bluuebunny/crossref_metadata_2025_split huggingface dataset:
Cutting Edge: Different Toll-Like Receptor Agonists Instruct Dendritic Cells to Induce Distinct Th Responses via Differential Modulation of Extracellular Signal-Regulated Kinase-Mitogen-Activated Protein Kinase and c-Fos
Authors: Agrawal Sudhanshu , Agrawal Anshu , Doughty Barbara , Gerwitz Andrew , Blenis John , Van Dyke Thomas , Pulendran Bali 
Published: April 2014

Abstract
Dendritic cells (DCs) are pivotal in determining the class of an adaptive immune response. However, the molecular mechanisms within DCs that determine this decision-making process are unknown. Here, we demonstrate that distinct Toll-like receptor (TLR) ligands instruct human DCs to induce distinct Th cell responses by differentially modulating mitogen-activated protein kinase signaling. Thus, Escherichia coli LPS and flagellin, which trigger TLR4 and TLR5, respectively, instruct DCs to stimulate Th1 responses via IL-12p70 production, which depends on the phosphorylation of p38 and c-Jun N-terminal kinase 1/2. In contrast, the TLR2 agonist, Pam3cys, and the Th2 stimulus, schistosome egg Ags: 1) barely induce IL-12p70; 2) stimulate sustained duration and magnitude of extracellular signal-regulated kinase 1/2 phosphorylation, which results in stabilization of the transcription factor c-Fos, a suppressor of IL-12; and 3) yield a Th2 bias. Thus, distinct TLR agonists differentially modulate extracellular signal-regulated kinase signaling, c-Fos activity, and cytokine responses in DCs to stimulate different Th responses.
Cutting Edge: Vasoactive Intestinal Peptide Acts as a Potent Suppressor of Inflammation In Vivo byTrans-Deactivating Chemokine Receptors
Authors: Grimm Michael C. , Newman Rosie , Hassim Zeenath , Cuan Natalia , Connor Susan J. , Le Yingying , Wang Ji Ming , Oppenheim Joost J. , Lloyd Andrew R. 
Published: April 2014

AbstractChemokines mediate trafficking of leukocytes to sites of inflammation and immune responses through activation of G protein-coupled receptors, which thereby provide appealing targets for novel anti-inflammatory agents. Vasoactive intestinal peptide (VIP) is an immunosuppressive neurotransmitter. We show that VIP inhibited the function of chemokine receptors on monocytes and CD4+ T lymphocytes, with impaired chemotaxis and calcium flux in response to the cognate chemokine ligands CXCL12, CCL3, CCL4, and CCL5. This was mediated by VIP receptor type 1 and was not caused by chemokine receptor internalization. However, VIP caused dose-dependent phosphorylation of the chemokine receptor CCR5. This trans-deactivation process was studied in a murine model of delayed-type hypersensitivity: continuous infusion of VIP resulted in significant abrogation of monocyte and lymphocyte infiltration. Circulating mononuclear cells from VIP-infused mice were unable to respond to chemokines. VIP may provide a novel approach to treatment of inflammatory diseases through inhibition of chemokine-dependent leukocyte recruitment.
Recipient T Cells Mediate Reperfusion Injury after Lung Transplantation in the Rat
Authors: de Perrot Marc , Young Kevin , Imai Yumiko , Liu Mingyao , Waddell Thomas K. , Fischer Stefan , Zhang Li , Keshavjee Shaf 
Published: April 2014

