bluuebunny/crossref_metadata_2025_split huggingface dataset:
Histone Peptide-Induced Nasal Tolerance: Suppression of Murine Lupus
Authors: Wu Henry Yim , Ward Frank J. , Staines Norman A. 
Published: April 2014

Abstract
Induced mucosal tolerance has been shown to be beneficial in preventing or treating a number of murine and human autoimmune disorders. However, this particular form of therapy has not been thoroughly tested in systemic lupus erythematosus. In this study, we investigated the conditions for induction of nasal tolerance using a histone peptide named H471 expressing a dominant T cell epitope in the histone protein H4 of mononucleosome in lupus-prone SNF1 female mice. We also tested the effect of chronic peptide nasal treatment on the development of autoimmune reactivities in these mice. Results demonstrated that a dose-dependent nasal tolerance to peptide H471 can be achieved before or after peptide sensitization in SNF1 mice. In addition, tolerance to mononucleosomes was induced by nasal instillation of SNF1 mice with H471. This was accompanied by an increase in IL-10 and suppression of IFN-γ production by lymph node cells. Suppression of Th1-type cytokines was also observed in SNF1 mice that were nasally administered with H471 before intradermal injection with the peptide. Finally, chronic nasal instillation of mice with the H471 peptide not only suppressed the development of autoantibodies, but also altered the severity of glomerulonephritis in lupus-prone SNF1 mice.
Cutting Edge: Targeted Ligation of CTLA-4 In Vivo by Membrane-Bound Anti-CTLA-4 Antibody Prevents Rejection of Allogeneic Cells
Authors: Hwang Kwang Woo , Sweatt William B. , Brown Ian E. , Blank Christian , Gajewski Thomas F. , Bluestone Jeffrey A. , Alegre Maria-Luisa 
Published: April 2014

AbstractNatural engagement of CTLA-4 on host B7 limits T cell activation. We hypothesized that therapeutic cross-linking of CTLA-4 in vivo may further inhibit T cell function and prevent allograft rejection. However, none of the currently available CTLA-4-binding reagents have ligating properties when injected in vivo. The observation that surface-immobilized anti-CTLA-4 mAb inhibits T cell activation in vitro prompted us to develop a membrane-bound single-chain anti-CTLA-4 Ab (7M). To model whether tissue expression of 7M could suppress allograft rejection, we examined the ability of H-2Ld-specific TCR-transgenic T cells to reject 7M-expressing allogeneic tumor cells injected s.c. Expression of 7M significantly inhibited allogeneic rejection in mice that received CTLA-4+/+ but not CTLA-4−/− T cells. Furthermore, CTLA-4+/+ T cells that had encountered 7M-expressing tumors in vivo acquired defects in cytokine production and cytotoxicity. Thus, deliberate ligation of CTLA-4 in vivo potently inhibits allogeneic T cell responses.
Cutting Edge: Changes in Histone Acetylation at the IL-4 and IFN-γ Loci Accompany Th1/Th2 Differentiation
Authors: Fields Patrick E. , Kim Sean T. , Flavell Richard A. 
Published: April 2014

Abstract
Peripheral T cell differentiation is accompanied by chromatin changes at the signature cytokine loci. Using chromatin immunoprecipitation we demonstrate that profound increases in histone acetylation occur at the IFN-γ and IL-4 loci during Th1/Th2 differentiation. These changes in histone acetylation status are locus and lineage specific, and are maintained by the transcription factors Tbet and GATA3 in a STAT-dependent manner. Our results suggest a model of cytokine locus activation in which TCR signals initiate chromatin remodeling and locus opening in a cytokine-independent fashion. Subsequently, cytokine signaling reinforces polarization by expanding and maintaining the accessible state at the relevant cytokine locus (IL-4 or IFN-γ). In this model, GATA3 and Tbet serve as transcriptional maintenance factors, which keep the locus accessible to the transcriptional machinery.
A Soluble Isoform of the Rhesus Monkey Nonclassical MHC Class I Molecule Mamu-AG Is Expressed in the Placenta and the Testis
Authors: Ryan Andy F. , Grendell Richard L. , Geraghty Daniel E. , Golos Thaddeus G. 
Published: April 2014

