bluuebunny/crossref_metadata_2025_split huggingface dataset:
Up-Regulation of Programmed Death-1 Expression on Beryllium-Specific CD4+ T Cells in Chronic Beryllium Disease
Authors: Palmer Brent E. , Mack Douglas G. , Martin Allison K. , Gillespie May , Mroz Margaret M. , Maier Lisa A. , Fontenot Andrew P. 
Published: April 2014

Abstract
Chronic beryllium disease (CBD) is caused by workplace exposure to beryllium and is characterized by the accumulation of memory CD4+ T cells in the lung. These cells respond vigorously to beryllium salts in culture by producing proinflammatory Th1-type cytokines. The presence of these inflammatory cytokines leads to the recruitment of alveolar macrophages, alveolitis, and subsequent granuloma development. It has been shown that chronic exposure to conventional Ags leads to up-regulation in the expression of negative regulators of T cells such as programmed death-1 (PD-1). Due to the persistence of beryllium in the lung after the cessation of exposure, aberrant regulation of the PD-1 pathway may play an important role in CBD development. In the present study, PD-1 expression was measured on blood and bronchoalveolar lavage (BAL) CD4+ T cells from beryllium-sensitized and CBD subjects. PD-1 expression was significantly higher on BAL CD4+ T cells compared with those cells in blood, with the highest expression on the beryllium-specific T cell subset. In addition, the expression of PD-1 on BAL CD4+ T cells directly correlated with the severity of the T cell alveolitis. Increased expression of the PD-1 ligands, PD-L1 and PD-L2, on BAL CD14+ cells compared with blood was also seen. The addition of anti-PD-1 ligand mAbs augmented beryllium-induced CD4+ T cell proliferation, and an inverse correlation was seen between PD-1 expression on beryllium-specific CD4+ T cells and beryllium-induced proliferation. Thus, the PD-1 pathway is active in beryllium-induced disease and plays a key role in controlling beryllium-induced T cell proliferation.
Cutting Edge: TNFR-Shedding by CD4+CD25+ Regulatory T Cells Inhibits the Induction of Inflammatory Mediators
Authors: van Mierlo Geertje J. D. , Scherer Hans U. , Hameetman Marjolijn , Morgan Mary E. , Flierman Roelof , Huizinga Tom W. J. , Toes René E. M. 
Published: April 2014

Abstract
CD4+CD25+ regulatory T (Treg) cells play an essential role in maintaining tolerance to self and nonself. In several models of T cell-mediated (auto) immunity, Treg cells exert protective effects by the inhibition of pathogenic T cell responses. In addition, Treg cells can modulate T cell-independent inflammation. We now show that CD4+CD25+ Treg cells are able to shed large amounts of TNFRII. This is paralleled by their ability to inhibit the action of TNF-α both in vitro and in vivo. In vivo, Treg cells suppressed IL-6 production in response to LPS injection in mice. In contrast, Treg cells from TNFRII-deficient mice were unable to do so despite their unhampered capacity to suppress T cell proliferation in a conventional in vitro suppression assay. Thus, shedding of TNFRII represents a novel mechanism by which Treg cells can inhibit the action of TNF, a pivotal cytokine driving inflammation.
Cutting Edge: IL-27 Is a Potent Inducer of IL-10 but Not FoxP3 in Murine T Cells
Authors: Batten Marcel , Kljavin Noelyn M. , Li Ji , Walter Michael J. , de Sauvage Frederic J. , Ghilardi Nico 
Published: April 2014

Abstract
The cytokine IL-27 is important for restricting inflammation in response to a wide variety of immune challenges. In this study, we demonstrate that IL-27 induces expression of the anti-inflammatory cytokine IL-10 by CD4+ and CD8+ T cells. IL-27 relied upon the Th1 transcription factor STAT1 to induce IL-10+IFN-γ+FoxP3− Th1 cells, which were recently shown to be key negative regulators during certain infections. Il27ra−/− mice generated fewer IL-10+ T cells during both Listeria monocytogenes infection and experimental autoimmune encephalomyelitis. The data presented here indicate a novel mechanism for the induction of IL-10 expression by T cells and provide a mechanistic basis for the suppressive effects of IL-27.
Cutting Edge: TGF-β-Induced Expression of Foxp3 in T cells Is Mediated through Inactivation of ERK
Authors: Luo Xunrong , Zhang Qiang , Liu Victoria , Xia Zhenbiao , Pothoven Kathryn L. , Lee Chung 
Published: April 2014