Abstract
Leukocytes have been implicated in ischemia-reperfusion (IR) injury of the lung, but the individual role of T cells has not been explored. Recent evidence in mice suggests that T cells may play a role in IR injury. Using a syngeneic (Lewis to Lewis) rat lung transplant model, we observed that recipient CD4+ T cells infiltrated lung grafts within 1 h of reperfusion and up-regulated the expression of CD25 over the ensuing 12 h. Nude rats (rnu/rnu) and heterozygous rats (rnu/+) were used to determine the role of T cells in IR injury. No significant difference in lung function was observed between nude and heterozygous recipient rats after 2 h of reperfusion. However, after 12 h of reperfusion, recipient nude rats had significantly higher oxygenation and lower peak airway pressure than recipient heterozygous rats. This was associated with significantly lower levels of IFN-γ in transplanted lung tissue of recipient nude rats. Reconstitution of recipient nude rats with T cells from heterozygous rats restored IR injury after 12 h of reperfusion. The effect of T cells was independent of neutrophil recruitment and activation in the transplanted lung. These results demonstrate that recipient T cells are activated and mediate IR injury during lung transplantation in rats.
The Protease Inhibitor Cystatin C Is Differentially Expressed among Dendritic Cell Populations, but Does Not Control Antigen Presentation
Authors: El-Sukkari Dima , Wilson Nicholas S. , Hakansson Katarina , Steptoe Raymond J. , Grubb Anders , Shortman Ken , Villadangos José A. 
Published: April 2014

AbstractDendritic cells (DC) undergo complex developmental changes during maturation. The MHC class II (MHC II) molecules of immature DC accumulate in intracellular compartments, but are expressed at high levels on the plasma membrane upon DC maturation. It has been proposed that the cysteine protease inhibitor cystatin C (CyC) plays a pivotal role in the control of this process by regulating the activity of cathepsin S, a protease involved in removal of the MHC II chaperone Ii, and hence in the formation of MHC II-peptide complexes. We show that CyC is differentially expressed by mouse DC populations. CD8+ DC, but not CD4+ or CD4−CD8− DC, synthesize CyC, which accumulates in MHC II+Lamp+ compartments. However, Ii processing and MHC II peptide loading proceeded similarly in all three DC populations. We then analyzed MHC II localization and Ag presentation in CD8+ DC, bone marrow-derived DC, and spleen-derived DC lines, from CyC-deficient mice. The absence of CyC did not affect the expression, the subcellular distribution, or the formation of peptide-loaded MHC II complexes in any of these DC types, nor the efficiency of presentation of exogenous Ags. Therefore, CyC is neither necessary nor sufficient to control MHC II expression and Ag presentation in DC. Our results also show that CyC expression can differ markedly between closely related cell types, suggesting the existence of hitherto unrecognized mechanisms of control of CyC expression.
CD4+CD25+ Regulatory T Cells Cure Murine Colitis: The Role of IL-10, TGF-β, and CTLA4
Authors: Liu Haiying , Hu Bin , Xu Damo , Liew Foo Y. 
Published: April 2014

AbstractRegulatory T cells are critical in regulating the immune response, and therefore play an important role in the defense against infection and control of autoimmune diseases. However, a therapeutic role of regulatory T cells in an established disease has not been fully established. In this study, we provide direct evidence that CD4+CD25+ regulatory T cells can cure an established, severe, and progressive colitis. SCID mice developed severe colitis when adoptively transferred with naive CD4+CD25− T cells and infected with the protozoan parasite Leishmania major. The disease development can be completely halted and symptoms reversed, with a healthy outcome, by transferring freshly isolated or activated CD4+CD25+ T cells from syngeneic donors. The therapeutic effect of the regulatory T cells was completely blocked by treatment of the recipients with anti-IL-10R, anti-CTLA4, or anti-TGF-β Ab. However, the resurgence of colitis under these treatments was not accompanied by the reactivation of Th1 or Th2 response nor was it correlated to the parasite load. These results therefore demonstrate that CD4+CD25+ T cells are therapeutic and that the effect is mediated by both IL-10/TGF-β-dependent and independent mechanisms. Furthermore, colitis can manifest independent of Th1 and Th2 responses.
A Comparative Study between T Regulatory Type 1 and CD4+CD25+ T Cells in the Control of Inflammation
Authors: Foussat Arnaud , Cottrez Françoise , Brun Valérie , Fournier Nathalie , Breittmayer Jean-Philippe , Groux Hervé 
Published: April 2014

