bluuebunny/crossref_metadata_2025_split huggingface dataset:
Differential Roles of CB1 and CB2 Cannabinoid Receptors in Mast Cells
Authors: Samson Maria-Teresa , Small-Howard Andrea , Shimoda Lori M. N. , Koblan-Huberson Murielle , Stokes Alexander J. , Turner Helen 
Published: April 2014

Abstract
Cannabinoid modulation of immune responses is a pathological consequence of marijuana abuse and a potential outcome of therapeutic application of the drug. Moreover, endogenous cannabinoids are physiological immune regulators. In the present report, we describe alterations in gene transcription that occur after cannabinoid exposure in a mast cell line, RBL2H3. Cannabinoid exposure causes marked changes in the transcript levels for numerous genes, acting both independently of and in concert with immunoreceptor stimulation via FcεRI. In two mast cell lines, we observed mRNA and protein expression corresponding to both CB1 and CB2 cannabinoid receptor isoforms, contrary to the prevailing view that CB1 is restricted to the CNS. We show that coexpression of the two isoforms is not functionally redundant in mast cells. Analysis of signaling pathways downstream of cannabinoid application reveals that activation of extracellular signal-regulated kinase, AKT, and a selected subset of AKT targets is accomplished by CB2 ligands and nonselective CB1/CB2 agonists in mast cells. CB1 inhibition does not affect AKT or extracellular signal-regulated kinase activation by cannabinoids, indicating that CB2 is the predominant regulatory receptor for these kinases in this cell context. CB1 receptors are, however, functional in these mast cells, since they can contribute to suppression of secretory responses.
Stochastic Model of T Cell Proliferation: A Calculus Revealing IL-2 Regulation of Precursor Frequencies, Cell Cycle Time, and Survival
Authors: Deenick Elissa K. , Gett Amanda V. , Hodgkin Philip D. 
Published: April 2014

AbstractThe outcome of Ag exposure is dictated by complex regulation of T cell proliferation. The rates of proliferation and survival are altered by numerous signals that the cell receives and integrates to achieve a net response. We have illustrated previously how small changes in kinetic parameters can lead to large differences, even under conditions of saturating IL-2. In this study, we examine the effect of varying IL-2 concentration on T cell response and develop a model incorporating additional parameters of proliferation and survival. Strikingly, the proportion of cells that enter the first division, but not the time at which they enter, is dramatically altered by IL-2. Furthermore, the survival and average division time of cells in later divisions are also altered by IL-2 concentration. Together, the small simultaneous effects on these parameters result in large differences in total cell number. These results reveal how in vitro systems may exaggerate the contribution of IL-2, and thus how costimuli or additional helper cells that alter IL-2 concentration, even by relatively small amounts, will generate large in vitro differences in cell number and therefore appear obligatory. Furthermore, they illustrate how a quantitative model of T cell activation can clarify how complex signal integration is handled by T cells in situ, and therefore more appropriately aid development of a theory of behavior.
Active Form of Notch Members Can Enforce T Lymphopoiesis on Lymphoid Progenitors in the Monolayer Culture Specific for B Cell Development
Authors: Hozumi Katsuto , Abe Natsumi , Chiba Shigeru , Hirai Hisamaru , Habu Sonoko 
Published: April 2014

Abstract
The in vitro induction of T lymphopoiesis needs the precise stereoscopic structure of thymus tissues as seen in fetal thymus organ culture. In this study, we demonstrated for the first time that the introduction of the intracellular region of Notch1 can induce T cells expressing TCR without any thymic environment. In the coculture on the monolayer of OP-9, which was originally known to support B cell specific development, hemopoietic progenitors developed into Thy-1+CD25+ T lineage cells if the progenitor cells were infected with the retrovirus containing Notch1 intracellular domains. The Thy-1+ cells progressed to a further developmental stage, CD4 and CD8 double-positive cells expressing TCR on the cell surface, if they were further cultured on OP-9 or in the thymus. However, T cell induction by intracellular Notch1 failed unless both OP-9 and IL-7 were present. It is notable that Notch2 and Notch3 showed an effect on T lymphopoiesis similar to that of Notch1. These results indicate that in vitro T lymphopoiesis is inducible by signaling via Notch family members in a lineage-specific manner but shares other stroma-derived factors including IL-7 with B lymphopoiesis.
Histone Deacetylation, But Not Hypermethylation, Modifies Class II Transactivator and MHC Class II Gene Expression in Squamous Cell Carcinomas
Authors: Kanaseki Takayuki , Ikeda Hideyuki , Takamura Yukio , Toyota Minoru , Hirohashi Yoshihiko , Tokino Takashi , Himi Tetsuo , Sato Noriyuki 
Published: April 2014