Abstract
The peripheral induction of T regulatory cells can be accomplished by TGF-β through an epigenetic regulation leading to the expression of Foxp3. However, the exact mechanism of such a TGF-β-mediated action remains unclear. In the current study, we found that TGF-β treatment of CD4+CD25− T cells during T cell activation led to a transient inhibition of the phosphorylation of ERK followed by the induction of Foxp3 expression in these cells. Direct treatment with a specific ERK inhibitor, UO126, during CD4+CD25− T cell activation also induced Foxp3 expression and conferred a suppressive function to the induced Foxp3+ T cells. Furthermore, treatment of T cells with either TGF-β or UO126 significantly down-regulated the expression of DNMTs, a reaction normally elicited by demethylation agents, such as 5-Aza-2′-deoxycytidine. These results indicate that the epigenetic regulation of TGF-β-induced expression of Foxp3 may be mediated through the inactivation of ERK.
Cutting Edge: Contributions of Apoptosis and Anergy to Systemic T Cell Tolerance
Authors: Barron Luke , Knoechel Birgit , Lohr Jens , Abbas Abul K. 
Published: April 2014

Abstract
Multiple pathways can induce and maintain peripheral T cell tolerance. The goal of this study was to define the contributions of apoptosis and anergy to the maintenance of self-tolerance to a systemic Ag. Upon transfer into mice expressing OVA systemically, OVA-specific DO11 CD4+ T cells are activated transiently, cease responding, and die. Bim is the essential apoptosis-inducing trigger and apoptosis proceeds despite increased expression of Bcl-2 and Bcl-x. However, preventing apoptosis by eliminating Bim does not restore proliferation or cytokine production by DO11 cells. While Foxp3 is transiently induced, anergy is not associated with the stable development of regulatory T cells. Thus, apoptosis is dispensable for tolerance to a systemic self-Ag and cell-intrinsic anergy is sufficient to tolerize T cells.
Cutting Edge: Selective Expression of Inhibitory or Activating Killer Cell Ig-Like Receptors in Circulating CD4+ T Lymphocytes
Authors: Remtoula Natacha , Bensussan Armand , Marie-Cardine Anne 
Published: April 2014

Abstract
Apart from NK cells, TCRγδ and CD8+ T cells, killer cell Ig-like receptor (KIR) expression was described on a minor subset of CD4+ T cells. However, their functions remain to be elucidated in this latter lymphocyte population. We demonstrated that KIR2DL2/L3 (CD158b) and KIR2DS2 (CD158j) transcripts were synthesized by sorted CD4+CD158b/j+ T cells obtained from healthy individuals. In contrast, we observed that only the inhibitory or activating receptor was expressed at the cell surface according to the donor tested. In CD158b-expressing cells, KIR triggering leads to an inhibition of the CD3-induced cell proliferation and Erk activation, and the receptor exhibits an activation-dependent tyrosine phosphorylation and association with the Src homology 2-containing phosphatase 1. In CD158j-positive cells, KIR-engagement results in an enhanced CD3-mediated cell growth and Erk phosphorylation. Our results suggested that, in contrast to NK cells, the functions of KIR in CD4+ T lymphocytes might derive from a selective expression of their activating or inhibiting forms.
1,25-Dihydroxyvitamin D3 Induces CCR10 Expression in Terminally Differentiating Human B Cells
Authors: Shirakawa Aiko-Konno , Nagakubo Daisuke , Hieshima Kunio , Nakayama Takashi , Jin Zhe , Yoshie Osamu 
Published: April 2014