AbstractThere is now compelling evidence that CD4+CD25+ T cells play a major role in the maintenance of tolerance. Besides CD4+CD25+ T cells, different populations of regulatory CD4+ T cells secreting high amounts of IL-10 (T regulatory type 1 (Tr1)) or TGF-β (Th3) have also been described in in vivo models. In the lymphocyte transfer model of inflammatory bowel disease, we show here that the control of inflammation during the first weeks is not due to a complete inhibition of differentiation of aggressive proinflammatory T cells, but is the result of a balance between proinflammatory and Tr cells. We also show that in the first weeks continuous IL-10 secretion was required to actively control inflammation. Indeed, treatment with anti-IL-10R Abs 3 wk after the start of the experiment completely reversed the protective effect of Tr cells. IL-10 secretion and control of inflammation could be provided by late injection of Tr1 cells that efficiently cure ongoing inflammatory responses in two different models of inflammation. In contrast, inflammation was not controlled when high numbers of CD4+CD45RBlow or CD4+CD25+ T cells were injected as early as 1 wk after the start of the experiment. These results confirm in vitro studies showing that CD4+CD45RBlow do not contain high IL-10-producing cells and suggest that CD4+CD45RBlow Tr cells maintain tolerance in vivo, in part indirectly, through the differentiation of IL-10-secreting Tr1 cells.
Uncoupling between Immunological Synapse Formation and Functional Outcome in Human γδ T Lymphocytes
Authors: Favier Benoit , Espinosa Eric , Tabiasco Julie , Dos Santos Cédric , Bonneville Marc , Valitutti Salvatore , Fournié Jean-Jacques 
Published: April 2014

AbstractHuman T lymphocytes expressing the Vγ9Vδ2 TCR recognize non-peptidic Ags, referred to as phosphoantigens, produced by microbial pathogens and by human tumor cells. Here we show that γδ T cells establish a mature immunological synapse (IS) with the myelomonocytic THP-1 tumoral cell line. This synapse is characterized by an enrichment for phosphotyrosine, CD2, and γδ TCR together with the exclusion of CD45. The CD94 and NKG2D receptors are also recruited to the signaling area, while the C-lectin-like activation marker CD69 segregates out of the synapse. γδ T cell conjugation to THP-1 increases upon stimulation by soluble phosphoantigen, is paralleled by the metabolic activation of γδ T cells and leads to cytokine production. Molecular segregation of the above molecules also occurs at the γδ T cell/THP-1 interface in the absence of exogenously added phosphoantigen, although it does not result in intracellular signaling and cytokine production under these conditions. Hence the molecular interactions at the γδ T cell-THP-1 target cell interface are sufficient to induce the formation of an IS, but cytokine production requires the full engagement of γδ TCR by a strong agonist. Thus in γδ T cells, formation of the IS is uncoupled from its functional outcome.
Reprogramming of IL-10 Activity and Signaling by IFN-γ
Authors: Herrero Carmen , Hu Xiaoyu , Li Wai Ping , Samuels Stuart , Sharif M. Nusrat , Kotenko Sergei , Ivashkiv Lionel B. 
Published: April 2014

