bluuebunny/crossref_metadata_2025_split huggingface dataset:
HIV-1 gp120 Stimulates the Production of β-Chemokines in Human Peripheral Blood Monocytes Through a CD4-Independent Mechanism
Authors: Fantuzzi Laura , Canini Irene , Belardelli Filippo , Gessani Sandra 
Published: April 2014

Abstract
The present study was designed to evaluate the effect of the HIV-1 envelope glycoprotein gp120 on the expression of β-chemokines in cultured monocytes/macrophages. Treatment of either freshly isolated 1-day-cultured monocytes or 7-day-cultured monocyte-derived macrophages (MDM) with recombinant gp120-IIIB resulted in a specific and dose-dependent enhancement of secretion of monocyte chemoattractant protein-1, macrophage inflammatory protein-1β, and RANTES as well as a clear-cut increase in transcript accumulation. The expression of these mRNA was increased, but not superinduced, in the presence of cycloheximide. β-Chemokine secretion was also induced after exposure of monocyte cultures to gp120-JRFL and aldrithiol-2-inactivated R5 and X4 HIV-1 strains, retaining conformational and functional integrity of envelope proteins. In contrast, no β-chemokine secretion was triggered by X4 and R5 gp120 or aldrithiol-2-inactivated virus treatment of monocytoid cell lines that were fully responsive to LPS. The gp120-mediated effect was independent of its interaction with CD4, as preincubation with soluble CD4 did not abrogate β-chemokine induction. Moreover, triggering of CD4 receptor by a specific Ab did not result in any β-chemokine secretion. Interestingly, engagement of CCR5 and CXCR4 receptors by specific Abs as well as treatment with CCR5 and CXCR4 ligands induced β-chemokine secretion. On the whole, these results indicate that HIV-1 stimulates monocytes/macrophages to produce β-chemokines by a specific interaction of gp120 with HIV-1 coreceptors on the cell membrane. The expression of these related polypeptides may represent an important cellular response for regulating both the extent of viral infection and the recruitment of immune cells.
Ceramide Inhibits Lipopolysaccharide-Mediated Nitric Oxide Synthase and Cyclooxygenase-2 Induction in Macrophages: Effects on Protein Kinases and Transcription Factors
Authors: Hsu Ya-Wen , Chi Kwan-Hwa , Huang Wan-Chen , Lin Wan-Wan 
Published: April 2014

Abstract
The goal of this study was to elucidate whether triggering the sphingomyelin pathway modulates LPS-initiated responses. For this purpose we investigated the effects of N-acetylsphingosine (C2-ceramide) on LPS-induced production of NO and PGE2 in murine RAW 264.7 macrophages and explored the signaling pathways involved. We found that within a range of 10–50 μM, C2-ceramide inhibited LPS-elicited NO synthase and cyclooxygenase-2 induction accompanied by a reduction in NO and PGE2 formation. By contrast, a structural analog of C2-ceramide that does not elicit functional activity, C2-dihydroceramide, did not affect the LPS response. The nuclear translocation and DNA binding study revealed that ceramide can inhibit LPS-induced NF-κB and AP-1 activation. The immunocomplex kinase assay indicated that IκB kinase activity stimulated by LPS was inhibited by ceramide, which concomitantly reduced the IκBα degradation caused by LPS within 1–6 h. In concert with the decreased cytosolic p65 protein level, LPS treatment resulted in rapid nuclear accumulation of NF-κB subunit p65 and its association with the cAMP-responsive element binding protein. Ceramide coaddition inhibited all the LPS responses. In addition, LPS-induced PKC and p38 mitogen-activated protein kinase activation were overcome by ceramide. In conclusion, we suggest that ceramide inhibition of LPS-mediated induction of inducible NO synthase and cyclooxygenase-2 is due to reduction of the activation of NF-κB and AP-1, which might result from ceramide’s inhibition of LPS-stimulated IκB kinase, p38 mitogen-activated protein kinase, and protein kinase C.
Mechanism of Immune Dysfunction in Cancer Mediated by Immature Gr-1+ Myeloid Cells
Authors: Gabrilovich Dmitry I. , Velders Markwin P. , Sotomayor Eduardo M. , Kast W. Martin 
Published: April 2014

