bluuebunny/crossref_metadata_2025_split huggingface dataset:
Dendritic Cell Surface Calreticulin Is a Receptor for NY-ESO-1: Direct Interactions between Tumor-Associated Antigen and the Innate Immune System
Authors: Zeng Gang , Aldridge Michael E. , Tian Xiaoli , Seiler Daniel , Zhang Xiaolong , Jin Yusheng , Rao Jianyu , Li Weidong , Chen Dequan , Langford Marlyn P. , Duggan Chris , Belldegrun Arie S. , Dubinett Steven M. 
Published: April 2014

Abstract
How the immune system recognizes endogenously arising tumors and elicits adaptive immune responses against nonmutated tumor-associated Ags is poorly understood. In search of intrinsic factors contributing to the immunogenicity of the tumor-associated Ag NY-ESO-1, we found that the NY-ESO-1 protein binds to the surface of immature dendritic cells (DC), macrophages, and monocytes, but not to that of B cells or T cells. Using immunoprecipitation coupled with tandem mass spectrometry, we isolated DC surface calreticulin as the receptor for NY-ESO-1. Calreticulin Abs blocked NY-ESO-1 binding on immature DC and its cross-presentation to CD8+ T cells in vitro. Calreticulin/NY-ESO-1 interactions provide a direct link between NY-ESO-1, the innate immune system, and, potentially, the adaptive immune response against NY-ESO-1.
B7H1-Ig Fusion Protein Activates the CD4+ IFN-γ Receptor+ Type 1 T Regulatory Subset through IFN-γ-Secreting Th1 Cells
Authors: Ding Qing , Lu Liming , Wang Baolong , Zhou Yun , Jiang Yang , Zhou Xiaorong , Xin Lijun , Jiao Zhijun , Chou Kuang-Yen 
Published: April 2014

Abstract
It has been demonstrated in our previous work that, in the human skin-grafting model, the expression of costimulatory molecule B7H1 (PD-L1) by keratinocytes plays an essential role in inducing local tolerance via activation of IL-10-secreting T cells. This study further analyzes the role of B7H1 in differentiation of type 1 T regulatory (Tr1) cells and explores underlying mechanisms. Mouse fusion protein B7H1-Ig is used, together with immobilized anti-CD3 mAb, to costimulate the purified naive CD4+ T cells. B7H1-Ig-treated CD4+ T cells were found to activate a characteristic Tr1 population possessing a CD4+CD25−Foxp3− CD45RBlow phenotype. These regulatory T cells strongly inhibited the Th1-dominated MLR by secretion of IL-10 and TGF-β. Moreover, B7H1-treated Tr1 cells also resulted in suppressed clinical scores and demyelination when adoptively transferred into mice with experimental allergic encephalomyelitis. Furthermore, analysis of the cytokine profile indicated that there were two differential reaction patterns during the B7H1-Ig-induced Tr1 development. These two patterns were characterized by activation of IFN-γR+IL-10R− Th1 and IFN-γR+IL-10R+ Tr1 cells, respectively. Secretion of IFN-γ by Th1 and the expression of IFN-γR on Tr1 were critical for further Tr1 differentiation, as demonstrated by mAb blocking and by analysis in IFN-γ−/− mice. In conclusion, B7H1 is capable of inducing Tr1 differentiation from naive CD4+ T cells by coactivation in an IFN-γ- or Th1-dependent manner. Our study may shed some light upon the clinical usage of B7H1 as a therapeutic reagent for induction of tolerance.
Liver Sinusoidal Endothelial Cells That Endocytose Allogeneic Cells Suppress T Cells with Indirect Allospecificity
Authors: Tokita Daisuke , Shishida Masayuki , Ohdan Hideki , Onoe Takashi , Hara Hidetaka , Tanaka Yuka , Ishiyama Kohei , Mitsuta Hiroshi , Ide Kentaro , Arihiro Koji , Asahara Toshimasa 
Published: April 2014