Abstract
The nonclassical MHC class I locus HLA-G is expressed primarily in the placenta, although other sites of expression have been noted in normal and pathological situations. In addition, soluble HLA-G isoforms have been detected in the serum of pregnant and nonpregnant women as well as men. The rhesus monkey placenta expresses a novel nonclassical MHC class I molecule Mamu-AG, which has features remarkably similar to those of HLA-G. We determined that the rhesus placenta expresses Mamu-AG mRNA (Mamu-AG5), retaining intron 4 as previously noted in HLA-G5. Immunostaining experiments with Ab 16G1 against the soluble HLA-G5 intron 4 peptide demonstrated that an immunoreactive protein(s) was present in the syncytiotrophoblasts of the chorionic villi of the rhesus placenta, within villous cytotrophoblasts, and occasionally within cells of the villous stroma. The Mamu-AG5 mRNA was readily detected in rhesus testis (although not in ejaculated sperm). Whereas an Ab against membrane-bound Mamu-AG stained few cells, primarily in the interstitium of the testis, there was consistent immunostaining for Mamu-AG5 in cells within the seminiferous tubules, which was corroborated by localization of Mamu-AG mRNA by in situ hybridization. While primary spermatocytes were negative, Sertoli cells, spermatocytes, and spermatids were consistently positive for 16G1 immunostaining. The specific recognition of the soluble Mamu-AG isoform was confirmed by Western blotting of Mamu-AG5 expressed in heterologous cells. The results demonstrate that a soluble nonclassical MHC class I molecule is expressed in the rhesus monkey placenta and testis, and confirm and extend the unique homology between HLA-G and the rhesus nonclassical molecule Mamu-AG.
CD94/NKG2 Expression Does Not Inhibit Cytotoxic Function of Lymphocytic Choriomeningitis Virus-Specific CD8+ T Cells
Authors: Miller Joseph D. , Peters Michael , Oran Alp E. , Beresford Guy W. , Harrington Laurie , Boss Jeremy M. , Altman John D. 
Published: April 2014

Abstract
Murine Ag-specific CD8+ T cells express various NK markers and NK inhibitory receptors that have been proposed to modulate immune responses. Following acute infection of C57BL/6 and BALB/cJ mice with lymphocytic choriomeningitis virus (LCMV), we observed that Ag-specific CD8+ T cells expressed CD94/NKG2. Only slight expression of Ly49A and Ly49C receptors was observed on NP396-specific T cells, while all NP396-specific T cells expressed the NKT cell marker U5A2-13 Ag. Expression of CD94/NKG2 was maintained for at least 1 year following LCMV infection, as was the NKT cell marker. By means of cell sorting and quantitative PCR, we found that NP118-specific CD8+ T cells primarily express transcripts for inhibitory NKG2 receptor isoforms. CD94/NKG2 expression was also observed on Ag-specific CD8+ T cells following infection with polyoma virus, influenza virus, and Listeria monocytogenes, suggesting that it may be a common characteristic of Ag-specific CD8+ T cells following infection with viral or bacterial pathogens. Expression of CD94/NKG2 on memory-specific CD8+ T cells did not change following secondary challenge with LCMV clone 13 and did not inhibit viral clearance. Furthermore, we found no evidence that CD94/NKG2 inhibits either the lytic function of LCMV-specific T cells or their capacity to produce effector cytokines upon peptide stimulation. Finally, down-regulation of CD94/NKG2 was found to occur only during chronic LCMV infection. Altogether, this study suggests that CD94/NKG2 expression is not necessarily correlated with inhibition of T cell function.
The Homeostasis But Not the Differentiation of T Cells Is Regulated by p27Kip1
Authors: Shen Randy , Kaplan Mark H. 
Published: April 2014

Abstract
The cyclin-dependent kinase inhibitor p27Kip1 is a critical regulator of T cell proliferation. To further examine the relationship of T cell proliferation and differentiation, we examined the ability of T cells deficient in p27Kip1 to differentiate into Th subsets. We observed increased Th2 differentiation in p27Kip1-deficient cultures. In addition to increases in CD4+ and CD8+ T cells, there is a similar increase in γδ T cells in p27Kip1-deficient mice compared with wild-type mice. The increase in Th2 differentiation is correlated to an increase of IL-4 secretion by CD4+DX5+TCRαβ+CD62Llow T cells but not to increased expansion of differentiating Th2 cells. While STAT4- and STAT6-deficient T cells have diminished proliferative responses to IL-12 and IL-4, respectively, proliferative responses are increased in T cells doubly deficient in p27Kip1 and STAT4 or STAT6. In contrast, the increased proliferation and differentiative capacity of p27Kip1-deficient T cells has no effect on the ability of STAT4/p27Kip1- or STAT6/p27Kip1-deficient CD4+ cells to differentiate into Th1 or Th2 cells, respectively. Thus, while p27Kip1 regulates the expansion and homeostasis of several T cell subsets, it does not affect the differentiation of Th subsets.
Src Homology Region 2 Domain-Containing Phosphatase 1 Positively Regulates B Cell Receptor-Induced Apoptosis by Modulating Association of B Cell Linker Protein with Nck and Activation of c-Jun NH2-Terminal Kinase
Authors: Mizuno Kazuya , Tagawa Yuko , Mitomo Katsuyuki , Watanabe Noriyuki , Katagiri Tatsuo , Ogimoto Mami , Yakura Hidetaka 
Published: April 2014