AbstractThe mechanism of tumor-associated T cell dysfunction remains an unresolved problem of tumor immunology. Development of T cell defects in tumor-bearing hosts are often associated with increased production of immature myeloid cells. In tumor-bearing mice, these immature myeloid cells are represented by a population of Gr-1+ cells. In this study we investigated an effect of these cells on T cell function. Gr-1+ cells were isolated from MethA sarcoma or C3 tumor-bearing mice using cell sorting. These Gr-1+ cells expressed myeloid cell marker CD11b and MHC class I molecules, but they lacked expression of MHC class II molecules. Tumor-induced Gr-1+ cells did not affect T cell responses to Con A and to a peptide presented by MHC class II. In sharp contrast, Gr-1+ cells completely blocked T cell response to a peptide presented by MHC class I in vitro and in vivo. Block of the specific MHC class I molecules on the surface of Gr-1+ cells completely abrogated the observed effects of these cells. Thus, immature myeloid cells specifically inhibited CD8-mediated Ag-specific T cell response, but not CD4-mediated T cell response. Differentiation of Gr-1+ cells in the presence of growth factors and all-trans retinoic acid completely eliminated inhibitory potential of these cells. This may suggest a new approach to cancer treatment.
The Involvement of TNF-α-Related Apoptosis-Inducing Ligand in the Enhanced Cytotoxicity of IFN-β-Stimulated Human Dendritic Cells to Tumor Cells
Authors: Liu Shuxun , Yu Yizhi , Zhang Minghui , Wang Wenya , Cao Xuetao 
Published: April 2014

Abstract
TNF-α-related apoptosis-inducing ligand (TRAIL) is characterized by its preferential induction of apoptosis of tumor cells but not normal cells. Dendritic cells (DCs), besides their role as APCs, now have been demonstrated to exert cytotoxicity or cytostasis on some tumor cells. Here, we report that both human CD34+ stem cell-derived DCs (CD34DCs) and human CD14+ monocyte-derived DCs (MoDCs) express TRAIL and exhibit cytotoxicity to some types of tumor cells partially through TRAIL. Moderate expression of TRAIL appeared on CD34DCs from the 8th day of culture and was also seen on freshly isolated monocytes. The level of TRAIL expression remained constant until DC maturation. TRAIL expression on immature CD34DCs or MoDCs was greatly up-regulated after IFN-β stimulation. Moreover, IFN-β could strikingly enhance the ability of CD34DCs or MoDCs to kill TRAIL-sensitive tumor cells, but LPS did not have such an effect. The up-regulation of TRAIL on IFN-β-stimulated DCs partially contributed to the increased cytotoxicity of DCs. Pretreatment of TRAIL-sensitive tumor cells with caspase-3 inhibitor could significantly increase their resistance to the cytotoxicity of IFN-β-stimulated DCs. In contrast, NF-κB inhibitor could significantly increase the sensitivity of tumor cells to the killing by nonstimulated or LPS-stimulated DCs. Our studies demonstrate that IFN-β-stimulated DCs are functionally cytotoxic. Thus, an innate mechanism of DC-mediated antitumor immunity might exist in vivo in which DCs act as effectors to directly kill tumor cells partially via TRAIL. Subsequently, DCs act as APCs involved in the uptake, processing, and presentation of apoptotic tumor Ags to cross-prime CD8+ CTL cells.
Modulation of CD8+ T Cell Response to Antigen by the Levels of Self MHC Class I
Authors: Santori Fabio R. , Arsov Ivica , Vukmanović Stanislav 
Published: April 2014