Abstract
A portal venous injection of allogeneic donor cells is known to prolong the survival of subsequently transplanted allografts. In this study, we investigated the role of liver sinusoidal endothelial cells (LSECs) in immunosuppressive effects induced by a portal injection of allogeneic cells on T cells with indirect allospecificity. To eliminate the direct CD4+ T cell response, C57BL/6 (B6) MHC class II-deficient C2tatm1Ccum (C2D) mice were used as donors. After portal injection of irradiated B6 C2D splenocytes into BALB/c mice, the host LSECs that endocytosed the irradiated allogeneic splenocytes showed enhanced expression of MHC class II molecules, CD80, and Fas ligand (FasL). Due to transmigration across the LSECs from BALB/c mice treated with a portal injection of B6 C2D splenocytes, the naive BALB/c CD4+ T cells lost their responsiveness to stimulus of BALB/c splenic APCs that endocytose donor-type B6 C2D alloantigens, while maintaining a normal response to stimulus of BALB/c splenic APCs that endocytose third-party C3H alloantigens. Similar results were not observed for naive BALB/c CD4+ T cells that transmigrated across the LSECs from BALB/c FasL-deficient mice treated with a portal injection of B6 C2D splenocytes. Adaptive transfer of BALB/c LSECs that had endocytosed B6 C2D splenocytes into BALB/c mice via the portal vein prolonged the survival of subsequently transplanted B6 C2D hearts; however, a similar effect was not observed for BALB/c FasL-deficient LSECs. These findings indicate that LSECs that had endocytosed allogeneic splenocytes have immunosuppressive effects on T cells with indirect allospecificity, at least partially via the Fas/FasL pathway.
CD4 Expression on Activated NK Cells: Ligation of CD4 Induces Cytokine Expression and Cell Migration
Authors: Bernstein Helene B. , Plasterer Mary C. , Schiff Sherrie E. , Kitchen Christina M. R. , Kitchen Scott , Zack Jerome A. 
Published: April 2014

Abstract
NK cells play an important role in the innate immune response. We have isolated NK cells from human lymphoid tissues and found that these cells express the CD4 molecule on their surface at levels higher than those found on peripheral blood NK cells. To study the functional role of the CD4 molecule on NK cells, we developed an in vitro system by which we are able to obtain robust CD4 expression on NK cells derived from blood. CD4+ NK cells efficiently mediate NK cell cytotoxicity, and CD4 expression does not appear to alter lytic function. CD4+ NK cells are more likely to produce the cytokines γ-IFN and TNF-α than are CD4− NK cells. Ligation of CD4 further increases the number of NK cells producing these cytokines. NK cells expressing CD4 are also capable of migrating toward the CD4-specific chemotactic factor IL-16, providing another function for the CD4 molecule on NK cells. Thus, the CD4 molecule is present and functional on NK cells and plays a role in innate immune responses as a chemotactic receptor and by increasing cytokine production, in addition to its well-described function on T cells as a coreceptor for Ag responsive cell activation.
Modelling Two Possible Mechanisms for the Regulation of the Germinal Center Dynamics
Authors: Moreira Joana S. , Faro Jose 
Published: April 2014

Abstract
Research on the germinal center has tried to unravel the mechanisms that control its dynamics. In this study we focus on the termination of the germinal center reaction, which is still an open problem. We propose two hypothetical biological mechanisms that may be responsible for the control of germinal center dynamics and analyze them through mathematical models. The first one is based on the differentiation of follicular dendritic cells and/or T cells. Interaction of these cells in the differentiated state with germinal center B cells would promote B cell differentiation into memory B cells and Ab-forming cells, ending the germinal center reaction. The second mechanism applies only to a scenario without recycling and consists of the decay of a hypothetical proliferation signal for centroblasts that limits the number of cell divisions. Each of the models makes predictions that can be experimentally tested.
Notch1 and IL-7 Receptor Interplay Maintains Proliferation of Human Thymic Progenitors while Suppressing Non-T Cell Fates
Authors: García-Peydró Marina , de Yébenes Virginia G. , Toribio María L. 
Published: April 2014

Abstract
Notch signaling is critical for T cell development of multipotent hemopoietic progenitors. Yet, how Notch regulates T cell fate specification during early thymopoiesis remains unclear. In this study, we have identified an early subset of CD34highc-kit+flt3+IL-7Rα+ cells in the human postnatal thymus, which includes primitive progenitors with combined lymphomyeloid potential. To assess the impact of Notch signaling in early T cell development, we expressed constitutively active Notch1 in such thymic lymphomyeloid precursors (TLMPs), or triggered their endogenous Notch pathway in the OP9-Delta-like1 stroma coculture. Our results show that proliferation vs differentiation is a critical decision influenced by Notch at the TLMP stage. We found that Notch signaling plays a prominent role in inhibiting non-T cell differentiation (i.e., macrophages, dendritic cells, and NK cells) of TLMPs, while sustaining the proliferation of undifferentiated thymocytes with T cell potential in response to unique IL-7 signals. However, Notch activation is not sufficient for inducing T-lineage progression of proliferating progenitors. Rather, stroma-derived signals are concurrently required. Moreover, while ectopic IL-7R expression cannot replace Notch for the maintenance and expansion of undifferentiated thymocytes, Notch signals sustain IL-7R expression in proliferating thymocytes and induce IL-7R up-regulation in a T cell line. Thus, IL-7R and Notch pathways cooperate to synchronize cell proliferation and suppression of non-T lineage choices in primitive intrathymic progenitors, which will be allowed to progress along the T cell pathway only upon interaction with an inductive stromal microenvironment. These data provide insight into a mechanism of Notch-regulated amplification of the intrathymic pool of early human T cell progenitors.
IL-21 Inhibits IFN-γ Production in Developing Th1 Cells through the Repression of Eomesodermin Expression
Authors: Suto Akira , Wurster Andrea L. , Reiner Steven L. , Grusby Michael J. 
Published: April 2014

