bluuebunny/crossref_metadata_2025_split huggingface dataset:
IL-15-Dependent Induction of 4-1BB Promotes Antigen-Independent CD8 Memory T Cell Survival
Authors: Pulle Gayle , Vidric Mariana , Watts Tania H. 
Published: April 2014

Abstract
Mice lacking CD137L (4-1BBL) show normal primary expansion and contraction of the CD8+ T cell response to influenza virus, but exhibit a defect in Ag-specific CD8+ T cell numbers at 3–6 wk postinfection. Previous results showed that the decrease in CD8+ T cell numbers in this model is not due to a programming defect during primary expansion. Thus, it appears that 4-1BB/4-1BBL interactions control the number of surviving CD8+ effector memory cells, late in the primary response. In this report, we asked how 4-1BB on T cells could play a role after Ag has apparently been cleared from the host. We show that IL-15, a cytokine involved in regulation of CD8+ memory T cell survival, induces the expression of 4-1BB on CD8+CD44high memory phenotype T cells, but not on CD4+ T cells. The Ag-independent induction of 4-1BB by IL-15 was dependent on MAPK p38 and ERK activation. Transfer of in vitro-generated OT-I CD8+ memory T cells into unimmunized wild-type or 4-1BBL-deficient hosts revealed a 2- to 3-fold survival advantage when 4-1BBL was present, recapitulating the effect seen in the endogenous response to influenza in mice. Decreases in the overall number of memory CD8+ T cells were also observed in the bone marrow of unmanipulated 4-1BBL-deficient mice. These data suggest a model whereby 4-1BB expression on memory CD8+ T cells, perhaps due to encounter with IL-15 in the bone marrow, allows 4-1BB/4-1BBL interactions to maintain memory CD8 T cell survival in the absence of Ag.
Oxidative Stress Promotes Polarization of Human T Cell Differentiation Toward a T Helper 2 Phenotype
Authors: King Miranda R. , Ismail Anisa S. , Davis Laurie S. , Karp David R. 
Published: April 2014

Abstract
These studies were conducted to determine the effects of oxidative stress on human T cell differentiation and polarization into Th1 or Th2 phenotypes. Highly purified naive CD4+ T cells were isolated from PBMC of healthy, nonatopic donors. CD4+ T cells were stimulated with anti-CD3 and anti-CD28 mAb in the presence or absence of oxidative stress as supplied by 2,3-dimethoxy-1,4-naphthoquinone (DMNQ), which generates a low level of superoxide anion. Increases in cellular superoxide were observed by exposure to DMNQ. Exposure of unpolarized CD4+ T cells to IL-12 or IL-4 resulted in a Th1 or Th2 phenotype, respectively. T cells stimulated in the absence of polarizing cytokines secreted modest amounts of IFN-γ and TNF-α. Cells stimulated in the continuous presence of 5 μM DMNQ, displayed a marked up-regulation in Th2 cytokines, including IL-4, IL-5, and IL-13, but not the Th1 cytokine IFN-γ. Th2 responses were blunted by concomitant exposure to thiol antioxidants. Long-term exposure of T cells to DMNQ resulted in growth of cells expressing CCR4, and a decrease in cells expressing CXCR3, indicating phenotypic conversion to Th2 cells. These results suggest that oxidative stress favors a Th2-polarizing condition.
IL-27 Suppresses CD28-Medicated IL-2 Production through Suppressor of Cytokine Signaling 3
Authors: Owaki Toshiyuki , Asakawa Masayuki , Kamiya Sadahiro , Takeda Kiyoshi , Fukai Fumio , Mizuguchi Junichiro , Yoshimoto Takayuki 
Published: April 2014

