bluuebunny/crossref_metadata_2025_split huggingface dataset:
IL-3 Acts Directly on Osteoclast Precursors and Irreversibly Inhibits Receptor Activator of NF-κB Ligand-Induced Osteoclast Differentiation by Diverting the Cells to Macrophage Lineage
Authors: Khapli Shruti M. , Mangashetti Latha S. , Yogesha S. D. , Wani Mohan R. 
Published: April 2014

AbstractOsteoclasts, the multinucleated cells that resorb bone, differentiate from hemopoietic precursors of the monocyte/macrophage lineage in the presence of M-CSF and receptor activator of NF-κB ligand (RANKL). In this study we investigated the role of IL-3 in osteoclast differentiation. We show here that IL-3, a cytokine secreted by activated T lymphocytes, inhibits RANKL-induced osteoclast differentiation by a direct action on early osteoclast precursors. Anti-IL-3 Ab neutralized the inhibitory effect of IL-3 on osteoclast differentiation. In addition, IL-3 inhibits TNF-α-induced osteoclast differentiation in bone marrow-derived macrophages. However, IL-3 has no inhibitory effect on mature osteoclasts. In osteoclast precursors, IL-3 prevents RANKL-induced nuclear translocation of NF-κB by inhibiting the phosphorylation and degradation of IκB. RT-PCR analysis revealed that IL-3 down-regulated c-Fos transcription. Interestingly, the osteoclast precursors in the presence of IL-3 showed strong expression of macrophage markers such as Mac-1, MOMA-2, and F4/80. Furthermore, the inhibitory effect of IL-3 on osteoclast differentiation was irreversible, and the osteoclast precursors preincubated in IL-3 were resistant to RANKL action. Thus, our results reveal for the first time that IL-3 acts directly on early osteoclast precursors and irreversibly blocks RANKL-induced osteoclast differentiation by diverting the cells to macrophage lineage.
Dendritic Cells Support Sequential Reprogramming of Chemoattractant Receptor Profiles During Naive to Effector T Cell Differentiation
Authors: Kim Chang H. , Nagata Kinya , Butcher Eugene C. 
Published: April 2014

Abstract
T cells undergo chemokine receptor switches during activation and differentiation in secondary lymphoid tissues. Here we present evidence that dendritic cells can induce changes in T cell expression of chemokine receptors in two continuous steps. In the first switch over a 4–5 day period, dendritic cells up-regulate T cell expression of CXCR3 and CXCR5. Additional stimulation leads to the second switch: down-regulation of lymphoid tissue homing related CCR7 and CXCR5, and up-regulation of Th1/2 effector tissue-targeting chemoattractant receptors such as CCR4, CCR5, CXCR6, and CRTH2. We show that IL-4 and IL-12 can determine the fate of the secondary chemokine receptor switch. IL-4 enhances the generation of CCR4+ and CRTH2+ T cells, and suppresses the generation of CXCR3+ T cells and CCR7− T cells, while IL-12 suppresses the level of CCR4 in responding T cells. Furthermore, IL-4 has positive effects on generation of CXCR5+ and CCR7+ T cells during the second switch. Our study suggests that the sequential switches in chemokine receptor expression occur during naive T cell interaction with dendritic cells. The first switch of T cell chemokine receptor expression is consistent with the fact that activated T cells migrate within lymphoid tissues for interaction with B and dendritic cells, while the second switch predicts the trafficking behavior of effector T cells away from lymphoid tissues to effector tissue sites.
CC Chemokine Receptor 9 Expression Defines a Subset of Peripheral Blood Lymphocytes with Mucosal T Cell Phenotype and Th1 or T-Regulatory 1 Cytokine Profile
Authors: Papadakis Konstantinos A. , Landers Carol , Prehn John , Kouroumalis Elias A. , Moreno Sofia T. , Gutierrez-Ramos Jose-Carlos , Hodge Martin R. , Targan Stephan R. 
Published: April 2014