AbstractSrc homology region 2 domain-containing phosphatase 1 (SHP-1) is a key mediator in lymphocyte differentiation, proliferation, and activation. We previously showed that B cell linker protein (BLNK) is a physiological substrate of SHP-1 and that B cell receptor (BCR)-induced activation of c-Jun NH2-terminal kinase (JNK) is significantly enhanced in cells expressing a form of SHP-1 lacking phosphatase activity (SHP-1-C/S). In this study, we confirmed that SHP-1 also exerts negative regulatory effects on JNK activation in splenic B cells. To further clarify the role of SHP-1 in B cells, we examined how dephosphorylation of BLNK by SHP-1 affects downstream signaling events. When a BLNK mutant (BLNKΔN) lacking the NH2-terminal region, which contains four tyrosine residues, was introduced in SHP-1-C/S-expressing WEHI-231 cells, the enhanced JNK activation was inhibited. Among candidate proteins likely to regulate JNK activation through BLNK, Nck adaptor protein was found to associate with tyrosine-phosphorylated BLNK and this association was more pronounced in SHP-1-C/S-expressing cells. Furthermore, expression of dominant-negative forms of Nck inhibited BCR-induced JNK activation. Finally, BCR-induced apoptosis was suppressed in SHP-1-C/S-expressing cells and coexpression of Nck SH2 mutants or a dominant-negative form of SEK1 reversed this phenotype. Collectively, these results suggest that SHP-1 acts on BLNK, modulating its association with Nck, which in turn negatively regulates JNK activation but exerts a positive effect on apoptosis.
B Cells Capturing Antigen Conjugated with CpG Oligodeoxynucleotides Induce Th1 Cells by Elaborating IL-12
Authors: Shirota Hidekazu , Sano Kunio , Hirasawa Noriyasu , Terui Tadashi , Ohuchi Kazuo , Hattori Toshio , Tamura Gen 
Published: April 2014

AbstractAPCs initiate T cell-mediated immune responses against foreign Ags. Dendritic cells are professional APCs that play unique roles, including Ag-nonspecific capture, priming of naive T cells, and Th1 induction, whereas B cells generally lack these functions. In this study we uncovered novel aspects of murine B cells as APCs using CpG oligodeoxynucleotides (CpG) conjugated with an Ag. B cells served as efficient APCs independently of surface Igs. This characteristic was underlaid by the CpG-mediated Ag uptake and presentation, which were functional only when CpG were covalently conjugated to Ag. The B cells cultured with CpG-conjugated Ag not only enhanced IFN-γ formation by Th1 cells, but also induced Th1 differentiation from unprimed T cells. These effects paralleled with the increase in the expression of CD40, CD86, and class II molecules on B cells and the coordinated production of IL-12 by the cells. To our knowledge this is the first report revealing that B cells share with dendritic cells common intrinsic characteristics, such as the Ag-nonspecific capture and presentation, and the induction of Th1 differentiation from unprimed T cells.
Inhibition of the Spontaneous Apoptosis of Neutrophil Granulocytes by the Intracellular Parasite Leishmania major
Authors: Aga Eresso , Katschinski Dörthe M. , van Zandbergen Ger , Laufs Helmut , Hansen Birgit , Müller Kerstin , Solbach Werner , Laskay Tamás 
Published: April 2014