Abstract
IL-27 is a novel IL-6/IL-12 family cytokine that not only plays a role in the early regulation of Th1 differentiation, but also exerts an inhibitory effect on immune responses, including the suppression of proinflammatory cytokine production. However, the molecular mechanism by which IL-27 exerts the inhibitory effect remains unclear. In this study we demonstrate that IL-27 inhibits CD28-mediated IL-2 production and that suppressor of cytokine signaling 3 (SOCS3) plays a critical role in the inhibitory effect. Although IL-27 enhanced IFN-γ production from naive CD4+ T cells stimulated with plate-coated anti-CD3 and anti-CD28 in the presence of IL-12, IL-27 simultaneously inhibited CD28-mediated IL-2 production. Correlated with the inhibition, IL-27 was shown to augment SOCS3 expression. Analyses using various mice lacking a signaling molecule revealed that the inhibition of IL-2 production was dependent on STAT1, but not on STAT3, STAT4, and T-bet, and was highly correlated with the induction of SOCS3 expression. Similar inhibition of CD28-mediated IL-2 production and augmentation of SOCS3 expression by IL-27 were observed in a T cell hybridoma cell line, 2B4. Forced expression of antisense SOCS3 or dominant negative SOCS3 in the T cell line blocked the IL-27-inudced inhibition of CD28-mediated IL-2 production. Furthermore, pretreatment with IL-27 inhibited IL-2-mediated cell proliferation and STAT5 activation, although IL-27 hardly affected the induction level of CD25 expression. These results suggest that IL-27 inhibits CD28-mediated IL-2 production and also IL-2 responses, and that SOCS3, whose expression is induced by IL-27, plays a critical role in the inhibitory effect in a negative feedback mechanism.
Antibody-Induced Transplantation Tolerance That Is Dependent on Thymus-Derived Regulatory T Cells
Authors: Deng Shaoping , Moore Daniel J. , Huang Xiaolun , Mohiuddin Mohammad , Lee Major K. , Velidedeoglu Ergun , Lian Moh-Moh , Chiaccio Meredith , Sonawane Samsher , Orlin Anton , Wang Jing , Chen Haiying , Caton Andrew , Zhong Robert , Markmann James F. 
Published: April 2014

Abstract
Targeting of the CD45RB isoform by mAb (anti-CD45RB) effectively induces donor-specific tolerance to allografts. The immunological mechanisms underlying the tolerant state remain unclear although some studies have suggested the involvement of regulatory T cells (T-regs). Although their generative pathway remains undefined, tolerance promoting T-regs induced by systemic anti-CD45RB treatment have been assumed to originate in the peripheral immune system. We demonstrate herein that separable effects on the peripheral and central immune compartments mediate graft survival induced by anti-CD45RB administration. In the absence of the thymus, anti-CD45RB therapy is not tolerogenic though it retains peripheral immunosuppressive activity. The thymus is required for anti-CD45RB to produce indefinite graft survival and donor-specific tolerance, and this effect is accomplished through thymic production of donor-specific T-regs. These data reveal for the first time an Ab-based tolerance regimen that relies on the central tolerance pathway.
Regulated Compartmentalization of Programmed Cell Death-1 Discriminates CD4+CD25+ Resting Regulatory T Cells from Activated T Cells
Authors: Raimondi Giorgio , Shufesky William J. , Tokita Daisuke , Morelli Adrian E. , Thomson Angus W. 
Published: April 2014

Abstract
More effective discrimination between CD4+CD25+ regulatory T cells (Treg) and activated T cells would significantly improve the current level of purification of Treg and their therapeutic application. We observed that ∼90% of Treg (positive for the nuclear transcription factor Forkhead winged helix protein-3 and able to inhibit naive T cell proliferation) isolated from the spleens or lymph nodes of normal mice did not express significant levels of the inhibitory receptor programmed cell death-1 (PD-1) on their surface, but retained PD-1 intracellularly. An identical phenotype was also identified for human CD4+CD25high T cells isolated from peripheral blood of healthy volunteers. By contrast, activated T cells expressed high levels of surface PD-1 that paralleled up-regulation of CD25 during effector cell expansion. This distinction allowed us to isolate CD4+CD25+PD-1− T cells with suppressive activity from mice immunized with mature allogeneic dendritic cells. Although purification was limited to resting Treg because TCR ligation induced up-regulation of surface PD-1, this strategy nevertheless represents a valuable step toward more definitive characterization of Treg and their improved purification for therapeutic assessment.
The Dual-Specific Binding of Dengue Virus and Target Cells for the Antibody-Dependent Enhancement of Dengue Virus Infection
Authors: Huang Kao-Jean , Yang Yu-Ching , Lin Yee-Shin , Huang Jyh-Hsiung , Liu Hsiao-Sheng , Yeh Trai-Ming , Chen Shun-Hua , Liu Ching-Chuan , Lei Huan-Yao 
Published: April 2014

