNAcT-Inull donors transferred into male recipients expressed P-selectin ligand in response to male Ag, although at reduced levels compared with wild-type HYtg CD8 T cells. Our data demonstrate that multiple C2GlcNAcT enzymes can contribute to P-selectin ligand formation and may cooperate with C2GlcNAcT-I in the control of CD8 T cell trafficking.
CD40 Engagement Prevents Peroxisome Proliferator-Activated Receptor γ Agonist-Induced Apoptosis of B Lymphocytes and B Lymphoma Cells by an NF-κB-Dependent Mechanism
Authors: Ray Denise M. , Akbiyik Filiz , Bernstein Steven H. , Phipps Richard P. 
Published: April 2014

Abstract
Peroxisome proliferator-activated receptor γ (PPARγ) is a transcription factor important in fat metabolism and is emerging as an important regulator of immunity and inflammation. We previously demonstrated that normal and malignant B lineage cells express PPARγ and die by apoptosis after PPARγ agonist exposure. In this study, we used the WEHI-231 mouse B lymphoma and normal mouse spleen B lymphocytes to elucidate the mechanism of PPARγ agonist-induced apoptosis, and to determine whether an apoptosis rescue mechanism exists. In WEHI-231 cells, the natural PPARγ agonist 15-deoxy-Δ12,14-PGJ2 and the synthetic PPARγ agonist ciglitazone induced activation of caspase 3 and caspase 9, a decrease in mitochondrial membrane potential, and caused cleavage of the caspase substrate poly(ADP-ribose) polymerase. We next tested whether CD40, whose engagement delivers a potent prosurvival signal for B cells, could protect B cells from PPARγ agonist-induced apoptosis. CD40 engagement with CD40L significantly blunted the ability of PPARγ agonists to induce apoptosis of B lymphocytes and prevented the inhibition of NF-κB mobilization by 15-deoxy-Δ12,14-PGJ2 and ciglitazone. Interestingly, PPARγ agonists induced an increase in IκBα and IκBβ protein levels, which was prevented with CD40 engagement. The rescue mechanism induced by CD40 engagement was dependent on NF-κB, as an NF-κB inhibitor prevented rescue. Apoptosis induction by PPARγ ligands may be important for immune regulation by killing B lymphocytes as a rapid means to dampen inflammation. Moreover, the ability of PPARγ agonists to kill malignant B lineage cells has implications for their use as anti-B lymphoma agents.
Cross-Linking of CD45 on Suppressive/Regulatory T Cells Leads to the Abrogation of Their Suppressive Activity In Vitro
Authors: Shimizu Jun , Iida Ryuji , Sato Yuji , Moriizumi Eiko , Nishikawa Atsushi , Ishida Yasumasa 
Published: April 2014

Abstract
CD4+CD25+ T cells have immunoregulatory and suppressive functions and are responsible for suppressing self-reactive cells and maintaining self-tolerance. In addition to CD4+CD25+ T cells, there is some evidence that a fraction of CD4+CD25− T cells exhibit suppressive activity in vitro or in vivo. We have shown, using aged mice, that aging not only leads to a decline in the ability to mount CD4+CD25− T cell responses, but, at the same time, renders aged CD4+CD25− T cells suppressive. In this study we report two newly established mAbs that could abrogate the suppressive function of aged CD4+CD25− T cells. These mAbs recognized the same protein, the transmembrane phosphatase CD45. Cross-linking of CD45 on aged CD4+CD25− T cells was required for the disruption of their suppressive activity. Surprisingly, these mAbs also abrogated the suppressive action of CD4+CD25+ T cells in vitro. Our results demonstrate an unexpected function of CD45 as a negative regulator neutralizing the suppressive activity of aged CD4+CD25− and young CD4+CD25+ T cells.
Peripheral Deletion of Antigen-Specific T Cells Leads to Long-Term Tolerance Mediated by CD8+ Cytotoxic Cells
Authors: Herndon John M. , Stuart Patrick M. , Ferguson Thomas A. 
Published: April 2014