Abstract
Macrophages are the major target cell population of the obligate intracellular parasites Leishmania. Although polymorphonuclear neutrophil granulocytes (PMN) are able to internalize Leishmania promastigotes, these cells have not been considered to date as host cells for the parasites, primarily due to their short life span. In vitro coincubation experiments were conducted to investigate whether Leishmania can modify the spontaneous apoptosis of human PMN. Coincubation of PMN with Leishmania major promastigotes resulted in a significant decrease in the ratio of apoptotic neutrophils as detected by morphological analysis of cell nuclei, TUNEL assay, gel electrophoresis of low m.w. DNA fragments, and annexin V staining. The observed antiapoptotic effect was found to be associated with a significant reduction of caspase-3 activity in PMN. The inhibition of PMN apoptosis depended on viable parasites because killed Leishmania or a lysate of the parasites did not have antiapoptotic effect. L. major did not block, but rather delayed the programmed cell death of neutrophils by ∼24 h. The antiapoptotic effect of the parasites could not be transferred by the supernatants, despite secretion of IL-8 by PMN upon coculture with L. major. In vivo, intact parasites were found intracellularly in PMN collected from the skin of mice 3 days after s.c. infection. This finding strongly suggests that infection with Leishmania prolongs the survival time of neutrophils also in vivo. These data indicate that Leishmania induce an increased survival of neutrophil granulocytes both in vitro and in vivo.
Vascular Adhesion Protein-1 Mediates Adhesion and Transmigration of Lymphocytes on Human Hepatic Endothelial Cells
Authors: Lalor Patricia F. , Edwards Sarah , McNab Gillian , Salmi Marko , Jalkanen Sirpa , Adams David H. 
Published: April 2014

AbstractVascular adhesion protein-1 (VAP-1) is an amine oxidase and adhesion receptor that is expressed by endothelium in the human liver. The hepatic sinusoids are perfused by blood at low flow rates, and sinusoidal endothelium lacks selectin expression and has low levels of CD31, suggesting that VAP-1 may play a specific role in lymphocyte recruitment to the liver. In support of this we now report the constitutive expression of VAP-1 on human hepatic sinusoidal endothelial cells (HSEC) in vitro and demonstrate that VAP-1 supports adhesion and transmigration of lymphocytes across these cells under physiological shear stress. These are the first studies to report the function of VAP-1 on primary human endothelial cells. Under static conditions lymphocyte adhesion to unstimulated HSEC was dependent on VAP-1 and ICAM-2, whereas adhesion to TNF-α-stimulated HSEC was dependent on ICAM-1, VCAM-1, and VAP-1. Under conditions of flow, blocking VAP-1 reduced lymphocyte adhesion to TNF-α-treated HSEC by 50% and significantly reduced the proportion of adherent lymphocytes that transmigrated across cytokine or LPS-activated endothelium. In addition, inhibition of the amine oxidase activity of VAP-1 reduced both adhesion and transmigration of lymphocytes to a level similar to that seen with VAP-1 Ab. Thus, VAP-1 can support transendothelial migration as well as adhesion, and both functions are dependent on its enzymatic activity. In the absence of selectins and CD31, VAP-1 may play a specific role in lymphocyte recruitment via hepatic sinusoidal endothelium. Moreover, since VAP-1 is induced on nonhepatic endothelium in response to inflammation, its ability to support lymphocyte transendothelial migration may be an important systemic function of VAP-1.
Cutting Edge: Profound Defect in T Cell Responses in TNF Receptor-Associated Factor 2 Dominant Negative Mice
Authors: Cannons Jennifer L. , Bertram Edward M. , Watts Tania H. 
Published: April 2014

Abstract
TNFR-associated factor 2 (TRAF2) is an adapter protein that links several members of the TNFR family to downstream signaling pathways. Mice expressing a dominant negative form of TRAF2 in their lymphoid cells (TRAF2.DN mice) have a profound defect in T cell responses to allogeneic APC. In contrast, APC from wild-type or TRAF2.DN mice show an equivalent level of stimulation in a MLR. Ab production and class switch are unimpaired in TRAF2.DN mice. Thus, defects in the TRAF.DN mice appear to be limited to T cells. TRAF2.DN mice demonstrate an impaired T cell response to influenza virus, including decreased secondary expansion of IFN-γ-secreting T cells as well as a decrease in CTL activity. CD4 T cell production of IL-2 was also dramatically impaired in TRAF2.DN mice. These studies suggest an essential role of TRAF2-linked receptors in secondary CD4 and CD8 T cell responses and have important implications for transplantation.
Cutting Edge: The Relative Distribution of T Cells Responding to Chemically Dominant or Minor Epitopes of Lysozyme Is Not Affected by CD40-CD40 Ligand and B7-CD28-CTLA-4 Costimulatory Pathways
Authors: DiPaolo Richard J. , Unanue Emil R. 
Published: April 2014