Abstract
Using flow cytometric assay and monoclonal anti-dengue Ab, we observed that both anti-E and anti-prM Abs could enhance dengue virus infection in a concentration-dependent but serotype-independent manner. Increases were found in both the percentage of dengue-infected cells and the expression of dengue E and NS1 protein per cell. Dengue virion binding and infection were enhanced on FcR-bearing cells via the Fc-FcγRII pathway. Furthermore, anti-prM Ab also enhanced dengue virion binding and infection on cells lacking FcR, such as BHK-21 or A549 cells, by the mechanism of peptide (CPFLKQNEPEDIDCW)-specific binding. Anti-prM Ab cross-reacted with BHK-21 or A549 cells and recognized self-Ags such as heat shock protein 60. In summary, a novel mechanism of anti-prM Ab-mediated enhancement on dengue virus infection was found to be mediated by dual specific binding to dengue virion and to target cells, in addition to the traditional enhancement on FcR-bearing cells.
Identification of Oncofetal Antigen/Immature Laminin Receptor Protein Epitopes That Activate BALB/c Mouse OFA/iLRP-Specific Effector and Regulatory T Cell Clones
Authors: Rohrer James W. , Barsoum Adel L. , Coggin Joseph H. 
Published: April 2014

Abstract
During tumor development in mice and humans, oncofetal Ag/immature laminin receptor (OFA/iLRP)-specific Th1, CTL, and IL-10-secreting T (Ts) cells are induced. The presence of too many Ts or too few effector T cells appears to predict a poor prognosis. We established clones of OFA/iLRP-specific splenic Th1, CTL, and Ts cells from the OFA/iLRP+ MCA1315 fibrosarcoma-bearing BALB/c mice or from BALB/c mice vaccinated with 1 or 10 μg of rOFA/iLRP. The MCA1315 tumor cell-reactive T cell clones were characterized as to surface Ag phenotype, cytokine secretion profile, and specificity for OFA/iLRP presented by syngeneic splenic APC. OFA/iLRP-specific Th1 and Ts clones were established from all mice. OFA/iLRP-specific CTL could be established from all mice except for mice immunized with 10 μg of rOFA/iLRP. Analysis of the proliferation profile of the OFA/iLRP-specific clones to overlapping OFA/iLRP 12-mer peptides that spanned the OFA/iLRP protein sequence defined the epitopes to which the T cell clones responded. There was a similar spatial distribution of the epitopes to which the two types of CD8 T cell clones responded. The nonapeptide epitopes of the Ts clones were located between aa 36 and 147 of OFA/iLRP, while the epitopes of the CTL clones were located between aa 52 and 163. Even though the CTL and Ts epitopes shared part of the protein, all of the CD8 CTL epitopes were distinct and separable from those of CD8 Ts cells.
The Immunogenicity and Immunomodulatory Function of Osteogenic Cells Differentiated from Mesenchymal Stem Cells
Authors: Liu Hua , Kemeny David Michael , Heng Boon Chin , Ouyang Hong Wei , Melendez Alirio J. , Cao Tong 
Published: April 2014