AbstractOne important mechanism of cross-regulation by opposing cytokines is inhibition of signal transduction, including inhibition of Janus kinase-STAT signaling by suppressors of cytokine signaling. We investigated whether IFN-γ, a major activator of macrophages, inhibited the activity of IL-10, an important deactivator. Preactivation of macrophages with IFN-γ inhibited two key anti-inflammatory functions of IL-10, the suppression of cytokine production and of MHC class II expression. Gene expression profiling showed that IFN-γ broadly suppressed the ability of IL-10 to induce or repress gene expression. Although IFN-γ induced expression of suppressor of cytokine signaling proteins, IL-10 signal transduction was not suppressed and IL-10 activation of Janus kinases and Stat3 was preserved. Instead, IFN-γ switched the balance of IL-10 STAT activation from Stat3 to Stat1, with concomitant activation of inflammatory gene expression. IL-10 activation of Stat1 required the simultaneous presence of IFN-γ. These results demonstrate that IFN-γ operates a switch that rapidly regulates STAT activation by IL-10 and alters macrophage responses to IL-10. Dynamic regulation of the activation of different STATs by the same cytokine provides a mechanism by which cells can integrate and balance signals delivered by opposing cytokines, and extends our understanding of cross-regulation by opposing cytokines to include reprogramming of signaling and alteration of function.
Loss of Tolerance and Autoimmunity Affecting Multiple Organs inSTAT5A/5B-Deficient Mice
Authors: Snow Jonathan W. , Abraham Ninan , Ma Melissa C. , Herndier Brian G. , Pastuszak Alexander W. , Goldsmith Mark A. 
Published: April 2014

AbstractSTAT5 has previously been reported to be dispensable for the maintenance of tolerance in vivo. However, in examining hemopoiesis in mice lacking both isoforms of STAT5, STAT5A, and STAT5B, we noted that a subset of these mice demonstrated dramatic alterations in several bone marrow progenitor populations concomitant with lymphocytic infiltration of the bone marrow. In addition, cellular infiltration affecting the colon, liver, and kidney was observed in these mice. Survival analysis revealed that STAT5A/5B−/− mice exhibited early death. The increased mortality and the pathology affecting multiple organs observed in these mice were abrogated on the recombination-activating gene 1−/− background. In light of the similarities between STAT5A/5B-deficient mice and mice unable to signal through the IL-2R, we hypothesized that the tolerizing role of STAT5A/5B was triggered via activation of the IL-2R. In agreement with this, we found that IL-2Rβ chain-deficient mice exhibited similar hemopoietic abnormalities. Because IL-2 signaling is thought to contribute to tolerance through maintenance of a CD4+CD25+ regulatory T cell population, we examined these cells and observed a numerical reduction in STAT5A/5B−/− mice along with a higher rate of apoptosis. These data provide strong evidence for a requirement for STAT5 in the maintenance of tolerance in vivo.
IL-2 Intratumoral Immunotherapy Enhances CD8+ T Cells That Mediate Destruction of Tumor Cells and Tumor-Associated Vasculature: A Novel Mechanism for IL-2
Authors: Jackaman Connie , Bundell Christine S. , Kinnear Beverley F. , Smith Alison M. , Filion Pierre , van Hagen Deborah , Robinson Bruce W. S. , Nelson Delia J. 
Published: April 2014

AbstractTherapeutic use of IL-2 can generate antitumor immunity; however, a variety of different mechanisms have been reported. We injected IL-2 intratumorally (i.t.) at different stages of growth, using our unique murine model of mesothelioma (AE17; and AE17 transfected with secretory OVA (AE17-sOVA)), and systematically analyzed real-time events as they occurred in vivo. The majority of mice with small tumors when treatment commenced displayed complete tumor regression, remained tumor free for &gt;2 mo, and survived rechallenge with AE17 tumor cells. However, mice with large tumors at the start of treatment failed to respond. Timing experiments showed that IL-2-mediated responses were dependent upon tumor size, not on the duration of disease. Although i.t. IL-2 did not alter tumor Ag presentation in draining lymph nodes, it did enhance a previously primed, endogenous, tumor-specific in vivo CTL response that coincided with regressing tumors. Both CD4+ and CD8+ cells were required for IL-2-mediated tumor eradication, because IL-2 therapy failed in CD4+-depleted, CD8+-depleted, and both CD4+- and CD8+-depleted C57BL/6J animals. Tumor-infiltrating CD8+ T cells, but not CD4+ T cells, increased in association with a marked reduction in tumor-associated vascularity. Destruction of blood vessels required CD8+ T cells, because this did not occur in nude mice or in CD8+-depleted C57BL/6J mice. These results show that repeated doses of i.t. (but not systemic) IL-2 mediates tumor regression via an enhanced endogenous tumor-specific CTL response concomitant with reduced vasculature, thereby demonstrating a novel mechanism for IL-2 activity.
DQ 65–79, A Peptide Derived from HLA Class II, Mimics p21 to Block T Cell Proliferation
Authors: Dong Chen , Lyu Shu-Chen , Krensky Alan M. , Clayberger Carol 
Published: April 2014