Abstract
Exposure of naive Th cell precursors (Thp) to IL-21 inhibits IFN-γ production from developing Th1 cells. The inhibition of IFN-γ seen in IL-21-treated Thp cells is specific as the expression of other Th1 cytokines is unaffected. Recently, it has been reported that Eomesodermin (Eomes), a member of the T-box gene family, is expressed in developing CD8+ T cells and plays an important role in regulating IFN-γ production and cytolytic effector function. In this study, we show that Eomes mRNA and protein are also expressed in developing Th1 cells, and exposure of naive Thp cells to IL-21 results in a decrease in Eomes expression. Moreover, the repression of Eomes expression by IL-21 is not due to an indirect effect of IL-21 on the expression of IFN-γ or STAT4 and is independent of STAT1 and T-bet expression. Finally, we show that ectopic expression of Eomes prevents the inhibition of IFN-γ production from IL-21-treated Thp cells. Taken together, these results demonstrate that Eomes plays a role in regulating IFN-γ production in CD4+ T cells and IL-21 inhibits IFN-γ production in developing Th1 cells through the repression of Eomes expression.
A New Memory CD27−IgG+ B Cell Population in Peripheral Blood Expressing VH Genes with Low Frequency of Somatic Mutation
Authors: Fecteau Jessie F. , Côté Geneviève , Néron Sonia 
Published: April 2014

Abstract
In humans, up to 40% of peripheral B cells express CD27 and have hypermutated variable regions in their Ig genes. The CD27+ B cells are considered to be derived from germinal center following specific antigenic stimulation. Actually, somatic hypermutation in Ig genes and CD27 expression are hallmarks of memory B cells. However, the blood IgM+IgD+CD27+ B cells were recently associated to splenic marginal zone B cells and proposed to be a subset distinct from germinal center-derived memory B cells showing premutated Igs. The results presented herein further weaken this bona fide association because B cells expressing surface IgG, but not CD27, were found in human blood. Representing 1–4% of all peripheral B cells and ∼25% of the IgG+ blood B cells, this population expressed mutated IgG genes showing antigenic selection characteristics but with lower mutation frequencies than that of CD27+IgG+ B cells. However, their morphology and phenotype were similar to that of CD27+IgG+ cells. Interestingly, the proportion of IgG2 over IgG3 transcripts was opposite in CD27−IgG+ and CD27+IgG+ cells, suggesting distinct functions or origins. Overall, these findings extend the memory B cell reservoir beyond the CD27+ compartment and could provide further insights into B cell disorders of unknown etiology.
Exosomes from Bone Marrow Dendritic Cells Pulsed with Diphtheria Toxoid Preferentially Induce Type 1 Antigen-Specific IgG Responses in Naive Recipients in the Absence of Free Antigen
Authors: Colino Jesus , Snapper Clifford M. 
Published: April 2014

Abstract
Exosomes derived from dendritic cells (DC) activate T cells in vivo, but whether exosomes are able to induce and/or modulate humoral immune responses is still unknown. We show that murine bone marrow DC pulsed in vitro with an intact protein (diphtheria toxoid (DT)) produce exosomes that induce, in the absence of free protein, in vivo Ig responses specific for DT in naive recipients. Furthermore, these exosomes stimulate secondary IgG anti-DT responses in mice primed with intact DT. Exosomes from mature, relative to immature, DC were more effective at inducing primary, although not secondary, IgG anti-DT responses. Whereas intact DT preferentially induced a type 2 (IgG1) anti-DT response, exosomes from DT-pulsed bone marrow DC favored induction of type 1 (IgG2b and IgG2a) DT-specific IgG. These results are the first to demonstrate the ability of exosomes derived from Ag-pulsed DC to induce and modulate Ag-specific humoral immunity in vivo.
IL-12 Instructs Skin Homing of Human Th2 Cells
Authors: Biedermann Tilo , Lametschwandtner Günther , Tangemann Kirsten , Kund Julia , Hinteregger Sonja , Carballido-Perrig Nicole , Rot Antal , Schwärzler Christoph , Carballido José M. 
Published: April 2014