Abstract
Multipotent mesenchymal stem cells (MSC) are reported to be immunoprivileged as well as immunosuppressive. Hence, they are ideal candidates for allogeneic transplantation to induce regeneration of diseased tissues and organs. However, it is not known whether MSC would retain their immunoprivileged and immunomodulatory properties after differentiating into the local cell types of the transplantation site. This study sought to investigate this question with a novel New Zealand White rabbit osteogenesis model. Results showed that osteogenic cells differentiated from MSC (DOC) in vitro did not express the MHC class II molecule, were incapable of inducing allogeneic lymphocyte proliferation in mixed lymphocyte culture or generating CTL, were inhibitory in ongoing lymphocyte proliferation, and secreted anti-inflammatory cytokines (IL-10 and TGF-β). There was a significantly higher secretion of IL-10 by DOC than that by MSC, while there was no significant difference between the TGF-β secretion of MSC and DOC in vitro. However, after IFN-γ treatment, TGF-β secretion by DOC significantly decreased despite the increased production by MSC. Four weeks after local DOC implantation, despite MHC class II expression, second-set allogeneic skin rejection showed similar survival to first-set allogeneic skin rejection and DOC appeared to function as osteoblasts. In conclusion, DOC retained their immunoprivileged and immunomodulatory properties in vitro, but the latter was lost following transplantation.
Lipoteichoic Acid Increases TLR and Functional Chemokine Expression while Reducing Dentin Formation in In Vitro Differentiated Human Odontoblasts
Authors: Durand Stéphanie H. , Flacher Vincent , Roméas Annick , Carrouel Florence , Colomb Evelyne , Vincent Claude , Magloire Henry , Couble Marie-Lise , Bleicher Françoise , Staquet Marie-Jeanne , Lebecque Serge , Farges Jean-Christophe 
Published: April 2014

Abstract
Gram-positive bacteria entering the dentinal tissue during the carious process are suspected to influence the immune response in human dental pulp. Odontoblasts situated at the pulp/dentin interface are the first cells encountered by these bacteria and therefore could play a crucial role in this response. In the present study, we found that in vitro-differentiated odontoblasts constitutively expressed the pattern recognition receptor TLR1–6 and 9 genes but not TLR7, 8, and 10. Furthermore, lipoteichoic acid (LTA), a wall component of Gram-positive bacteria, triggered the activation of the odontoblasts. LTA up-regulated the expression of its own receptor TLR2, as well as the production of several chemokines. In particular, an increased amount of CCL2 and CXCL10 was detected in supernatants from LTA-stimulated odontoblasts, and those supernatants augmented the migration of immature dendritic cells in vitro compared with controls. Clinical relevance of these observations came from immunohistochemical analysis showing that CCL2 was expressed in vivo by odontoblasts and blood vessels present under active carious lesions but not in healthy dental pulps. In contrast with this inflammatory response, gene expression of major dentin matrix components (type I collagen, dentin sialophosphoprotein) and TGF-β1 was sharply down-regulated in odontoblasts by LTA. Taken together, these data suggest that odontoblasts activated through TLR2 by Gram-positive bacteria LTA are able to initiate an innate immune response by secreting chemokines that recruit immature dendritic cells while down-regulating their specialized functions of dentin matrix synthesis and mineralization.
TLR7/8 Triggering Exerts Opposing Effects in Acute versus Latent HIV Infection
Authors: Schlaepfer Erika , Audigé Annette , Joller Helene , Speck Roberto F. 
Published: April 2014

Abstract
TLRs trigger innate immunity by recognizing conserved motifs of microorganisms. Recently, ssRNAs from HIV and influenza virus were shown to trigger TLR7 and 8. Thus, we hypothesized that HIV ssRNA, by triggering TLR7/8, affects HIV pathogenesis. Indeed, HIV ssRNA rendered human lymphoid tissue of tonsillar origin or PBMC barely permissive to HIV replication. The synthetic compound R-848, which also triggers TLR7/8, showed similar anti-HIV activity. Loss of R-848’s activity in lymphoid tissue depleted of B cells suggested a role for B cells in innate immunity. TLR7/8 triggering appears to exert antiviral effects through soluble factors: conditioned medium reduced HIV replication in indicator cells. Although a number of cytokines and chemokines were increased upon adding R-848 to lymphoid tissue, blocking those cytokines/chemokines (i.e., IFN-α receptor, IFN-γ, MIP-1α, -1β, RANTES, and stromal cell-derived factor-1) did not result in the reversal of R-848’s anti-HIV activity. Thus, the nature of this soluble factor(s) remains unknown. Unlike lymphoid tissue acutely infected with HIV, triggering latently infected promonocytic cells induced the release of HIV virions. The anti-HIV effects of triggering TLR7/8 may inhibit rapid killing, while pro-HIV effects may guarantee a certain replication level. Compounds triggering TLR7/8 may be attractive drug candidates to purge latent HIV while preventing new infections.
IL-18 Reduces Ultraviolet Radiation-Induced DNA Damage and Thereby Affects Photoimmunosuppression
Authors: Schwarz Agatha , Maeda Akira , Ständer Sonja , van Steeg Harry , Schwarz Thomas 
Published: April 2014