Abstract
Peripheral deletion is one mechanism by which potentially self-reactive clones are removed whether they escape thymic deletion. We have examined the consequences of deleting Ag-specific T cells by i.v. injection of soluble Ag. Deletion of DO11.10 T cells by peptide was mediated predominately via a Fas/FasL mechanism. Animals that underwent deletion were tolerant to subsequent immunization with Ag, even when tolerant mice were given fresh Ag-specific DO11.10 T cells before immunization. Tolerance was mediated by CD8+ T cells that killed the DO11.10-transgenic T cells in vivo. These data demonstrate that the programmed cell death of large numbers of T cells leads to peripheral tolerance mediated by CD8+ CTLs.
Stat5a Inhibits IL-12-Induced Th1 Cell Differentiation through the Induction of Suppressor of Cytokine Signaling 3 Expression
Authors: Takatori Hiroaki , Nakajima Hiroshi , Kagami Shin-ichiro , Hirose Koichi , Suto Akira , Suzuki Kotaro , Kubo Masato , Yoshimura Akihiko , Saito Yasushi , Iwamoto Itsuo 
Published: April 2014

Abstract
In previous studies, we have shown that Th2 cell differentiation is diminished but Th1 cell differentiation is increased in Stat5a-deficient (Stat5a−/−) CD4+ T cells. In the present study, we clarified the molecular mechanisms of Stat5a-mediated Th cell differentiation. We found that enhanced Th1 cell differentiation and the resultant IFN-γ production played a dominant inhibitory role in the down-regulation of IL-4-induced Th2 cell differentiation of Stat5a−/− CD4+ T cells. We also found that IL-12-induced Stat4 phosphorylation and Th1 cell differentiation were augmented in Stat5a−/− CD4+ T cells. Importantly, the expression of suppressor of cytokine signaling (SOCS)3, a potent inhibitor of IL-12-induced Stat4 activation, was decreased in Stat5a−/− CD4+ T cells. Moreover, a reporter assay showed that a constitutively active form of Stat5a but not Stat6 activated the SOCS3 promoter. Furthermore, chromatin immunoprecipitation assays revealed that Stat5a binds to the SOCS3 promoter in CD4+ T cells. Finally, the retrovirus-mediated expression of SOCS3 restored the impaired Th cell differentiation of Stat5a−/− CD4+ T cells. These results suggest that Stat5a forces the Th1/Th2 balance toward a Th2-type by preventing IL-12-induced Th1 cell differentiation through the induction of SOCS3.
Receptors and Counterreceptors Involved in NK-B Cell Interactions
Authors: Gao Ning , Dang Tam , Dunnick Wesley A. , Collins John T. , Blazar Bruce R. , Yuan Dorothy 
Published: April 2014

Abstract
In addition to the well-documented effect of NK cells on B cell differentiation via their ability to secrete IFN-γ, NK cells can also induce, via direct cell-cell interactions, germline transcripts (Iγ2a) necessary for switch recombination to IgG2a. Analysis of the ligand-receptor pairs that could be involved in this induction revealed that the expression of CD48 on B cells is crucial for the induction. NK cells from mice with targeted deletions of either the CD2 or the CD244 gene, both of which encode ligands for CD48, are compromised in their ability to induce B cell Iγ2a expression. Interestingly, although CD244 can bind to CD48 with a higher affinity, the ability of NK cells from CD244−/− mice to stimulate Iγ2a is not as compromised as NK cells from CD2−/− mice. Despite the difference between cell surface receptors that are stimulated by NK cells vs those stimulated by the combination of LPS and IFN-γ, we show in this study that the initiation of γ2a germline transcription is regulated by similar cis-acting elements located at the 3′ end of the IgH locus. However, NK cells cannot induce the final steps of switch recombination resulting in the production of mature mRNA from recombined DNA. Our findings suggest that these different signaling pathways converge on regulatory elements that are common to germline transcription; however, because NK induction does not result in the final steps of switch recombination, some signals initiated by LPS plus IFN-γ are not induced by NK cells.
Stable Activation of Phosphatidylinositol 3-Kinase in the T Cell Immunological Synapse Stimulates Akt Signaling to FoxO1 Nuclear Exclusion and Cell Growth Control
Authors: Fabre Stéphanie , Lang Valérie , Harriague Julie , Jobart Aude , Unterman Terry G. , Trautmann Alain , Bismuth Georges 
Published: April 2014