AbstractWe examined the frequencies and specificities of the CD4+ T cell responses to the protein hen egg white lysozyme in mice deficient in the CD40-CD40 ligand or B7-CD28 costimulatory pathways. The frequency of T cells was decreased by between 3- and 4-fold in CD40−/− mice, and 12-fold in B7-1/B7-2−/− mice, but surprisingly, the relative distribution of T cells responding to peptides that were presented at levels that differed by &gt;250-fold was similar. We also examined the CD4 response after blocking the regulatory molecule CTLA-4 during immunization. We observed no difference in either the frequency or specificity of the CD4+ T cell response if CTLA-4 was blocking during priming. Thus, the T cell response was generated toward the constellation of chemically dominant and subdominant epitopes as a whole, and did not discriminate among them based on their relative abundance.
Cutting Edge: Quantitative Imaging of Raft Accumulation in the Immunological Synapse
Authors: Burack W. Richard , Lee Kyeong-Hee , Holdorf Amy D. , Dustin Michael L. , Shaw Andrey S. 
Published: April 2014

Abstract
Although the accumulation of lipid rafts at the immunological synapse is now well accepted, the degree of the accumulation, the localization within the fine structure of the immunological synapse, and the region from which lipid rafts are recruited have not been defined. In this work we show that lipid rafts preferentially accumulate in the central zone of the immunological synapse, the central supramolecular activation complex (C-SMAC). However, quantitative analyses indicate that the level of recruitment of lipid rafts to the C-SMAC is relatively small and suggests that rearrangement of lipid rafts from the peripheral zone of the synapse into the C-SMAC can account for this accumulation. We also assessed the effects of CD28 deficiency on lipid raft recruitment to the immunological synapse. The accumulation of lipid occurred independently of the CD28/B7 system and was not measurably altered by CD28.
Cutting Edge: Salmonella AvrA Effector Inhibits the Key Proinflammatory, Anti-Apoptotic NF-κB Pathway
Authors: Collier-Hyams Lauren S. , Zeng Hui , Sun Jun , Tomlinson Amelia D. , Bao Zhao Qin , Chen Huaqun , Madara James L. , Orth Kim , Neish Andrew S. 
Published: April 2014

Abstract
Secreted prokaryotic effector proteins have evolved to modulate the cellular functions of specific eukaryotic hosts. Generally, these proteins are considered virulence factors that facilitate parasitism. However, in certain plant and insect eukaryotic/prokaryotic relationships, effector proteins are involved in the establishment of commensal or symbiotic interactions. In this study, we report that the AvrA protein from Salmonella typhimurium, a common enteropathogen of humans, is an effector molecule that inhibits activation of the key proinflammatory NF-κB transcription factor and augments apoptosis in human epithelial cells. This activity is similar but mechanistically distinct from that described for YopJ, an AvrA homolog expressed by the bacterial pathogen Yersinia. We suggest that AvrA may limit virulence in vertebrates in a manner analogous to avirulence factors in plants, and as such, is the first bacterial effector from a mammalian pathogen that has been ascribed such a function.
Endogenous Granulocyte-Macrophage Colony-Stimulating Factor Overexpression In Vivo Results in the Long-Term Recruitment of a Distinct Dendritic Cell Population with Enhanced Immunostimulatory Function
Authors: Miller George , Pillarisetty Venu G. , Shah Alaap B. , Lahrs Svenja , Xing Zhou , DeMatteo Ronald P. 
Published: April 2014

AbstractGM-CSF is critical for dendritic cell (DC) survival and differentiation in vitro. To study its effect on DC development and function in vivo, we used a gene transfer vector to transiently overexpress GM-CSF in mice. We found that up to 24% of splenocytes became CD11c+ and the number of DC increased up to 260-fold to 3 × 108 cells. DC numbers remained substantially elevated even 75 days after treatment. The DC population was either CD8α+CD4− or CD8α−CD4− but not CD8α+CD4+ or CD8α−CD4+. This differs substantially from subsets recruited in normal or Flt3 ligand-treated mice or using GM-CSF protein injections. GM-CSF-recruited DC secreted extremely high levels of TNF-α compared with minimal amounts in DC from normal or Flt3 ligand-treated mice. Recruited DC also produced elevated levels of IL-6 but almost no IFN-γ. GM-CSF DC had robust immune function compared with controls. They had an increased rate of Ag capture and caused greater allogeneic and Ag-specific T cell stimulation. Furthermore, GM-CSF-recruited DC increased NK cell lytic activity after coculture. The enhanced T cell and NK cell immunostimulation by GM-CSF DC was in part dependent on their secretion of TNF-α. Our findings show that GM-CSF can have an important role in DC development and recruitment in vivo and has potential application to immunotherapy in recruiting massive numbers of DC with enhanced ability to activate effector cells.