Abstract
UV-induced DNA damage has been recognized as the major molecular trigger for photoimmunosuppression. IL-12 prevents UV-induced immunosuppression via its recently discovered capacity to reduce DNA damage presumably via induction of DNA repair. Because IL-18 shares some biological activities with IL-12 we studied the effect of IL-18 on UV-induced DNA damage and immunosuppression. IL-18 reduced UV-induced apoptosis of keratinocytes and supported long-term cell survival on UV exposure. Injection of IL-18 into mice that were exposed to UV radiation significantly lowered the number of apoptotic keratinocytes. Accordingly, radiation immunohistochemistry revealed reduced amounts of DNA damage in epidermal cells upon injection of IL-18. These effects were not observed in DNA repair-deficient (XpaKO) mice, indicating that IL-18 like IL-12 reduces DNA damage via DNA repair. UV-mediated suppression of the induction of contact hypersensitivity, which is known to be primarily triggered by DNA damage, was prevented upon injection of IL-18 before UV exposure in wild-type but not in XpaKO mice. In contrast to IL-12, IL-18 was not able either in wild-type or in XpaKO mice to break UV-induced immunotolerance that is mediated via regulatory T cells rather than in a DNA damage-dependent fashion. This result indicates that IL-12 is still unique in its capacity to restore immune responses because of its effect on regulatory T cells. Together, these data identify IL-18 as a further cytokine that exhibits the capacity to affect DNA repair. Though being primarily a proinflammatory cytokine through this capacity, IL-18 can also foster an immune response that is suppressed by UV radiation.
Murine B16 Melanomas Expressing High Levels of the Chemokine Stromal-Derived Factor-1/CXCL12 Induce Tumor-Specific T Cell Chemorepulsion and Escape from Immune Control
Authors: Vianello Fabrizio , Papeta Natalia , Chen Tao , Kraft Paul , White Natasha , Hart William K. , Kircher Moritz F. , Swart Eric , Rhee Sarah , Palù Giorgio , Irimia Daniel , Toner Mehmet , Weissleder Ralph , Poznansky Mark C. 
Published: April 2014

Abstract
The chemokine, stromal-derived factor-1/CXCL12, is expressed by normal and neoplastic tissues and is involved in tumor growth, metastasis, and modulation of tumor immunity. T cell-mediated tumor immunity depends on the migration and colocalization of CTL with tumor cells, a process regulated by chemokines and adhesion molecules. It has been demonstrated that T cells are repelled by high concentrations of the chemokine CXCL12 via a concentration-dependent and CXCR4 receptor-mediated mechanism, termed chemorepulsion or fugetaxis. We proposed that repulsion of tumor Ag-specific T cells from a tumor expressing high levels of CXCL12 allows the tumor to evade immune control. Murine B16/OVA melanoma cells (H2b) were engineered to constitutively express CXCL12. Immunization of C57BL/6 mice with B16/OVA cells lead to destruction of B16/OVA tumors expressing no or low levels of CXCL12 but not tumors expressing high levels of the chemokine. Early recruitment of adoptively transferred OVA-specific CTL into B16/OVA tumors expressing high levels of CXCL12 was significantly reduced in comparison to B16/OVA tumors, and this reduction was reversed when tumor-specific CTLs were pretreated with the specific CXCR4 antagonist, AMD3100. Memory OVA-specific CD8+ T cells demonstrated antitumor activity against B16/OVA tumors but not B16/OVA.CXCL12-high tumors. Expression of high levels of CXCL12 by B16/OVA cells significantly reduced CTL colocalization with and killing of target cells in vitro in a CXCR4-dependent manner. The repulsion of tumor Ag-specific T cells away from melanomas expressing CXCL12 confirms the chemorepellent activity of high concentrations of CXCL12 and may represent a novel mechanism by which certain tumors evade the immune system.
Expression of Glycosylphosphatidylinositol-Anchored CD59 on Target Cells Enhances Human NK Cell-Mediated Cytotoxicity
Authors: Omidvar Nader , Wang Eddie C. Y. , Brennan Paul , Longhi M. Paula , Smith Richard A. G. , Morgan B. Paul 
Published: April 2014