Abstract
We have previously reported at the single cell level that PI3K is activated after conjugate formation between T lymphocytes and APCs. However, in contrast to cells exposed to an asymmetrical signal that usually increase 3′-phosphoinositides (3′-PI) transiently in the region of the activated receptors, T cells contacting APC accumulate 3′-PI across their whole plasma membrane far beyond the region of the immunological synapse (IS). Importantly, this effect is maintained over time, for hours, and although PI3K-dependent pathways translate in various cell types extracellular stimuli into a wide range of biological events, in primary T cells this stability is mostly required for cell division induced by Ag. Using imaging methodologies, the present article elucidates the molecular mechanisms responsible for this particular functioning of the PI3K pathway in primary human T lymphocytes interacting with APCs, especially with dendritic cells. The results reveal that the IS unremittingly recruits PI3K to maintain high 3′-PI levels in T cells through phosphotyrosine-dependent mechanisms, suggesting a major participation of class Ia PI3K. This persistent activation of PI3K results in the Akt-dependent sequestration of the FoxO transcription factor, FoxO1, outside the nucleus of T cells interacting with APCs. Using an active form of FoxO1, we demonstrate that this compartmentalization process can affect T cell growth after Ag recognition. We conclude that the need for sustained PI3K signaling within the consolidated IS is probably an undemanding tactic used by primary T cells critical for initiating cell cycle progression through the prolonged inactivation of FoxO1, one important factor that can control cell quiescence.
Linking C5 Deficiency to an Exonic Splicing Enhancer Mutation
Authors: Pfarr Nicole , Prawitt Dirk , Kirschfink Michael , Schroff Claudia , Knuf Markus , Habermehl Pirmin , Mannhardt Wilma , Zepp Fred , Fairbrother William , Loos Michael , Burge Christopher B. , Pohlenz Joachim 
Published: April 2014

Abstract
As an important component of the innate immune system, complement provides the initial response to prevent infections by pathogenic microorganisms. Patients with dysfunction of C5 display a propensity for severe recurrent infections. In this study, we present a patient with C5 deficiency demonstrated by immunochemical and functional analyses. Direct sequencing of all C5 exons displayed no mutation of obvious functional significance, except for an A to G transition in exon 10 predicting an exchange from lysine to arginine. This sequence alteration was present in only one allele of family members with a reduced serum C5 concentration and in both alleles of the patient with almost complete C5 deficiency, suggesting that this alteration may be producing the phenotype. Recent findings indicate that distinct nucleotide sequences, termed exonic splicing enhancers (ESEs), influence the splicing process. cDNA from all family members harboring the mutated allele showed skipping of exon 10, which resulted in a premature STOP codon, explaining the lack of C5 in the propositus. Sequence analysis of the mutated region revealed the substitution to be located within an ESE, as predicted by the RESCUE-ESE program. The altered ESE sequence is located close to the 5′ splicing site and also lowers the predicted strength of the splice site itself. This apparently inconsequential sequence alteration represents a noncanonical splicing mutation altering an ESE. Our finding sheds a new light on the role of putative silent/conservative mutations in disease-associated genes.
p38 MAPK Autophosphorylation Drives Macrophage IL-12 Production during Intracellular Infection
Authors: Kim Leesun , Rio Laura Del , Butcher Barbara A. , Mogensen Trine H. , Paludan Søren R. , Flavell Richard A. , Denkers Eric Y. 
Published: April 2014

Abstract
The intracellular protozoan Toxoplasma gondii triggers rapid MAPK activation in mouse macrophages (Mφ). We used synthetic inhibitors and dominant-negative Mφ mutants to demonstrate that T. gondii triggers IL-12 production in dependence upon p38 MAPK. Chemical inhibition of stress-activated protein kinase/JNK showed that this MAPK was also required for parasite-triggered IL-12 production. Examination of upstream MAPK kinases (MKK) 3, 4, and 6 that function as p38 MAPK activating kinases revealed that parasite infection activates only MKK3. Nevertheless, in MKK3−/− Mφ, p38 MAPK activation was near normal and IL-12 production was unaffected. Recently, MKK-independent p38α MAPK activation via autophosphorylation was described. Autophosphorylation depends upon p38α MAPK association with adaptor protein, TGF-β-activated protein kinase 1-binding protein-1. We observed TGF-β-activated protein kinase 1-binding protein-1-p38α MAPK association that closely paralleled p38 MAPK phosphorylation during Toxoplasma infection of Mφ. Furthermore, a synthetic p38 catalytic-site inhibitor blocked tachyzoite-induced p38α MAPK phosphorylation. These data are the first to demonstrate p38 MAPK autophosphorylation triggered by intracellular infection.
Maintenance of Pulmonary Th1 Effector Function in Chronic Tuberculosis Requires Persistent IL-12 Production
Authors: Feng Carl G. , Jankovic Dragana , Kullberg Marika , Cheever Allen , Scanga Charles A. , Hieny Sara , Caspar Patricia , Yap George S. , Sher Alan 
Published: April 2014