Abstract
In the B cell lineage, CCR10 is known to be selectively expressed by plasma cells, especially those secreting IgA. In this study, we examined the regulation of CCR10 expression in terminally differentiating human B cells. As reported previously, IL-21 efficiently induced the differentiation of activated human CD19+ B cells into IgD−CD38+ plasma cells in vitro. A minor proportion of the resulting CD19+IgD−CD38+ cells expressed CCR10 at low levels. 1,25-Dihydroxyvitamin D3 (1,25-(OH)2D3), the active metabolite of vitamine D3, dramatically increased the proportion of CD19+IgD−CD38+ cells expressing high levels of CCR10. The 1,25-(OH)2D3 also increased the number of CCR10+ cells expressing surface IgA, although the majority of CCR10+ cells remained negative for surface IgA. Thus, 1,25-(OH)2D3 alone may not be sufficient for the induction of IgA expression in terminally differentiating human B cells. To further determine whether 1,25-(OH)2D3 directly induces CCR10 expression in terminally differentiating B cells, we next performed the analysis on the human CCR10 promoter. We identified a proximal Ets-1 site and an upstream potential vitamin D response element to be critical for the inducible expression of CCR10 by 1,25-(OH)2D3. We confirmed the specific binding of Ets-1 and 1,25-(OH)2D3-activated vitamin D receptor to the respective sites. In conclusion, 1,25-(OH)2D3 efficiently induces CCR10 expression in terminally differentiating human B cells in vitro. Furthermore, the human CCR10 promoter is cooperatively activated by Ets-1 and vitamin D receptor in the presence of 1,25-(OH)2D3.
Notch1 Signaling and Regulatory T Cell Function
Authors: Asano Naoki , Watanabe Tomohiro , Kitani Atsushi , Fuss Ivan J. , Strober Warren 
Published: April 2014

Abstract
Previous studies have shown that the Notch1 and TGF-β signaling pathways are mutually re-enforcing. Given recent evidence that regulatory T cell (Treg) effector function is mediated by TGF-β signaling, we investigated whether Notch1 signaling also participated in Treg effector function. Initial studies showed that Notch1 ligands, particularly Jagged1, are present on Tregs and that, indeed, blockade of Notch1 signaling with an anti-Jagged1 or a blocking anti-Notch1 Ab inhibits Treg suppressor function in vitro. We then showed that a signaling component generated by Notch1 activation (Notch1 intracellular domain) of dendritic cells physically interacts with a signaling component generated by TGF-β signaling (pSmad3). Furthermore, this interaction has functional downstream effects because over-expression of Notch1 intracellular domain facilitates pSmad3 translocation to the nucleus and enhances pSmad3 transcriptional activity of a Smad-sensitive promoter linked to a luciferase reporter. Finally, we showed that blockade of TGF-β signaling and Notch signaling did not have additive inhibitory effects on Treg suppressor function. These results are consistent with the conclusion that Notch1 signaling facilitates TGF-β-mediated effector function of Tregs.
Polyclonal MHC Ib-Restricted CD8+ T Cells Undergo Homeostatic Expansion in the Absence of Conventional MHC-Restricted T Cells
Authors: Jay David C. , Reed-Loisel Lisa M. , Jensen Peter E. 
Published: April 2014