Abstract
The chemokine receptor CCR9 is expressed on most small intestinal lamina propria and intraepithelial lymphocytes and on a small subset of peripheral blood lymphocytes. CCR9-expressing lymphocytes may play an important role in small bowel immunity and inflammation. We studied the phenotype and functional characteristics of CCR9+ lymphocytes in blood from normal donors. A subset of CCR9+ T cells have a phenotype of activated cells and constitutively express the costimulatory molecules CD40L and OX-40. In contrast to CCR9−, CCR9+CD4+ peripheral blood T cells proliferate to anti-CD3 or anti-CD2 stimulation and produce high levels of IFN-γ and IL-10. IL-10-producing cells were exclusively detected within the CCR9+ subset of CD4+ T cells by intracellular staining and were distinct from IL-2- and IFN-γ-producing cells. Moreover, memory CCR9+CD4+ lymphocytes respond to CD2 stimulation with proliferation and IFN-γ/IL-10 production, whereas memory CCR9−CD4+ cells were unresponsive. In addition, memory CCR9+CD4+ T cells support Ig production by cocultured CD19+ B cells in the absence of prior T cell activation or addition of exogenous cytokines. Our data show that the memory subset of circulating CCR9+CD4+ T cells has characteristics of mucosal T lymphocytes and contains cells with either Th1 or T-regulatory 1 cytokine profiles. Studies on the cytokine profile and Ag specificity of this cell subset could provide important insight into small intestinal immune-mediated diseases and oral tolerance in humans.
CD28 and Inducible Costimulatory Protein Src Homology 2 Binding Domains Show Distinct Regulation of Phosphatidylinositol 3-Kinase, Bcl-xL, and IL-2 Expression in Primary Human CD4 T Lymphocytes
Authors: Parry Richard V. , Rumbley Catherine A. , Vandenberghe Luk H. , June Carl H. , Riley James L. 
Published: April 2014

AbstractLigation of either CD28 or inducible costimulatory protein (ICOS) produces a second signal required for optimal T cell activation and proliferation. One prominent difference between ICOS- and CD28-costimulated T cells is the quantity of IL-2 produced. To understand why CD28 but not ICOS elicits major increases in IL-2 expression, we compared the abilities of these molecules to activate the signal transduction cascades implicated in the regulation of IL-2. Major differences were found in the regulation of phosphatidylinositol 3-kinase activity (PI3K) and c-jun N-terminal kinase. ICOS costimulation led to greatly augmented levels of PI3K activity compared with CD28 costimulation, whereas only CD28 costimulation activated c-jun N-terminal kinase. To examine how these differences in signal transduction affected IL-2 production, we transduced primary human CD4 T cells with a lentiviral vector that expressed the murine CD28 extracellular domain with a variety of human CD28 and ICOS cytoplasmic domain swap constructs. These domains were able to operate as discrete signaling units, suggesting that they can function independently. Our results show that even though the ICOS Src homology (SH) 2 binding domain strongly activated PI3K, it was unable to substitute for the CD28 SH2 binding domain to induce high levels of IL-2 and Bcl-xL. Moreover, the CD28 SH2 binding domain alone was sufficient to mediate optimal levels of Bcl-xL induction, whereas the entire CD28 cytoplasmic tail was required for high levels of IL-2 expression. Thus, differences within their respective SH2 binding domains explain, at least in part, the distinct regulation of IL-2 and Bcl-xL expression following ICOS- or CD28-mediated costimulation.
Cutting Edge: Rapid In Vivo CTL Activity by Polyoma Virus-Specific Effector and Memory CD8+ T Cells
Authors: Byers Anthony M. , Kemball Christopher C. , Moser Janice M. , Lukacher Aron E. 
Published: April 2014

Abstract
For viruses that establish persistent infection, continuous immunosurveillance by effector-competent antiviral CD8+ T cells is likely essential for limiting viral replication. Although it is well documented that virus-specific memory CD8+ T cells synthesize cytokines after short term in vitro stimulation, there is limited evidence that these T cells exhibit cytotoxicity, the dominant antiviral effector function. Here, we show that antiviral CD8+ T cells in mice acutely infected by polyoma virus, a persistent mouse pathogen, specifically eliminate viral peptide-pulsed donor spleen cells within minutes after adoptive transfer and do so via a perforin-dependent mechanism. Antiviral memory CD8+ T cells were similarly capable of rapidly mobilizing potent Ag-specific cytotoxic activity in vivo. These findings strongly support the concept that a cytotoxic effector-memory CD8+ T cell population operates in vivo to control this persistent viral infection.
Inhibition of IFN-γ-Induced Class II Transactivator Expression by a 19-kDa Lipoprotein fromMycobacterium tuberculosis: A Potential Mechanism for Immune Evasion
Authors: Pai Rish K. , Convery Marilyn , Hamilton Thomas A. , Boom W. Henry , Harding Clifford V. 
Published: April 2014