AbstractDQ 65–79, a peptide derived from residues 65–79 of the α-chain HLA class II molecule DQA03011, blocks T cell proliferation and induces T cell apoptosis. Using a yeast two-hybrid assay, we previously identified proliferating cell nuclear Ag (PCNA) as an intracellular ligand for DQ 65–79. In this study, we show that three regions of PCNA, residues 81–100, 121–140, and 241–261, interact with DQ 65–79. Residues 241–261 of PCNA also interact with the C terminus (residues 139–160) of the cell cycle regulator, p21, suggesting that DQ 65–79 and p21 might function similarly. We show here that DQ 65–79 competitively inhibits binding of p21 to PCNA and that both DQ 65–79 and p21 139–160 induce T cell apoptosis, suggesting that DQ 65–79 and p21 act similarly to inhibit cell growth.
CD8+ T Lymphocytes Regulating Th2 Pathology Escape Neonatal Tolerization
Authors: Adams Brigitte , Nagy Nathalie , Paulart Frédéric , Vanderhaeghen Marie-Line , Goldman Michel , Flamand Véronique 
Published: April 2014

AbstractTransplantation tolerance induced by neonatal injection of semiallogeneic spleen cells is associated in several strain combinations with a pathological syndrome caused by Th2 differentiation of donor-specific CD4+ T lymphocytes. We investigated the role of host CD8+ T cells in the regulation of this Th2 pathology. IgE serum levels and eosinophilia significantly increased in BALB/c mice neonatally injected with (A/J × BALB/c)F1 spleen cells when CD8+ T cells were depleted by administration of anti-CD8 mAb or when β2-microglobulin-deficient mice were used as recipients. In parallel, increased serum levels of IL-5 and IL-13 were measured in blood of tolerant CD8+ T cell-deficient mice. Whereas neonatally injected mice were unable to generate anti-donor cytotoxic effectors, their CD8+ T cells were as efficient as control CD8+ T cells in reducing the severity of Th2 pathology and in restoring donor-specific cytotoxicity in vitro after in vivo transfer in β2-microglobulin-deficient mice. Likewise, CD8+ T cells from control and tolerant mice equally down-regulated the production of Th2 cytokines by donor-specific CD4+ T cells in vitro. The regulatory activity of CD8+ T cells depended on their secretion of IFN-γ for the control of IL-5 production but not for IL-4 or IL-13. Finally, we found that CD8+ T cells from 3-day-old mice were already able to down-regulate IL-4, IL-5, and IL-13 production by CD4+ T cells. We conclude that regulatory CD8+ T cells controlling Th2 responses are functional in early life and escape neonatal tolerization.
CD8α+ and CD11b+ Dendritic Cell-Restricted MHC Class II Controls Th1 CD4+ T Cell Immunity
Authors: Lemos Maria P. , Fan Lian , Lo David , Laufer Terri M. 
Published: April 2014