Abstract
NK cell-mediated cytotoxicity of target cells is the result of a balance between the activating and inhibitory signals provided by their respective ligand-receptor interactions. In our current study, we have investigated the significance of CD59 on human target cells in modulating this process. A range of CD59 site-specific Abs were used in NK cytotoxicity blocking studies against the CD59-expressing K562 target cell line. Significantly reduced cytotoxicity was observed in the presence of Abs previously shown to lack blocking capacity for C-mediated lysis. We investigated the consequences for alternative membrane attachment modalities, namely bis-myristoylated-peptidyl (BiMP) and GPI anchoring, on CD59-negative U937 cells. Expression of GPI-anchored CD59 either via transfection or incorporation rendered U937 targets more susceptible to NK cytotoxicity, whereas incorporation of CD59 via a BiMP anchor to similar levels did not alter susceptibility to NK cytotoxicity. Localization of both BiMP- and GPI-anchored CD59 proteins was shown to be within the lipid raft microdomain. A role for the GPI anchor and independence from glycosylation status was confirmed by expression of transmembrane-anchored CD59 or unglycosylated CD59 and by testing in NK cytotoxicity assays. To investigate mechanisms, we compared the signaling capacity of the various forms of expressed and incorporated CD59 following Ab cross-linking in calcium flux assays. GPI-anchored CD59, with or without glycosylation, mediated activation events, whereas CD59 forms lacking the GPI anchor did not. The data show that the increased susceptibility of target cells expressing CD59 to NK cytotoxicity requires GPI anchor-mediating signaling events, likely mediated by interactions between GPI-anchored CD59 on targets and NK receptors.
Evidence for Epigenetic Maintenance of Ly49a Monoallelic Gene Expression
Authors: Rouhi Arefeh , Gagnier Liane , Takei Fumio , Mager Dixie L. 
Published: April 2014

Abstract
Although structurally unrelated, the human killer cell Ig-like (KIR) genes and the rodent lectin-like Ly49 genes serve similar functional roles in NK cells. Moreover, both gene families display variegated, monoallelic expression patterns established at the transcriptional level. DNA methylation has been shown to play an important role in maintenance of expression patterns of KIR genes, which have CpG island promoters. The potential role of DNA methylation in expression of Ly49 genes, which have CpG-poor promoters, is unknown. In this study, we show that hypomethylation of the region encompassing the Pro-2 promoter of Ly49a and Ly49c in primary C57BL/6 NK cells correlates with expression of the gene. Using C57BL/6 × BALB/c F1 hybrid mice, we demonstrate that the expressed allele of Ly49a is hypomethylated while the nonexpressed allele is heavily methylated, indicating a role for epigenetics in maintaining monoallelic Ly49 gene expression. Furthermore, the Ly49a Pro-2 region is heavily methylated in fetal NK cells but variably methylated in nonlymphoid tissues. Finally, in apparent contrast to the KIR genes, we show that DNA methylation and the histone acetylation state of the Pro-2 region are strictly linked with Ly49a expression status.