AbstractMycobacterium tuberculosis (MTB) persists inside macrophages despite vigorous immune responses. MTB and MTB 19-kDa lipoprotein inhibit class II MHC (MHC-II) expression and Ag processing by a Toll-like receptor 2-dependent mechanism that is shown in this study to involve a defect in IFN-γ induction of class II transactivator (CIITA). Exposure of macrophages to MTB or MTB 19-kDa lipoprotein inhibited IFN-γ-induced MHC-II expression, but not IL-4-induced MHC-II expression, by preventing induction of mRNA for CIITA (total, type I, and type IV), IFN regulatory factor-1, and MHC-II. MTB 19-kDa lipoprotein induced mRNA for suppressor of cytokine signaling (SOCS)1 but did not inhibit IFN-γ-induced Stat1 phosphorylation. Furthermore, the lipoprotein inhibited MHC-II Ag processing in SOCS1−/− macrophages. MTB 19-kDa lipoprotein did not inhibit translocation of phosphorylated Stat1 to the nucleus or Stat1 binding to and transactivation of IFN-γ-sensitive promoter constructs. Thus, MTB 19-kDa lipoprotein inhibited IFN-γ signaling independent of SOCS1 and without interfering with the activation of Stat1. Inhibition of IFN-γ-induced CIITA by MTB 19-kDa lipoprotein may allow MTB to evade detection by CD4+ T cells.
Genetic Disassociation of Autoimmunity and Resistance to Costimulation Blockade-Induced Transplantation Tolerance in Nonobese Diabetic Mice
Authors: Pearson Todd , Markees Thomas G. , Serreze David V. , Pierce Melissa A. , Marron Michele P. , Wicker Linda S. , Peterson Laurence B. , Shultz Leonard D. , Mordes John P. , Rossini Aldo A. , Greiner Dale L. 
Published: April 2014

AbstractCuring type 1 diabetes by islet transplantation requires overcoming both allorejection and recurrent autoimmunity. This has been achieved with systemic immunosuppression, but tolerance induction would be preferable. Most islet allotransplant tolerance induction protocols have been tested in nonobese diabetic (NOD) mice, and most have failed. Failure has been attributed to the underlying autoimmunity, assuming that autoimmunity and resistance to transplantation tolerance have a common basis. Out of concern that NOD biology could be misleading in this regard, we tested the hypothesis that autoimmunity and resistance to transplantation tolerance in NOD mice are distinct phenotypes. Unexpectedly, we observed that (NOD × C57BL/6)F1 mice, which have no diabetes, nonetheless resist prolongation of skin allografts by costimulation blockade. Further analyses revealed that the F1 mice shared the dendritic cell maturation defects and abnormal CD4+ T cell responses of the NOD but had lost its defects in macrophage maturation and NK cell activity. We conclude that resistance to allograft tolerance induction in the NOD mouse is not a direct consequence of overt autoimmunity and that autoimmunity and resistance to costimulation blockade-induced transplantation tolerance phenotypes in NOD mice can be dissociated genetically. The outcomes of tolerance induction protocols tested in NOD mice may not accurately predict outcomes in human subjects.
Peroxisome Proliferator-Activated Receptor α Negatively Regulates T-bet Transcription Through Suppression of p38 Mitogen-Activated Protein Kinase Activation
Authors: Jones Dallas C. , Ding Xiaohong , Zhang Tian Y. , Daynes Raymond A. 
Published: April 2014

Abstract
Expression of the nuclear hormone receptor peroxisome proliferator-activated receptor α (PPARα) in resting lymphocytes was recently established, although the physiologic role(s) played by this nuclear hormone receptor in these cell types remains unresolved. In this study, we used CD4+ T cells isolated from PPARα−/− and wild-type mice, as well as cell lines that constitutively express PPARα, in experiments designed to evaluate the role of this hormone receptor in the regulation of T cell function. We report that activated CD4+ T cells lacking PPARα produce increased levels of IFN-γ, but significantly lower levels of IL-2 when compared with activated wild-type CD4+ T cells. Furthermore, we demonstrate that PPARα regulates the expression of these cytokines by CD4+ T cells in part, through its ability to negatively regulate the transcription of T-bet. The induction of T-bet expression in CD4+ T cells was determined to be positively influenced by p38 mitogen-activated protein (MAP) kinase activation, and the presence of unliganded PPARα effectively suppressed the phosphorylation of p38 MAP kinase. The activation of PPARα with highly specific ligands relaxed its capacity to suppress p38 MAP kinase phosphorylation and promoted T-bet expression. These results demonstrate a novel DNA-binding independent and agonist-controlled regulatory influence by the nuclear hormone receptor PPARα.
Development of Infectious Tolerance After Donor-Specific Transfusion and Rat Heart Transplantation
Authors: Kataoka Masaaki , Margenthaler Julie A. , Ku Grace , Flye M. Wayne 
Published: April 2014