AbstractThe response of H-Y-specific TCR-transgenic CD8+ T cells to Ag is characterized by poor proliferation, cytolytic activity, and IFN-γ secretion. IFN-γ secretion, but not cytotoxic function, can be rescued by the B7.1 molecule, suggesting that costimulation can selectively enhance some, but not all, effector CD8+ T cell responses. Although the H-Y epitope binds H-2Db relatively less well than some other epitopes, it can induce potent CTL responses in nontransgenic mice, suggesting that the observed poor responsiveness of transgenic CD8+ T cells cannot be ascribed to the epitope itself. Previously reported reactivity of this TCR to H-2Ab is also not the cause of the poor responsiveness of the H-Y-specific CD8+ T cells, as H-Y-specific CD8+ T cells obtained from genetic backgrounds lacking H-2Ab also responded poorly. Rather, reducing the levels of H-2b class I molecules by breeding the mice to (C57BL/6 × B10.D2)F1 or TAP1+/− backgrounds partially restored cytotoxic activity and enhanced proliferative responses. These findings demonstrate that the self MHC class I gene dosage may regulate the extent of CD8+ T cell responsiveness to Ag.
META-Controlled env-Initiated Transcripts Encoding Superantigens of Murine Mtv29 and Mtv7 and Their Possible Role in B Cell Lymphomagenesis
Authors: Sen Namita , Simmons William J. , Thomas Rajan M. , Erianne Gregory , Zhang Da-Jun , Jaeggli Nelson S. , Huang Ching , Xiong Xiaozhong , Tsiagbe Vincent K. , Ponzio Nicholas M. , Thorbecke G. Jeanette 
Published: April 2014

Abstract
Spontaneous germinal center (GC)-derived B cell lymphomas of SJL mice (RCS) transcribe a 1.8-kb Mtv-29 mRNA under control of the META-env promoter. The encoded vSAg29 stimulates syngeneic Vβ16+ CD4+ T cells, thereby acquiring T cell help necessary for RCS growth. Other strains of B cell lymphoma-prone mice include Mtv29+ C57L and MA/MyJ, and the Mtv29− Mtv7+-recombinant inbred strain, SW × J-1. The lymphomas of these mice produce similar mouse mtv-vSAg-encoding mRNA, as characterized by Northern blotting, PCR, and RNase protection. A 1.8-kb mRNA in C57L/J and MA/MyJ lymphomas hybridized with an Mtv29-specific oligonucleotide, whereas SW × J-1 lymphomas produced 1.8-kb transcripts hybridizing with an Mtv7-specific oligonucleotide. Similar META-env-initiated transcripts were absent from LPS-activated B cells from any strain examined but were detected in Peyer’s patch RNA from SJL mice. Like typical SJL-derived RCS, all these lymphomas stimulated syngeneic CD4+ T cells and Vβ16+ T hybridoma cells. Immunohistochemical staining of primary tumors showed the presence of peanut agglutinin binding (PNA+) highly mitotic lymphoblasts, suggesting their GC derivation. The findings indicate that this novel mRNA for Mtv29 is present in B cell lymphomas from several Mtv29+ mouse strains. Additionally, this is the first description of the ability of Mtv7 to produce transcripts that are controlled and spliced identically to those of Mtv29 and that are expressed in SW × J-1, I-As+, lymphomas that also stimulate Vβ16+ T cells. Our results suggest an important role for mouse mtv-vSAgs and Vβ16 T cell stimulation in the development of GC-derived murine B cell lymphomas.
Antigen-Specific Primary Activation of CD8+ T Cells Within the Liver
Authors: Bertolino Patrick , Bowen David G. , McCaughan Geoffrey W. , Fazekas de St. Groth Barbara 
Published: April 2014