Abstract
In this study, we first categorized nine squamous cell carcinoma (SCC) cell lines into two groups in terms of the expression of HLA-DR, -DP, and -DQ molecules. Subsequently, the expression of class II transactivator (CIITA) was studied in these cell lines, because it is widely accepted that the expression of MHC class II molecules is regulated by different types of CIITA transcripts that are initiated by distinct promoters. The majority of the SCC cell lines (six of nine) expressed HLA-DR molecules and CIITA promoter IV (pIV) transcripts in the presence of IFN-γ. In contrast, three of the nine SCC cell lines were completely negative for class II molecules and all types of CIITA, suggesting epigenetic changes in the promoter region in these cells. Previously, methylation of CIITA pIV was reported to silence CIITA gene expression. We extensively studied the methylation status of CIITA pIV using a panel of 22 SCC cell lines. Remarkably, none of the SCC cell lines demonstrated hypermethylation at the site. In contrast, treatment with a histone deacetylation inhibitor in combination with IFN-γ clearly restored the expression of the CIITA type IV gene in the HLA-DR-negative SCC cell lines, and the acetylation status of histone H3 examined by chromatin immunoprecipitation analysis was closely associated with the gene expression. Moreover, stable transfection of the CIITA gene into an HLA-DR-negative cell line restored constitutive expression of MHC class II molecules. Therefore, histone deacetylation, but not hypermethylation, modifies CIITA DNA and class II gene expression in SCC.
Differential Control of Cell Cycle, Proliferation, and Survival of Primary T Lymphocytes by Purine and Pyrimidine Nucleotides
Authors: Quéméneur Laurence , Gerland Luc-Marie , Flacher Monique , Ffrench Martine , Revillard Jean-Pierre , Genestier Laurent 
Published: April 2014

Abstract
Purine and pyrimidine nucleotides play critical roles in DNA and RNA synthesis as well as in membrane lipid biosynthesis and protein glycosylation. They are necessary for the development and survival of mature T lymphocytes. Activation of T lymphocytes is associated with an increase of purine and pyrimidine pools. However, the question of how purine vs pyrimidine nucleotides regulate proliferation, cell cycle, and survival of primary T lymphocytes following activation has not yet been specifically addressed. This was investigated in the present study by using well-known purine (mycophenolic acid, 6-mercaptopurine) and pyrimidine (methotrexate, 5-fluorouracil) inhibitors, which are used in neoplastic diseases or as immunosuppressive agents. The effect of these inhibitors was analyzed according to their time of addition with respect to the initiation of mitogenic activation. We showed that synthesis of both purine and pyrimidine nucleotides is required for T cell proliferation. However, purine and pyrimidine nucleotides differentially regulate the cell cycle since purines control both G1 to S phase transition and progression through the S phase, whereas pyrimidines only control progression from early to intermediate S phase. Furthermore, inhibition of pyrimidine synthesis induces apoptosis whatever the time of inhibitor addition whereas inhibition of purine nucleotides induces apoptosis only when applied to already cycling T cells, suggesting that both purine and pyrimidine nucleotides are required for survival of cells committed into S phase. These findings reveal a hitherto unknown role of purine and pyrimidine de novo synthesis in regulating cell cycle progression and maintaining survival of activated T lymphocytes.
Mechanisms of Accelerated Immune-Mediated Diabetes Resulting from Islet β Cell Expression of a Fas Ligand Transgene
Authors: Silva Diego G. , Petrovsky Nikolai , Socha Luis , Slattery Robyn , Gatenby Paul , Charlton Brett 
Published: April 2014