Abstract
Naive T cells have the capacity to expand in a lymphopenic environment in a process called homeostatic expansion, where they gain a memory-like phenotype. Homeostatic expansion is dependent on competition for a number of factors, including growth factors and interactions with their selecting self-MHC molecules. In contrast to conventional T cells, it is unclear whether class Ib-restricted CD8+ T cells have a capacity to undergo homeostatic expansion. In this study, we demonstrate that polyclonal MHC Ib-restricted CD8+ T cells can undergo homeostatic expansion and that their peripheral expansion is suppressed by conventional MHC-restricted T cells. The acute depletion of CD4+ T cells in MHC class Ia-deficient Kb−/−Db−/− mice led to the substantial expansion of class Ib-restricted CD8+ T cells. Adoptive transfer of class Ib-restricted CD8+ T cells to congenic lymphopenic recipients revealed their ability to undergo homeostatic expansion in a MHC Ib-dependent manner. To further study the homeostatic expansion of MHC Ib-restricted T cells in the absence of all conventional MHC-restricted T cells, we generated mice that express only MHC Ib molecules by crossing H-2Kb−/−Db−/− with CIITA−/− mice. CD8+ T cells in these mice exhibit all of the hallmarks of naive T cells actively undergoing homeostatic expansion with constitutive memory-like surface and functional phenotype. These findings provide direct evidence that MHC Ib-restricted CD8+ T cells have the capacity to undergo homeostatic expansion. Their peripheral expansion is suppressed under normal conditions by a numerical excess of conventional MHC class Ia- and class II-restricted T cells.
Critical Synergy of CD30 and OX40 Signals in CD4 T Cell Homeostasis and Th1 Immunity to Salmonella
Authors: Gaspal Fabrina , Bekiaris Vasileios , Kim Mi-Yeon , Withers David R. , Bobat Saeeda , MacLennan Ian C. M. , Anderson Graham , Lane Peter J. , Cunningham Adam F. 
Published: April 2014

Abstract
CD30 and OX40 (CD134) are members of the TNFR superfamily expressed on activated CD4 T cells, and mice deficient in both these molecules harbor a striking defect in the capacity to mount CD4 T cell-dependent memory Ab responses. This article shows that these mice also fail to control Salmonella infection because both CD30 and OX40 signals are required for the survival but not commitment of CD4 Th1 cells. These signals are also needed for the survival of CD4 T cells activated in a lymphopenic environment. Finally, Salmonella and lymphopenia are shown to act synergistically in selectively depleting CD4 T cells deficient in OX40 and CD30. Collectively these findings identify a novel mechanism by which Th1 responses are sustained.
Constitutive Expression of IL-7 Receptor α Does Not Support Increased Expansion or Prevent Contraction of Antigen-Specific CD4 or CD8 T Cells following Listeria monocytogenes Infection
Authors: Haring Jodie S. , Jing Xuefang , Bollenbacher-Reilley Julie , Xue Hai-Hui , Leonard Warren J. , Harty John T. 
Published: April 2014

Abstract
Expression of IL-7Rα (CD127) has been suggested as a major determinant in the survival of memory T cell precursors. We investigated whether constitutive expression of IL-7Rα on T cells increased expansion and/or decreased contraction of endogenous Ag-specific CD4 and CD8 T cells following infection with Listeria monocytogenes. The results indicate that constitutive expression of IL-7Rα alone was not enough to impart an expansion or survival advantage to CD8 T cells responding to infection, and did not increase memory CD8 T cell numbers over those observed in wild-type controls. Constitutive expression of IL-7Rα did allow for slightly prolonged expansion of Ag-specific CD4 T cells; however, it did not alter the contraction phase or protect against the waning of memory T cell numbers at later times after infection. Memory CD4 and CD8 T cells generated in IL-7Rα transgenic mice expanded similarly to wild-type T cells after secondary infection, and immunized IL-7Rα transgenic mice were fully protected against lethal bacterial challenge demonstrating that constitutive expression of IL-7Rα does not impair, or markedly improve memory/secondary effector T cell function. These results indicate that expression of IL-7Rα alone does not support increased survival of effector Ag-specific CD4 or CD8 T cells into the memory phase following bacterial infection.
B Lymphocyte Depletion by CD20 Monoclonal Antibody Prevents Diabetes in Nonobese Diabetic Mice despite Isotype-Specific Differences in FcγR Effector Functions
Authors: Xiu Yan , Wong Carmen P. , Bouaziz Jean-David , Hamaguchi Yasuhito , Wang Yaming , Pop Shannon M. , Tisch Roland M. , Tedder Thomas F. 
Published: April 2014