Abstract
Regulatory cells developed after donor-specific transfusion (DST)-induced acceptance of a LEW heart transplanted into a DA rat. Both DST and the cardiac transplant were necessary to generate the regulatory cells. This donor-specific tolerance can then be transferred into a new DA recipient by adoptive transfer of lymphocytes from the DST-treated long term survivor (LTS) in a dose-dependent manner. The effectiveness of tolerance did not diminish over five generations of adoptive transfer, thus supporting its infectious nature. Although both spleen and lymph node cells were equally effective, graft-infiltrating lymphocytes were more potent. A high level of indirect CTL activity and MLC proliferation were observed in lymphocytes from LTS. In vivo tracking of adoptively transferred CFSE-labeled splenocytes from LTS showed equivalent FACS proliferation and a higher percentage of graft-infiltrating lymphocytes 7 days after heart transplantation, compared with adoptively transferred naive splenocytes. Adoptive transfer of CD8+-depleted LTS splenocytes resulted in 100% subsequent LEW allograft acceptance; whereas CD4+ depletion decreased acceptance to 40%, and depletion of both CD4 and CD8 resulted in 0% acceptance. When positively selected CD4+ or CD8+ cells were adoptively transferred, 100% or 62.5% of LEW cardiac allografts survived, respectively. In conclusion, DST alone promotes a donor-specific infectious tolerance of a heart graft that can be adoptively transferred to subsequent naive allograft recipients despite the undiminished in vitro immunological response to donor Ag. Although both CD4+ and CD8+ populations are responsible for the regulatory mechanism in DST-induced tolerance, the CD4+ population appears to dominate.
Plasmacytoid Dendritic Cell-Derived IFN-α Induces TNF-Related Apoptosis-Inducing Ligand/Apo-2L-Mediated Antitumor Activity by Human Monocytes Following CpG Oligodeoxynucleotide Stimulation
Authors: Kemp Troy J. , Elzey Bennett D. , Griffith Thomas S. 
Published: April 2014

AbstractImmunostimulatory oligodeoxynucleotides (ODN) containing the CpG motif are being tested as immune adjuvants in many disease settings. Of the human PBMC examined, plasmacytoid dendritic cells (pDC) are a major source of type I IFN upon stimulation with CpG ODN. IFNs have numerous immunostimulatory effects, including the induction of TNF-related apoptosis-inducing ligand (TRAIL)/Apo-2L on monocytes, NK cells, and T cells. Importantly, IFN has also been linked to antitumor responses. Thus, we tested whether CpG ODN stimulation of PBMC led to TRAIL/Apo-2L-induced tumor cell death. When PBMC were stimulated with CpG ODN, TRAIL/Apo-2L-dependent tumor cell death was observed. Further examination of CpG ODN-stimulated PBMC revealed that TRAIL/Apo-2L expression was limited to CD14+ cells, which, when depleted, led to a loss of the TRAIL/Apo-2L-mediated tumor cell killing. Moreover, pDC depletion also abolished the TRAIL/Apo-2L-mediated killing of tumor cell targets. Analysis of the pDC showed IFN-α production after CpG ODN stimulation. Finally, inclusion of neutralizing IFN-α antiserum with the PBMC during CpG ODN stimulation abrogated TRAIL/Apo-2L-mediated tumor cell killing. These results define a mechanism by which CpG ODN induces TRAIL/Apo-2L-dependent killing of tumor cells by CD14+ PBMC, in which CpG ODN-activated pDC produce IFN-α that stimulates CD14+ PBMC to express functional TRAIL/Apo-2L.
A MAGE-3 Peptide Presented by HLA-DR1 to CD4+ T Cells That Were Isolated from a Melanoma Patient Vaccinated with a MAGE-3 Protein
Authors: Zhang Yi , Chaux Pascal , Stroobant Vincent , Eggermont Alexander M. M. , Corthals Jurgen , Maillère Bernard , Thielemans Kris , Marchand Marie , Boon Thierry , van der Bruggen Pierre 
Published: April 2014