Abstract
Nonobese diabetic (NOD) mice transgenic for Fas ligand (FasL) on islet β cells (HIPFasL mice) exhibit an accelerated diabetes distinct from the normal autoimmune diabetes of NOD mice. This study was undertaken to define the mechanism underlying accelerated diabetes development in HIPFasL mice. It was found that diabetes in HIPFasL mice is dependent on the NOD genetic background, as HIPFasL does not cause diabetes when crossed into other mice strains and is lymphocyte dependent, as it does not develop in HIPFasLSCID mice. Diabetes development in NODSCID recipients of diabetic HIPFasL splenocytes is slower than when using splenocytes from diabetic NOD mice. β cells from HIPFasL mice are more susceptible to cytokine-induced apoptosis than wild-type NOD β cells, and this can be blocked with anti-FasL Ab. HIPFasL islets are more rapidly destroyed than wild-type islets when transplanted into nondiabetic NOD mice. This confirms that FasL+ islets do not obtain immune privilege, and instead NOD β cells constitutively expressing FasL are more susceptible to apoptosis induced by Fas-FasL interaction. These findings are consistent with the accelerated diabetes of young HIPFasL mice being a different disease process from the autoimmune diabetes of wild-type NOD mice. The data support a mechanism by which cytokines produced by the insulitis lesion mediate up-regulation of β cell Fas expression, resulting in suicide or fratricide of HIPFasL β cells that overexpress FasL.
IL-18 and IL-12 Signal Through the NF-κB Pathway to Induce NK-1R Expression on T Cells
Authors: Weinstock Joel V. , Blum Arthur , Metwali Ahmed , Elliott David , Arsenescu Razvan 
Published: April 2014

AbstractSubstance P engages the T cell neurokinin 1 receptor (NK-1R) to enhance IFN-γ production. NK-1R on T cells is inducible. We studied mechanisms regulating T cell NK-1R expression. Murine splenocytes were cultured for 4 h with or without rIL-12 or rIL-18. Both IL-12 and IL-18 induced splenic T cells to express NK-1R transcripts. Induction was blocked by actinomycin D, but not cycloheximide, suggesting that protein synthesis was not required for initiation of NK-1R gene transcription. Inhibition of T cell NF-κB activation or NF-κB nuclear translocation also blocked NK-1R transcription. IL-12 and IL-18 strongly induce NK-1R mRNA expression in splenocytes from Stat4−/− mice, suggesting that the Stat4 pathway was not required for the induction of NK-1R transcription. Splenic T cells exposed to IL-12 or IL-18 in the presence of IL-10 expressed no NK-1R mRNA. However, TGFβ did not prevent NK-1R mRNA expression. Thus, IL-12 and IL-18 induce T cells to express NK-1R through NF-κB activation. IL-10, a regulator of the Th1 response, blocks this activation. These data further suggest that SP and NK-1R, which promote IFN-γ synthesis, are part of the Th1 pathway of immunity.
Superantigen-Induced Regulatory T Cells Display Different Suppressive Functions in the Presence or Absence of Natural CD4+CD25+ Regulatory T Cells In Vivo
Authors: Grundström Susanna , Cederbom Lukas , Sundstedt Anette , Scheipers Peter , Ivars Fredrik 
Published: April 2014

Abstract
Repeated exposures to both microbial and innocuous Ags in vivo have been reported to both eliminate and tolerize T cells after their initial activation and expansion. The remaining tolerant T cells have been shown to suppress the response of naive T cells in vitro. This feature is reminiscent of natural CD4+CD25+ regulatory T cells. However, it is not known whether the regulatory function of in vivo-tolerized T cells is similar to the function of natural CD4+CD25+ regulatory T cells. In this study, we demonstrate that CD4+CD25+ as well as CD4+CD25− T cells isolated from mice treated with superantigen three consecutive times to induce tolerance were functionally comparable to natural CD4+CD25+ regulatory T cells, albeit more potent. The different subpopulations of in vivo-tolerized CD4+ T cells efficiently down-modulated costimulatory molecules on dendritic cells, and their suppressive functions were strictly cell contact dependent. Importantly, we demonstrate that conventional CD4+CD25− T cells could also be induced to acquire regulatory functions by the same regimen in the absence of natural regulatory T cells in vivo, but that such regulatory cells were functionally different.
IL-15 Promotes the Survival of Naive and Memory Phenotype CD8+ T Cells
Authors: Berard Marion , Brandt Katja , Paus Silvia Bulfone , Tough David F. 
Published: April 2014