AbstractNOD mice deficient for B lymphocytes from birth fail to develop autoimmune or type 1 diabetes. To assess whether B cell depletion influences type 1 diabetes in mice with an intact immune system, NOD female mice representing early and late preclinical stages of disease were treated with mouse anti-mouse CD20 mAbs. Short-term CD20 mAb treatment in 5-wk-old NOD female mice reduced B cell numbers by ∼95%, decreased subsequent insulitis, and prevented diabetes in &gt;60% of littermates. In addition, CD20 mAb treatment of 15-wk-old NOD female mice significantly delayed, but did not prevent, diabetes onset. Protection from diabetes did not result from altered T cell numbers or subset distributions, or regulatory/suppressor T cell generation. Rather, impaired CD4+ and CD8+ T cell activation in the lymph nodes of B cell-depleted NOD mice may delay diabetes onset. B cell depletion was achieved despite reduced sensitivity of NOD mice to CD20 mAbs compared with C57BL/6 mice. Decreased B cell depletion resulted from deficient FcγRI binding of IgG2a/c CD20 mAbs and 60% reduced spleen monocyte numbers, which in combination reduced Ab-dependent cellular cytotoxicity. With high-dose CD20 mAb treatment (250 μg) in NOD mice, FcγRIII and FcγRIV compensated for inadequate FcγRI function and mediated B cell depletion. Thereby, NOD mice provide a model for human FcγR polymorphisms that reduce therapeutic mAb efficacy in vivo. Moreover, this study defines a new, clinically relevant approach whereby B cell depletion early in the course of disease development may prevent diabetes or delay progression of disease.
AIMP1/p43 Protein Induces the Maturation of Bone Marrow-Derived Dendritic Cells with T Helper Type 1-Polarizing Ability
Authors: Kim Eugene , Kim Seung Hyun , Kim Sunghoon , Cho Daeho , Kim Tae Sung 
Published: April 2014

Abstract
AIMP1 (ARS-interacting multifunctional protein 1), previously known as p43, was initially identified as a factor associated with a macromolecular tRNA synthetase complex. Recently, we demonstrated that AIMP1 is also secreted and acts as a novel pleiotropic cytokine. In this study, we investigated whether AIMP1 induces the activation and maturation of murine bone marrow-derived dendritic cells (DCs). AIMP1-treated DCs exhibited up-regulated expression of cell-surface molecules, including CD40, CD86, and MHC class II. Additionally, microarray analysis and RT-PCR determinations indicated that the expression of known DC maturation genes also increased significantly following treatment with AIMP1. Treatment of DCs with AIMP1 resulted in a significant increase in IL-12 production and Ag-presenting capability, and it also stimulated the proliferation of allogeneic T cells. Importantly, AIMP1-treated DCs induced activation of Ag-specific Th type 1 (Th1) cells in vitro and in vivo. AIMP1-stimulated DCs significantly enhanced the IFN-γ production of cocultured CD4+ T cells. Immunization of mice with keyhole limpet hemocyanin-pulsed AIMP1 DCs efficiently led to Ag-specific Th1 cell responses, as determined by flow cytometry and ELISA. The addition of a neutralizing anti-IL-12 mAb to the cell cultures that had been treated with AIMP1 resulted in the decreased production of IFN-γ, thereby indicating that AIMP1-stimulated DCs may enhance the Th1 response through increased production of IL-12 by APCs. Taken together, these results indicate that AIMP1 protein induces the maturation and activation of DCs, which skew the immune response toward a Th1 response.
Late Signals from CD27 Prevent Fas-Dependent Apoptosis of Primary CD8+ T Cells
Authors: Dolfi Douglas V. , Boesteanu Alina C. , Petrovas Constantinos , Xia Dong , Butz Eric A. , Katsikis Peter D. 
Published: April 2014