AbstractDistinct pattern of homing receptors determines the tissue preference for T cells to exert their effector functions. This homing competence is mostly determined early during T cell activation of naive T cells. In contrast, mechanisms governing the acquisition of particular homing receptors by T cells of the memory phenotype remain enigmatic. Th2 cell-mediated allergic diseases tend to flare during infections despite that these infections prime APCs to produce the prototypic Th1 cell-differentiating cytokine IL-12. In this study, we investigate the effect of IL-12 on the regulation of cutaneous lymphocyte Ag (CLA) on differentiated Th2 cells and consequences of this expression for allergic inflammation. Upon activation with IL-12, CLA− Th2 cells rapidly up-regulated IL-12Rβ2 chain, α(1-3)-fucosyltransferase VII, and CLA molecules. IL-12-mediated CLA expression on Th2 cells was functional because it mediated rolling of these Th2 cells on E-selectin in vitro and migration into human skin grafts in SCID mice. CLA induction occurred immediately after exposure to IL-12 and was independent of IFN-γ expression. In accordance, the transcription factor mediating IFN-γ expression, T-bet, does not directly affect CLA expression. However, CLA expression was further enhanced after IL-12 treatment of T-bet+-transfected Th2 cells in agreement with an increased IL-12 responsiveness of these cells caused by T-bet. The finding that IL-12 conferred skin-homing potential to already differentiated Th2 cells before inducing a switch in their cytokine production profile may explain the observed exacerbation of allergic skin diseases following bacterial infections.
Receptor Activator of NF-κB Ligand and Osteoprotegerin Regulate Proinflammatory Cytokine Production in Mice
Authors: Maruyama Kenta , Takada Yasunari , Ray Neelanjan , Kishimoto Yukiko , Penninger Josef M. , Yasuda Hisataka , Matsuo Koichi 
Published: April 2014

Abstract
Receptor activator of NF-κB ligand (RANKL) is a membrane-bound or soluble cytokine essential for osteoclast differentiation, whereas the decoy receptor osteoprotegerin (OPG) masks RANKL activity. In mouse serum, both soluble RANKL and OPG are detectable. We observed that mice injected with LPS showed significantly down-regulated serum RANKL levels, whereas serum OPG levels were up-regulated. However, the roles of RANKL and OPG in innate immunity remain obscure. We found that RANKL pretreatment suppressed production of proinflammatory cytokines in macrophages in response to stimulation by bacteria and their components. Furthermore, such RANKL-induced tolerance in macrophages was inhibited by GM-CSF treatment, which blocks RANKL signaling. RANKL-induced tolerance occurred in the absence of c-Fos, which is essential for osteoclast differentiation. In mice lacking OPG, LPS-induced production of proinflammatory cytokines was reduced, whereas in mice lacking RANKL, it was increased, and lethality following LPS injection was also elevated, suggesting that constitutive activities of RANKL suppress cytokine responsiveness to LPS in vivo. Strikingly, prior administration of RANKL protected mice from LPS-induced death. These data reveal prophylactic potential of RANKL in acute inflammatory diseases.
The Cathepsin B Inhibitor, z-FA-FMK, Inhibits Human T Cell Proliferation In Vitro and Modulates Host Response to Pneumococcal Infection In Vivo
Authors: Lawrence Clare P. , Kadioglu Aras , Yang Ai-Li , Coward William R. , Chow Sek C. 
Published: April 2014

Abstract
The cathepsin B inhibitor, benzyloxycarbonyl-phenyl-alanyl-fluoromethylketone (z-FA-FMK) at nontoxic doses was found to be immunosuppressive and repressed human T cell proliferation induced by mitogens and IL-2 in vitro. We showed that z-FA-FMK suppresses the secretion of IL-2 and IFN-γ as well as the expression of IL-2R α-chain (CD25) in activated T cells, whereas the expression of the early activated T cell marker, CD69, was unaffected. Furthermore, z-FA-FMK blocks NF-κB activation, inhibits T cell blast formation, and prevents cells from entering and leaving the cell cycle. z-FA-FMK inhibits the processing of caspase-8 and caspase-3 to their respective subunits in resting T cells stimulated through the Ag receptor, but has no effect on the activation of these caspases during Fas-induced apoptosis in proliferating T cells. When administered in vivo, z-FA-FMK significantly increased pneumococcal growth in both lungs and blood, compared with controls, in a mouse model of intranasal pneumococcal infection. Because host response to bronchopneumonia in mice is T cell dependent, our collective results demonstrated that z-FA-FMK is immunosuppressive in vitro and in vivo.
IgG Fc Receptor III Homologues in Nonhuman Primate Species: Genetic Characterization and Ligand Interactions
Authors: Rogers Kenneth A. , Scinicariello Franco , Attanasio Roberta 
Published: April 2014