AbstractThe activation, proliferation, differentiation, and trafficking of CD4 T cells is central to the development of type I immune responses. MHC class II (MHCII)-bearing dendritic cells (DCs) initiate CD4+ T cell priming, but the relative contributions of other MHCII+ APCs to the complete Th1 immune response is less clear. To address this question, we examined Th1 immunity in a mouse model in which I-Aβb expression was targeted specifically to the DCs of I-Aβb−/− mice. MHCII expression is reconstituted in CD11b+ and CD8α+ DCs, but other DC subtypes, macrophages, B cells, and parenchymal cells lack of expression of the I-Aβb chain. Presentation of both peptide and protein Ags by these DC subsets is sufficient for Th1 differentiation of Ag-specific CD4+ T cells in vivo. Thus, Ag-specific CD4+ T cells are primed to produce Th1 cytokines IL-2 and IFN-γ. Additionally, proliferation, migration out of lymphoid organs, and the number of effector CD4+ T cells are appropriately regulated. However, class II-negative B cells cannot receive help and Ag-specific IgG is not produced, confirming the critical MHCII requirement at this stage. These findings indicate that DCs are not only key initiators of the primary response, but provide all of the necessary cognate interactions to control CD4+ T cell fate during the primary immune response.
Differential Roles for IL-15R α-Chain in NK Cell Development and Ly-49 Induction
Authors: Kawamura Toshihiko , Koka Rima , Ma Averil , Kumar Vinay 
Published: April 2014

AbstractIL-15Rα-deficient (IL-15Rα−/−) mice lack NK cells. However, when bone marrow (BM) progenitors from IL-15Rα−/− mice were cultured with IL-7, stem cell factor and flt3 ligand, followed by IL-15, they were able to differentiate into functional NK cells, indicating that IL-15Rα is not critical for NK cell development. Whereas NK cells generated in vitro from IL-15Rα−/− BM progenitors expressed CD94/NKG2, they failed to express Ly-49 receptors. In keeping with this, when IL-15Rα−/− BM cells were transferred into wild type recipients, they gave rise to NK cells in vivo, but with greatly reduced expression of Ly-49 receptors. Furthermore, the small numbers of NK cells found in IL-15−/− as well as IL-15Rα−/− but not flt3 ligand−/− mice expressed much lower levels of Ly-49 receptors than those from wild type mice. These results indicate a novel role for IL-15Rα-chain in Ly-49 induction on developing NK cells.
Adiponectin, a Fat Cell Product, Influences the Earliest Lymphocyte Precursors in Bone Marrow Cultures by Activation of the Cyclooxygenase-Prostaglandin Pathway in Stromal Cells
Authors: Yokota Takafumi , Meka C. S. Reddy , Kouro Taku , Medina Kay L. , Igarashi Hideya , Takahashi Masahiko , Oritani Kenji , Funahashi Tohru , Tomiyama Yoshiaki , Matsuzawa Yuji , Kincade Paul W. 
Published: April 2014

AbstractAdiponectin, an adipocyte-derived hormone, is attracting considerable interest as a potential drug for diabetes and obesity. Originally cloned from human s.c. fat, the protein is also found in bone marrow fat cells and has an inhibitory effect on adipocyte differentiation. The aim of the present study is to explore possible influences on lymphohematopoiesis. Recombinant adiponectin strongly inhibited B lymphopoiesis in long-term bone marrow cultures, but only when stromal cells were present and only when cultures were initiated with the earliest category of lymphocyte precursors. Cyclooxygenase inhibitors abrogated the response of early lymphoid progenitors to adiponectin in stromal cell-containing cultures. Furthermore, PGE2, a major product of cyclooxygenase-2 activity, had a direct inhibitory influence on purified hematopoietic cells, suggesting a possible mechanism of adiponectin action in culture. In contrast to lymphopoiesis, myelopoiesis was slightly enhanced in adiponectin-treated bone marrow cultures, and even when cultures were initiated with single lymphomyeloid progenitors. Finally, human B lymphopoiesis was also sensitive to adiponectin in stromal cell cocultures. These results suggest that adiponectin can negatively and selectively influence lymphopoiesis through induction of PG synthesis. They also indicate ways that adipocytes in bone marrow can contribute to regulation of blood cell formation.