Abstract
The role of costimulation has previously been confined to the very early stages of the CD8+ T cell response. In this study, we demonstrate the requirement for CD27 costimulation during the later phase, but not programming of the primary CD8+ T cell response to influenza virus and reveal a novel mechanism of action for CD27 costimulation. CD27 signals, during the later phase of the primary CD8+ T cell response, prevent apoptosis of Ag-specific CD8+ T cells. Blocking CD27L (CD70) on days 6 and 8 after infection reduces the number of NP(366–374)-specific CD8+ T cells, increases their sensitivity to CD95/Fas-mediated apoptosis, and up-regulates FasL on CD4+ T cells. This reduction of NP(366–374)-specific CD8+ T cells requires the presence of CD4+ T cells and Fas signaling. Lack of CD27 signals also decreases the quality of memory CD8+ T cell responses. Memory CD8+ T cells, which express surface CD27 similar to naive cells, however, do not require CD27 costimulation during a secondary response. Thus, CD27 acts indirectly to regulate primary Ag-specific CD8+ T cell responses by preventing apoptosis of CD8+ T cells during the later phase of the primary response and is required for optimal quality of memory cells, but is not required during normally primed secondary CD8+ T cell responses.
KIR2DL4 Differentially Signals Downstream Functions in Human NK Cells through Distinct Structural Modules
Authors: Shahjahan Miah S. M. , Hughes Tracey L. , Campbell Kerry S. 
Published: April 2014

Abstract
KIR2DL4 (2DL4) is a member of the killer cell Ig-like receptor (KIR) family in human NK cells. It can stimulate potent cytokine production and weak cytolytic activity in resting NK cells, but the mechanism for 2DL4-mediated signaling remains unclear. In this study we characterized the signaling pathways stimulated by 2DL4 engagement. In a human NK-like cell line, KHYG-1, cross-linking of 2DL4 activated MAPKs including JNK, ERK, and p38. Furthermore, 2DL4 cross-linking resulted in phosphorylation of IκB kinase β (IKKβ) and the phosphorylation and degradation of IκBα, which indicate activation of the classical NF-κB pathway. Engagement of 2DL4 was also shown to activate the transcription and translation of a variety of cytokine genes, including TNF-α, IFN-γ, MIP1α, MIP1β, and IL-8. Pharmacological inhibitors of JNK, MEK1/2 and p38, blocked IFN-γ, IL-8, and MIP1α production, suggesting that MAPKs are regulating 2DL4-mediated cytokine production in a nonredundant manner. Activation of both p38 and ERK appear to be upstream of the stimulation of NF-κB. Mutation of a transmembrane arginine in 2DL4 to glycine (R/G mutant) abrogated FcεRI-γ association, as well as receptor-mediated cytolytic activity and calcium responses. Surprisingly, the R/G mutant still activated MAPKs and the NF-κB pathway and selectively stimulated the production of MIP1α, but not that of IFN-γ or IL-8. In conclusion, we provide evidence that the activating functions of 2DL4 can be compartmentalized into two distinct structural modules: 1) through transmembrane association with FcεRI-γ; and 2) through another receptor domain independent of the transmembrane arginine.
Mutation in the Fas Pathway Impairs CD8+ T Cell Memory
Authors: Dudani Renu , Russell Marsha , van Faassen Henk , Krishnan Lakshmi , Sad Subash 
Published: April 2014

Abstract
Fas death pathway is important for lymphocyte homeostasis, but the role of Fas pathway in T cell memory development is not clear. We show that whereas the expansion and contraction of CD8+ T cell response against Listeria monocytogenes were similar for wild-type (WT) and Fas ligand (FasL) mutant mice, the majority of memory CD8+ T cells in FasL mutant mice displayed an effector memory phenotype in the long-term in comparison with the mainly central memory phenotype displayed by memory CD8+ T cells in WT mice. Memory CD8+ T cells in FasL mutant mice expressed reduced levels of IFN-γ and displayed poor homeostatic and Ag-induced proliferation. Impairment in CD8+ T cell memory in FasL mutant hosts was not due to defective programming or the expression of mutant FasL on CD8+ T cells, but was caused by perturbed cytokine environment in FasL mutant mice. Although adoptively transferred WT memory CD8+ T cells mediated protection against L. monocytogenes in either the WT or FasL mutant hosts, FasL mutant memory CD8+ T cells failed to mediate protection even in WT hosts. Thus, in individuals with mutation in Fas pathway, impairment in the function of the memory CD8+ T cells may increase their susceptibility to recurrent/latent infections.