Abstract
“Cancer-germline” genes such as those of the MAGE family are expressed in many tumors and in male germline cells, but are silent in normal tissues. They encode shared tumor-specific Ags, which have been used in therapeutic vaccination trials of cancer patients. MAGE-3 is expressed in 74% of metastatic melanoma and in 50% of carcinomas of esophagus, head and neck, bladder, and lung. We report here the identification of a new MAGE-3 peptide, which is recognized by three different CD4+ T cell clones isolated from a melanoma patient vaccinated with a MAGE-3 protein. These clones, which express different TCRs, recognize on HLA-DR1 peptide ACYEFLWGPRALVETS, which corresponds to the MAGE-3267–282 and the MAGE-12267–282 protein sequences. One of the T cell clones, which expresses LFA-1 at a high level, lysed tumor cells expressing DR1 and MAGE-3. Another of these DR1-restricted CD4+ clones recognized not only the MAGE-3/12 peptide but also homologous peptides encoded by genes MAGE-1, 2, 4, 6, 10, and 11.
Cutting Edge: Class I Presentation of Host Peptides Following HIV Infection
Authors: Hickman Heather D. , Luis Angela D. , Bardet Wilfried , Buchli Rico , Battson Casey L. , Shearer Michael H. , Jackson Kenneth W. , Kennedy Ronald C. , Hildebrand William H. 
Published: April 2014

Abstract
Class I MHC molecules bind intracellular peptides for presentation to cytotoxic T lymphocytes. Identification of peptides presented by class I molecules during infection is therefore a priority for detecting and targeting intracellular pathogens. To understand which host-encoded peptides distinguish HIV-infected cells, we have developed a mass spectrometric approach to characterize HLA-B*0702 peptides unique to or up-regulated on infected T cells. In this study, we identify 15 host proteins that are differentially presented on infected human T cells. Peptides with increased expression on HIV-infected cells were derived from multiple categories of cellular proteins including RNA binding proteins and cell cycle regulatory proteins. Therefore, comprehensive analysis of the B*0702 peptide repertoire demonstrates that marked differences in host protein presentation occur after HIV infection.
T Cell Receptor Revision Does Not Solely Target Recent Thymic Emigrants
Authors: Cooper Cristine J. , Orr Mark T. , McMahan Catherine J. , Fink Pamela J. 
Published: April 2014

Abstract
CD4+Vβ5+ T cells enter one of two tolerance pathways after recognizing a peripherally expressed superantigen encoded by an endogenous retrovirus. One pathway leads to deletion, while the other, termed TCR revision, results in cellular rescue upon expression of an alternate TCR that no longer recognizes the tolerogen. TCR revision requires the rearrangement of novel TCR β-chain genes and depends on recombinase-activating gene (RAG) expression in peripheral T cells. In line with recent findings that RAG+ splenic B cells are immature cells that have maintained RAG expression, it has been hypothesized that TCR revision is limited to recent thymic emigrants that have maintained RAG expression and TCR loci in a recombination-permissive configuration. Using mice in which the expression of green fluorescent protein is driven by the RAG2 promoter, we now show that in vitro stimulation can drive reporter expression in noncycling, mature, peripheral CD4+ T cells. In addition, thymectomized Vβ5 transgenic RAG reporter mice are used to demonstrate that TCR revision can target peripheral T cells up to 2 mo after thymectomy. Both sets of experiments strongly suggest that reinduction of RAG genes triggers TCR revision. Approximately 3% of CD4+Vβ5+ T cells in thymectomized Vβ5 transgenic reporter mice have undergone TCR revision within the previous 4–5 days. TCR revision can also occur in Vβ5+ T cells from nontransgenic mice, illustrating the relevance of this novel tolerance mechanism in unmanipulated animals.
NK Cells Regulate CD4 Responses Prior to Antigen Encounter
Authors: Dowdell Kennichi C. , Cua Daniel J. , Kirkman Erlinda , Stohlman Stephen A. 
Published: April 2014

Abstract
NK cells not only respond rapidly to infection, shaping subsequent adaptive immunity, but also play a role in regulating autoimmune disease. The ability of NK cells to influence adaptive immunity before Ag exposure was examined in a gender-dependent model of preferential Th1 and Th2 activation. The inability of young adult male SJL mice to activate Th1 cells was reversed via depletion of NK1.1+ cells, whereas the presence or the absence of NK1.1+ cells did not alter responses in age-matched females. Consistent with a gender-dependent role in regulating adaptive immunity, significantly more NK1.1+ cells were present in males compared with females, and this difference was reversed by castration. In contrast to NK1.1+ cells derived from C57BL/6 mice, no spontaneous cytokine secretion was detected in NK1.1+ cells derived from either male or female SJL mice, although an increased frequency of IL-10-secreting NK1.1+ cells was observed in males vs females following in vitro stimulation. Direct evidence that NK1.1+ cells in males influence CD4+ T cell activation before Ag exposure was demonstrated via the adoptive transfer of APC from control and NK1.1-depleted males. The absence of a functional NK T cell population in SJL mice suggests that NK cells influence adaptive immunity before Ag exposure via alterations in APC activity.