AbstractIL-15 stimulates the proliferation of memory phenotype CD44highCD8+ T cells and is thought to play a key role in regulating the turnover of these cells in vivo. We have investigated whether IL-15 also has the capacity to affect the life span of naive phenotype (CD44low) CD8+ T cells. We report that IL-15 promotes the survival of both CD44low and CD44high CD8+ T cells, doing so at much lower concentrations than required to induce proliferation of CD44high cells. Rescue from apoptosis was associated with the up-regulation of Bcl-2 in both cell types, whereas elevated expression of Bcl-xL was observed among CD44high but not CD44low CD8+ cells. An investigation into the role of IL-15R subunits in mediating the effects of IL-15 revealed distinct contributions of the α- and β- and γ-chains. Most strikingly, IL-15Rα was not essential for either induction of proliferation or promotion of survival by IL-15, but did greatly enhance the sensitivity of cells to low concentrations of IL-15. By contrast, the β- and γ-chains of the IL-15R were absolutely required for the proliferative and pro-survival effects of IL-15, although it was not necessary for CD44highCD8+ cells to express higher levels of IL-15Rβ than CD44low cells to proliferate in response to IL-15. These results show that IL-15 has multiple effects on CD8 T cells and possesses the potential to regulate the life span of naive as well as memory CD8+ T cells.
A Peptide from Heat Shock Protein 60 Is the Dominant Peptide Bound To Qa-1 in the Absence of the MHC Class Ia Leader Sequence Peptide Qdm
Authors: Davies Adrian , Kalb Suzanne , Liang Bitao , Aldrich Carla J. , Lemonnier François A. , Jiang Hong , Cotter Robert , Soloski Mark J. 
Published: April 2014

AbstractThe MHC class Ib molecule Qa-1 binds specifically and predominantly to a single 9-aa peptide (AMAPRTLLL) derived from the leader sequence of many MHC class Ia proteins. This peptide is referred to as Qdm. In this study, we report the isolation and sequencing of a heat shock protein 60-derived peptide (GMKFDRGYI) from Qa-1. This peptide is the dominant peptide bound to Qa-1 in the absence of Qdm. A Qa-1-restricted CTL clone recognizes this heat shock protein 60 peptide, further verifying that it binds to Qa-1 and a peptide from the homologous Salmonella typhimurium protein GroEL (GMQFDRGYL). These observations have implications for how Qa-1 can influence NK cell and T cell effector function via the TCR and CD94/NKG2 family members, and how this effect can change under conditions that cause the peptides bound to Qa-1 to change.
Extracellular Matrix Conditions T Cells for Adhesion to Tissue Interstitium
Authors: Krivacic Kimberly A. , Levine Alan D. 
Published: April 2014

AbstractThe activation and differentiation of peripheral blood T cells (PBT) are known to correlate with increased surface expression and adhesive capacity of β1 integrins, which mediate adhesion to the extracellular matrix (ECM). However, little is known about the regulation of integrin expression, affinity, and avidity on tissue T cells after they are embedded in the interstitial ECM. In this study we show that tissue T cells, freshly isolated from their residence in the interstitial ECM of the intestinal lamina propria, express a distinct subset of functionally active integrins that contribute to enhanced adhesion to purified collagen, fibronectin, and cell-derived ECM when compared with freshly isolated, short term activated, and long term cultured PBT. Furthermore, integrin usage is distinct between circulating and tissue-derived T cells, in that lamina propria T cells prefer to bind to collagen, while PBT lymphoblasts choose fibronectin when presented with a complex, three-dimensional, cell-derived matrix. To identify the extrinsic factors that regulate the conversion from a nonadhesive PBT to highly adhesive tissue T cell, we demonstrate that activation of PBT in the presence of fibronectin or collagen rapidly generates a surface integrin expression profile, an integrin usage pattern, and adhesive capacity mirroring that of a tissue T cell. These results indicate that the tissue ECM microenvironment instructs newly arrived T cells for further interactions with the underlying matrix and thereby imprints them with a signature tissue adhesive phenotype.
Mast Cells Express Novel Functional IL-15 Receptor α Isoforms
Authors: Bulanova Elena , Budagian Vadim , Orinska Zane , Krause Hans , Paus Ralf , Bulfone-Paus Silvia 
Published: April 2014

AbstractMast cells previously have been reported to be regulated by IL-15 and to express a distinct IL-15R, termed IL-15RX. To further examine IL-15 binding and signaling in mast cells, we have studied the nature of the IL-15R and some of its biological activities in these cells. In this study, we report the existence of three novel isoforms of the IL-15Rα chain in murine bone marrow-derived mast cells as a result of an alternative exon-splicing mechanism within the IL-15Rα gene. These correspond to new mRNA transcripts lacking exon 4; exons 3 and 4; or exons 3, 4, and 5 (IL-15RαΔ4, IL-15RαΔ3,4, IL-15RαΔ3,4,5). After transient transfection in COS-7 cells, all IL-15Rα isoforms associate with the Golgi apparatus, the endoplasmic reticulum, the perinuclear space, and the cell membrane. Analysis of glycosylation pattern demonstrates the usage of a single N-glycosylation site, while no O-glycosylation is observed. Importantly, IL-15 binds with high affinity to, and promotes the survival of, murine BA/F3 cells stably transfected with the IL-15Rα isoforms. Furthermore, we report that signaling mediated by IL-15 binding to the newly identified IL-15Rα isoforms involves the phosphorylation of STAT3, STAT5, STAT6, Janus kinase 2, and Syk kinase. Taken together, our data indicate that murine mast cells express novel, fully functional IL-15Rα isoforms, which can explain the selective regulatory effects of IL-15 on these cells.
Attenuation of Immunological Symptoms of Allergic Asthma in Mice Lacking the Tyrosine Kinase ITK
Authors: Mueller Cynthia , August Avery 
Published: April 2014