Abstract
Ig Fc receptors bind to immune complexes through interactions with the Fc regions of specific Ab subclasses to initiate or inhibit the defense mechanisms of the leukocytes on which they are expressed. The mechanism of action of IgG-based therapeutic molecules, which are routinely evaluated in nonhuman primate models, involves binding to the low-affinity FcRIII (CD16). The premise that IgG/CD16 interactions in nonhuman primates mimic those present in humans has not been evaluated. Therefore, we have identified and characterized CD16 and associated TCR ζ-chain homologues in rhesus macaques, cynomolgus macaques, baboons, and sooty mangabeys. Similar to humans, CD16 expression was detected on a lymphocyte subpopulation, on monocytes, and on neutrophils of sooty mangabeys. However, CD16 was detected only on a lymphocyte subpopulation and on monocytes in macaques and baboons. A nonhuman primate rCD16 generated in HeLa cells interacted with human IgG1 and IgG2. By contrast, human CD16 binds to IgG1 and IgG3. As shown for humans, the mAb 3G8 was able to block IgG binding to nonhuman primate CD16 and inhibition of nonhuman primate CD16 N-glycosylation enhanced IgG binding. Clearly, differences in interaction with IgG subclasses and in cell-type expression should be considered when using these models for in vivo evaluation of therapeutic Abs.
A Model for TCR Gene Segment Use
Authors: Warmflash Aryeh , Dinner Aaron R. 
Published: April 2014

AbstractThe TCR α-chain is assembled by somatic recombination of variable (V) and joining (J) gene segments at the CD4+CD8+ stage of development. In this study, we present the first analytical model for deletional rearrangement and show that it is consistent with almost all available data on VαJα use in mice and humans. A key feature of the model is that both “local” and “express service” models of rearrangement can be obtained by varying a single parameter that describes the number of gene segments accessible at a time. We find that the window is much larger for Vα segments than Jα segments, which reconciles seemingly conflicting data for the former. Implications for the properties of the repertoire as a whole and experiments that seek to probe them are discussed. Special considerations for allelic inclusion are treated in the Appendices.
Recombinant HLA-DP2 Binds Beryllium and Tolerizes Beryllium-Specific Pathogenic CD4+ T Cells
Authors: Fontenot Andrew P. , Keizer Timothy S. , McCleskey Mark , Mack Douglas G. , Meza-Romero Roberto , Huan Jianya , Edwards David M. , Chou Yuan K. , Vandenbark Arthur A. , Scott Brian , Burrows Gregory G. 
Published: April 2014

Abstract
Chronic beryllium disease is a lung disorder caused by beryllium exposure in the workplace and is characterized by granulomatous inflammation and the accumulation of beryllium-specific, HLA-DP2-restricted CD4+ T lymphocytes in the lung that proliferate and secrete Th1-type cytokines. To characterize the interaction among HLA-DP2, beryllium, and CD4+ T cells, we constructed rHLA-DP2 and rHLA-DP4 molecules consisting of the α-1 and β-1 domains of the HLA-DP molecules genetically linked into single polypeptide chains. Peptide binding to rHLA-DP2 and rHLA-DP4 was consistent with previously published peptide-binding motifs for these MHC class II molecules, with peptide binding dominated by aromatic residues in the P1 pocket. 9Be nuclear magnetic resonance spectroscopy showed that beryllium binds to the HLA-DP2-derived molecule, with no binding to the HLA-DP4 molecule that differs from DP2 by four amino acid residues. Using beryllium-specific CD4+ T cell lines derived from the lungs of chronic beryllium disease patients, beryllium presentation to those cells was independent of Ag processing because fixed APCs were capable of presenting BeSO4 and inducing T cell proliferation. Exposure of beryllium-specific CD4+ T cells to BeSO4-pulsed, plate-bound rHLA-DP2 molecules induced IFN-γ secretion. In addition, pretreatment of beryllium-specific CD4+ T cells with BeSO4-pulsed, plate-bound HLA-DP2 blocked proliferation and IL-2 secretion upon re-exposure to beryllium presented by APCs. Thus, the rHLA-DP2 molecules described herein provide a template for engineering variants that retain the ability to tolerize pathogenic CD4+ T cells, but do so in the absence of the beryllium Ag.