AbstractIt is generally accepted that naive T cells recirculate via the blood and lymph, but do not enter nonlymphoid tissues without prior activation and differentiation. In this study, we demonstrate that the liver is an exception to this rule. Naive Des-TCR transgenic CD8+ T cells specific for H-2Kb were selectively retained in the liver within a few minutes of adoptive transfer into transgenic Met-Kb mice expressing H-2Kb in the liver. Activated CD8+ cells were found in the liver, but not the blood, as soon as 2 h after transfer and underwent cell division and started to recirculate within 24 h of transfer. In contrast, CD8+ cells activated in the lymph nodes remained sequestered at that site for 2 days before entering the blood. Our results therefore suggest that, in addition to its previously described role as a non Ag-specific activated T cell graveyard, the liver is involved in Ag-specific activation of naive recirculating CD8+ T cells. This particular property of the liver, combined with the previously demonstrated ability of hepatocytes to induce tolerance by means of premature CD8+ T cell death, may be a major mechanism contributing to the acceptance of liver allografts and the chronicity of viral hepatitis.
The Mechanism of a Defective IFN-γ Response to Bacterial Toxins in an Atopic Dermatitis Model, NC/Nga Mice, and the Therapeutic Effect of IFN-γ, IL-12, or IL-18 on Dermatitis
Authors: Habu Yoshiko , Seki Shuhji , Takayama Eiji , Ohkawa Takashi , Koike Yuji , Ami Katsunori , Majima Takashi , Hiraide Hoshio 
Published: April 2014

AbstractNC/Nga (NC) mice raised under conventional conditions (Conv. NC mice) spontaneously develop dermatitis similar to human atopic dermatitis, whereas NC mice raised under the specific pathogen-free conditions do not develop dermatitis. In the present study, we show that the representative Th1 cytokine, IFN-γ levels in the sera of NC mice, injected with either staphylococcal enterotoxin B or endotoxin (LPS), to be severalfold lower than those of normal mice. The low IFN-γ response to staphylococcal enterotoxin B was correlated to the lack of regular Vβ8+ T cells and Vβ8+ NK T cells, and the low IFN-γ response to LPS was correlated to an impaired IL-18 production of macrophages. The CD3-stimulated IL-4 production from liver and spleen T cells from Conv. NC mice in vitro was greatly augmented. The serum IL-4 levels of untreated Conv. NC mice also were higher than those of normal mice and specific pathogen-free NC mice. Treatment of Conv. NC mice either with IFN-γ, IL-12, or IL-18 twice a week from 4 wk of age substantially inhibited the elevation of the serum IgE levels, serum IL-4 levels, and dermatitis, and IL-12 or IL-18 treatment also reduced the in vitro IL-4 production from CD3-stimulated liver T cells. The systemic deficiency in the Th1 response to bacterial stimulation thus leads to a Th2-dominant state and may induce an abnormal cellular immune response in the skin accompanied with an overproduction of IgE and a susceptibility to dermatitis in NC mice.
Differential Production of IL-12, IFN-α, and IFN-γ by Mouse Dendritic Cell Subsets
Authors: Hochrein Hubertus , Shortman Ken , Vremec David , Scott Bernadette , Hertzog Paul , O’Keeffe Meredith 
Published: April 2014

AbstractDendritic cells (DC) not only stimulate T cells effectively but are also producers of cytokines that have important immune regulatory functions. In this study we have extended information on the functional differences between DC subpopulations to include differences in the production of the major immune-directing cytokines IL-12, IFN-α, and IFN-γ. Splenic CD4−8+ DC were identified as the major IL-12 producers in response to microbiological or T cell stimuli when compared with splenic CD4−8− or CD4+8− DC; however, all three subsets of DC showed similar IL-12 regulation and responded with increased IL-12 p70 production if IL-4 was present during stimulation. High level CD8 expression also correlated with extent of IL-12 production for DC isolated from thymus and lymph nodes. By using gene knockout mice we ruled out any role for CD8α itself, or of priming by T cells, on the superior IL-12-producing capacity of the CD8+ DC. Additionally, CD8+ DC were identified as the major producers of IFN-α compared with the two CD8− DC subsets, a finding that suggests similarity to the human plasmacytoid DC lineage. In contrast, the CD4−8− DC produced much more IFN-γ than the CD4−8+ or the CD4+8− DC under all conditions tested.
Distinct Autoreactive T Cell Responses to Native and Fragmented DNA Topoisomerase I: Influence of APC Type and IL-2
Authors: Oriss Timothy B. , Hu Paul Q. , Wright Timothy M. 
Published: April 2014