AbstractAllergic asthma patients manifest airway inflammation and some show increases in eosinophils, TH2 cells, and cytokines, increased mucous production in the lung, and elevated serum IgE. This TH2-type response suggests a prominent role for TH2 cells and their cytokines in the pathology of this disease. The Tec family nonreceptor tyrosine kinase inducible T cell kinase (ITK) has been shown to play a role in the differentiation and/or function of TH2-type cells, suggesting that ITK may represent a good target for the control of asthma. Using a murine model of allergic asthma, we show here that ITK is involved in the development of immunological symptoms seen in this model. We show that mice lacking ITK have drastically reduced lung inflammation, eosinophil infiltration, and mucous production following induction of allergic asthma. Notably, T cell influx into the lung was reduced in mice lacking ITK. T cells from ITK−/− mice also exhibited reduced proliferation and cytokine secretion, in particular IL-5 and IL-13, in response to challenge with the allergen OVA, despite elevated levels of total IgE and increased OVA-specific IgE responses. Our results suggest that the tyrosine kinase ITK preferentially regulates the secretion of the TH2 cytokines IL-5 and IL-13 and may be an attractive target for antiasthmatic drugs.
Nitric Oxide-Independent CTL Suppression during Tumor Progression: Association with Arginase-Producing (M2) Myeloid Cells
Authors: Liu Yuanqing , Van Ginderachter Jo A. , Brys Lea , De Baetselier Patrick , Raes Geert , Geldhof Anja B. 
Published: April 2014

AbstractMost of the mice bearing a s.c. BW-Sp3 lymphoma tumor mount a CD8+ T cell-mediated response resulting in tumor regression. Nonetheless, tumor progression occurs in some of the recipients and is associated with CTL inactivity. We demonstrated that T cell-activating APC were induced in regressors whereas T cell suppressive myeloid cells predominated in the spleen of progressors. Indeed, in vitro depletion of either the adherent or the CD11b+ populations restored T cell cytotoxicity and proliferation in these mice. This CTL inhibition was cell-to-cell contact-dependent but not mediated by NO. However, the same progressor suppressive cells prevented the activity of in vitro-restimulated CTLs derived from regressors in a cell-to-cell contact and NO-dependent fashion. Thus, either the NO-dependent or -independent suppressive pathway prevailed, depending on the target CTL population. In addition, the suppressive population expressed a high arginase activity, suggesting an association of the suppressive phenotype with alternatively activated (M2) myeloid cells. However, the high arginase activity is not directly involved in the suppressive process. Our results provide new insights for myeloid cell-mediated CTL inhibition during cancer progression.
Early IL-2 Production by Mouse Dendritic Cells Is the Result of Microbial-Induced Priming
Authors: Granucci Francesca , Feau Sonia , Angeli Véronique , Trottein François , Ricciardi-Castagnoli Paola 
Published: April 2014

Abstract
Dendritic cells (DCs) are professional APCs able to initiate innate and adaptive immune responses against invading pathogens. Different properties such as the efficient Ag processing machinery, the high levels of expression of costimulatory molecules and peptide-MHC complexes, and the production of cytokines contribute in making DCs potent stimulators of naive T cell responses. Recently we have observed that DCs are able to produce IL-2 following bacterial stimulation, and we have demonstrated that this particular cytokine is a key molecule conferring to early bacterial activated DCs unique T cell priming capacity. In the present study we show that many different microbial stimuli, but not inflammatory cytokines, are able to stimulate DCs to produce IL-2, indicating that DCs can distinguish a cytokine-mediated inflammatory process from the actual presence of an infection. The capacity to produce IL-2 following a microbial stimuli encounter is a feature shared by diverse DC subtypes in vivo, such as CD8α+ and CD8α− splenic DCs and epidermal Langerhans cells. When early activated DCs interact with T cells, IL-2 produced by DCs is enriched at the site of cell-cell contact, confirming the importance of DCs-derived IL-2 in T cell activation.