Abstract
The mechanisms that prevent reactivation of latent Mycobacterium tuberculosis infection in asymptomatic individuals are poorly understood. Although IL-12 is critical for the induction of IFN-γ-dependent host control of M. tuberculosis, the requirement for the cytokine in the maintenance of host resistance and pulmonary Th1 effector function has not yet been formally examined. In this study, we reconstituted IL-12p40-deficient mice with IL-12 during the first 4 wk of infection and then assessed the effects of cytokine withdrawal. Although IL-12 administration initially resulted in restricted mycobacterial growth and prolonged survival, the reconstituted animals eventually succumbed to infection. This breakdown in bacterial control was accompanied by a marked reduction in the numbers of IFN-γ-producing CD4+ T cells in lungs. Moreover, whereas CD4+ T cells isolated from chronically infected wild-type mice expanded and transferred long-term protection to M. tuberculosis-challenged RAG−/− mice, they failed to do so in IL-12p40-deficient RAG−/− recipients and were clearly reduced in frequency within pulmonary granulomas in the latter animals. These studies establish that continuous IL-12 production is necessary for maintenance of the pulmonary Th1 cells required for host control of persistent M. tuberculosis infection and suggest that breakdown of this mechanism could be a contributing factor in reactivated disease.
Smad3 Deficiency in Mast Cells Provides Efficient Host Protection against Acute Septic Peritonitis
Authors: Kanamaru Yutaka , Sumiyoshi Koji , Ushio Hiroko , Ogawa Hideoki , Okumura Ko , Nakao Atsuhito 
Published: April 2014

Abstract
Mast cells play an important role in innate immunity as well as in allergic reaction. However, regulatory mechanisms underlying mast cell-mediated innate immune responses remain largely unknown. Here we determined whether Smad3, a major signal transducer of TGF-β, regulates innate immune response by mast cells against Gram-negative bacteria. Bone marrow-derived mast cells (BMMC) obtained from Smad3 null mutant mice showed augmented capacity to produce proinflammatory cytokines upon stimulation with a Gram-negative bacteria-associated product, LPS. In acute septic peritonitis model induced by cecal ligation and puncture, mast cell-deficient W/Wv mice reconstituted with Smad3 null BMMC had significantly higher survival rate than W/Wv mice reconstituted with wild-type BMMC, which was associated with higher production of proinflammatory cytokines in the peritoneal cavity. These in vitro and in vivo results suggest that Smad3 in mast cells functions as inhibitory for mast cell-mediated innate immune response against Gram-negative bacteria. Suppression of Smad3 expression in mast cells may thus have therapeutic potential for Gram-negative bacterial infection such as acute septic peritonitis by augmenting innate immune responses of mast cells.
Inverse Correlation of Maturity and Antibacterial Activity in Human Dendritic Cells
Authors: Buettner Maike , Meinken Christoph , Bastian Max , Bhat Rauf , Stössel Elmar , Faller Gerhard , Cianciolo George , Ficker Joachim , Wagner Manfred , Röllinghoff Martin , Stenger Steffen 
Published: April 2014

AbstractDendritic cells (DCs) are a key part of host defense against microbial pathogens, being part of the innate immune system, but also instructing the adaptive T cell response. This study was designed to evaluate whether human DCs directly contribute to innate immunity by killing intracellular bacteria, using tuberculosis as a model. DCs were detected in bronchoalveolar lavage samples indicating that DCs are available for immediate interaction with Mycobacterium tuberculosis (M. Tb) after inhalation of the pathogen. The phenotype of DC in bronchoalveolar lavage closely resembles monocyte-derived immature DC (iDC) according to the expression of CD1a, CD83, and CCR7. The antimicrobial activity of iDC against intracellular M. Tb inversely correlated with TNF-α-release and was enhanced by treatment with anti-TNF-α Abs. Differentiation of iDC into mature DC by addition of TNF-α or activation via Toll-like receptors further reduced killing of M. Tb. The antibacterial activity against intracellular M. Tb of all DCs was significantly lower than alveolar macrophages. Therefore, the maintenance of a pool of DCs at the site of disease activity in tuberculosis, and the maturation of these DC by TNF-α provides a mechanism by which M. Tb escapes the innate immune system.