Abstract
Systemic sclerosis (SSc) is an autoimmune connective tissue disease of unknown etiology in which T cell responses to various autoantigens, including DNA topoisomerase I (Topo I), have been implicated. We investigated whether dendritic cells, generally considered to be the most potent APCs for the initiation of immune responses, would present either of two forms of Topo I to T cells more efficiently than PBMC APCs. Using cells from healthy controls and SSc patients, several important observations were made. First, neither APC type was able to initiate T cell proliferative responses to full-length native Topo I unless exogenous IL-2 was added. This is in contrast to vigorous T cell proliferation in response to Topo I polypeptide fragments presented by either APC type. Second, T cell responses to the full-length form of Topo I presented by dendritic cells were considerably lower than responses to Ag presented by PBMC APCs. Finally, no secondary T cell responses were observed unless the same Ag/APC combination as that used in the primary stimulation was maintained. These data indicate that different peptides are generated based upon the form of the Topo I and the APC that processes it. Taken together, these results suggest that a very specific combination of antigenic form and APC may be involved in breaking tolerance to Topo I in the early stages of development of SSc.
Fine Tuning of TCR Signaling by CD5
Authors: Azzam Hala S. , DeJarnette Jan B. , Huang Kun , Emmons Rebecca , Park Cheung-Seog , Sommers Connie L. , El-Khoury Dalal , Shores Elizabeth W. , Love Paul E. 
Published: April 2014

Abstract
Current data indicate that CD5 functions as an inhibitor of TCR signal transduction. Consistent with this role, thymocyte selection in TCR transgenic/CD5−/− mice is altered in a manner suggestive of enhanced TCR signaling. However, the impact of CD5 deletion on thymocyte selection varies depending on the transgenic TCR analyzed, ranging from a slight to a marked shift from positive toward negative selection. An explanation for the variable effect of CD5 on selection is suggested by the observation that CD5 surface expression is regulated by TCR signal intensity during development and CD5 surface levels on mature thymocytes and T cells parallel the avidity of the positively selecting TCR/MHC/ligand interaction. In this study, we generated mice that overexpress CD5 during thymocyte development (CD5-tg), and then examined the effect of CD5 overexpression or CD5 deletion (CD5−/−) on selection of thymocytes that express the same TCR transgenes. The results demonstrate that the effect on thymocyte selection of altering CD5 expression depends on the avidity of the selecting interaction and, consequently, the level of basal (endogenous) CD5 surface expression. Substitution of endogenous CD5 with a transgene encoding a truncated form of the protein failed to rescue the CD5−/− phenotype, demonstrating that the cytoplasmic domain of CD5 is required for its inhibitory function. Together, these results indicate that inducible regulation of CD5 surface expression during thymocyte selection functions to fine tune the TCR signaling response.
Prime-Boost Immunization with DNA Vaccine: Mucosal Route of Administration Changes the Rules
Authors: Eo Seong Kug , Gierynska Malgorzata , Kamar Amal Abou , Rouse Barry T. 
Published: April 2014

Abstract
In this study we assessed prime-boost immunization strategies with a DNA vaccine (gB DNA) and attenuated recombinant vaccinia virus vector (rvacgB), both encoding the gB protein of HSV, for their effectiveness at inducing mucosal as well as systemic immunity to HSV. Confirming the reports of others, systemic priming with gB DNA and systemic boosting with rvacgB were the most effective means of inducing serum Ab and splenic T cell responses. Nevertheless, the systemic prime-boost approach failed to induce detectable humoral or T cell responses at mucosal sites. However, such responses, at both proximal and distal locations, were induced if immunizations, especially the priming dose, were administered mucosally. Curiously, whereas optimal immunity with systemic priming and boosting occurred when gB DNA was used to prime and rvacgB was used as a boost, mucosal responses were optimal when animals were mucosally primed with rvacgB and boosted with gB DNA given mucosally. Furthermore, notable mucosal responses also occurred in animals mucosally primed with rvacgB and subsequently boosted systemically with gB DNA. Because the mucosal prime-boost immunization protocol also induced excellent systemic immune responses, the approach should be useful to vaccinate against agents for which both mucosal and systemic immunity are important for protection.
CD150 Association with Either the SH2-Containing Inositol Phosphatase or the SH2-Containing Protein Tyrosine Phosphatase Is Regulated by the Adaptor Protein SH2D1A
Authors: Shlapatska Larysa M. , Mikhalap Svitlana V. , Berdova Anna G. , Zelensky Oleksander M. , Yun Theodore J. , Nichols Kim E. , Clark Edward A. , Sidorenko Svetlana P. 
Published: April 2014

Abstract
CD150 (SLAM/IPO-3) is a cell surface receptor that, like the B cell receptor, CD40, and CD95, can transmit positive or negative signals. CD150 can associate with the SH2-containing inositol phosphatase (SHIP), the SH2-containing protein tyrosine phosphatase (SHP-2), and the adaptor protein SH2 domain protein 1A (SH2D1A/DSHP/SAP, also called Duncan’s disease SH2-protein (DSHP) or SLAM-associated protein (SAP)). Mutations in SH2D1A are found in X-linked lymphoproliferative syndrome and non-Hodgkin’s lymphomas. Here we report that SH2D1A is expressed in tonsillar B cells and in some B lymphoblastoid cell lines, where CD150 coprecipitates with SH2D1A and SHIP. However, in SH2D1A-negative B cell lines, including B cell lines from X-linked lymphoproliferative syndrome patients, CD150 associates only with SHP-2. SH2D1A protein levels are up-regulated by CD40 cross-linking and down-regulated by B cell receptor ligation. Using GST-fusion proteins with single replacements of tyrosine at Y269F, Y281F, Y307F, or Y327F in the CD150 cytoplasmic tail, we found that the same phosphorylated Y281 and Y327 are essential for both SHP-2 and SHIP binding. The presence of SH2D1A facilitates binding of SHIP to CD150. Apparently, SH2D1A may function as a regulator of alternative interactions of CD150 with SHP-2 or SHIP via a novel TxYxxV/I motif (immunoreceptor tyrosine-based switch motif (ITSM)). Multiple sequence alignments revealed the presence of this TxYxxV/I motif not only in CD2 subfamily members but also in the cytoplasmic domains of the members of the SHP-2 substrate 1, sialic acid-binding Ig-like lectin, carcinoembryonic Ag, and leukocyte-inhibitory receptor families.
Quantitation of Lysozyme Peptides Bound to Class II MHC Molecules Indicates Very Large Differences in Levels of Presentation
Authors: Velazquez Carlos , DiPaolo Richard , Unanue Emil R. 
Published: April 2014

Abstract
Knowing the abundance of peptides presented by MHC molecules is a crucial aspect for understanding T cell activation and tolerance. In this report we determined the relative abundance of four distinct peptide families after the processing of the model Ag hen egg-white lysozyme. The development of a sensitive immunochemical approach reported here made it possible to directly quantitate the abundance of these four epitopes presented by APCs, both in vitro and in vivo. We observed a wide range of presentation among these four different epitopes presented on the surface of APCs, with 250-fold differences or more between the most abundant epitope (48–63) and the least abundant epitopes. Importantly, we observe similar ratios of presentation from APCs in vitro as well as from APCs from the spleens and thymi of hen egg-white lysozyme transgenic mice. We discuss the relationship between the amount of peptide presented and their binding to I-Ak molecules, immunogenicity, and tolerogenicity.