bluuebunny/crossref_metadata_2025_split huggingface dataset:
Essential Roles of the Fas-Associated Death Domain in Autoimmune Encephalomyelitis
Authors: Sun Jing , Hilliard Brendan , Xu Lingyun , Chen Youhai H. 
Published: April 2014

Abstract
The Fas-associated death domain (FADD) protein mediates apoptosis by coupling death receptors with the caspase cascade. Paradoxically, it also promotes cell mitosis through its C-terminal region. Apoptosis and mitosis are opposing processes that can have radically different consequences. To determine which of the FADD effects prevails in T cell-mediated autoimmune diseases, we studied myelin oligodendrocyte glycoprotein-induced experimental autoimmune encephalomyelitis (EAE) using mice that express a dominant-negative FADD (FADD-DN) transgene in the T cell lineage. We found that FADD blockade in T cells prevented the development of autoimmune encephalomyelitis and inhibited both Th1 and Th2 type responses. Myelin oligodendrocyte glycoprotein-specific T cell proliferation was also dramatically reduced in FADD-DN mice despite the resistance of T cells to activation-induced cell death. These results indicate that although FADD expressed by T cells is involved in regulating both mitosis and apoptosis, its effect on mitosis prevails in EAE, and that strategies inhibiting FADD functions in T cells could be effective in preventing the disease.
Cutting Edge: Differential Self-Peptide/MHC Requirement for Maintaining CD8 T Cell Function versus Homeostatic Proliferation
Authors: Jabbari Ali , Harty John T. 
Published: April 2014

Abstract
Memory T cells do not require self-peptide/MHC (spMHC) complexes to survive long term in vivo. However, memory CD4 T cells lose the ability to reject skin grafts when transiently placed in an environment in which these low-level TCR stimulations are absent. Whether or not spMHC alters the ability of CD8 T cells to respond to stimulation in vivo remains unknown. Here, we show that memory CD8 T cells retain the ability to respond to dendritic cell-mediated stimulation after adoptive transfer into either TAP−/− (MHC class I-deficient) or wild-type mice. Surprisingly, naive CD8 T cells, which fail to undergo homeostatic proliferation and erode in number in the absence of MHC class I, also retain the ability to respond to dendritic cell-mediated antigenic stimulation for at least 1 wk after transfer into TAP−/− mice. These findings suggest a differential requirement for spMHC signals for maintenance of CD8 T cell function and homeostatic proliferation.
Inefficient Cell Spreading and Cytoskeletal Polarization by CD4+CD8+ Thymocytes: Regulation by the Thymic Environment
Authors: Hailman Eric , Allen Paul M. 
Published: April 2014

Abstract
CD4+CD8+ double-positive (DP) thymocytes express a lower level of surface TCR than do mature T cells or single-positive (SP) thymocytes. Regulation of the TCR on DP thymocytes appears to result from intrathymic signaling, as in vitro culture of these cells results in spontaneous TCR up-regulation. In this study, we examined cell spreading and cytoskeletal polarization responses that have been shown to occur in response to TCR engagement in mature T cells. Using DP thymocytes stimulated on lipid bilayers or nontransgenic thymocytes added to anti-CD3-coated surfaces, we found that cell spreading and polarization of the microtubule organizing center and the actin cytoskeleton were inefficient in freshly isolated DP thymocytes, but were dramatically enhanced after overnight culture. SP (CD4+) thymocytes showed efficient responses to TCR engagement, suggesting that releasing DP thymocytes from the thymic environment mimics some aspects of positive selection. The poor translation of a TCR signal to cytoskeletal responses could limit the ability of DP thymocytes to form stable contacts with APCs and may thereby regulate thymocyte selection during T cell development.
Propensity of Adult Lymphoid Progenitors to Progress to DN2/3 Stage Thymocytes with Notch Receptor Ligation
Authors: Huang Jiaxue , Garrett Karla P. , Pelayo Rosana , Zúñiga-Pflücker Juan Carlos , Petrie Howard T. , Kincade Paul W. 
Published: April 2014

Abstract
Notch family receptors control critical events in the production and replenishment of specialized cells in the immune system. However, it is unclear whether Notch signaling regulates abrupt binary lineage choices in homogeneous progenitors or has more gradual influence over multiple aspects of the process. A recently developed coculture system with Delta 1-transduced stromal cells is being extensively used to address such fundamental questions. Different from fetal progenitors, multiple types of adult marrow cells expanded indefinitely in murine Delta-like 1-transduced OP9 cell cocultures, progressed to a DN2/DN3 thymocyte stage, and slowly produced TCR+ and NK cells. Long-term cultured cells of this kind retained some potential for T lymphopoiesis in vivo. Adult marrow progressed through double-positive and single-positive stages only when IL-7 concentrations were low and passages were infrequent. Lin−c-KitlowGFP+IL-7Rα+/− prolymphocytes were the most efficient of adult bone marrow cells in short-term cultures, but the assay does not necessarily reflect cells normally responsible for replenishing the adult thymus. Although marrow-derived progenitors with Ig DH-JH rearrangements acquired T lineage characteristics in this model, that was not the case for more B committed cells with VH-DHJH rearrangement products.
Memory T Cells and Their Costimulators in Human Allograft Injury
Authors: Shiao Stephen L. , McNiff Jennifer M. , Pober Jordan S. 
Published: April 2014

Abstract
Both CD4+ and CD8+ human memory but not naive T cells respond to allogeneic human dermal microvascular endothelial cells (HDMEC) in vitro by secreting cytokines and by proliferating. Several recently identified costimulators, namely, 4-1BB ligand, ICOS ligand, and OX40 ligand, are up-regulated on cultured HDMEC in response to TNF or coculture with allogeneic T cells. Blockade of these costimulators each partially reduces IFN-γ and IL-2 secretion and proliferation of previously resting memory T cells. The effects of these costimulators are overlapping but not identical. Memory but not naive T cells are the principal effectors of microvascular injury in human skin allografts following adoptive transfer into immunodeficient mice. Furthermore, blocking 4-1BB ligand, ICOS ligand, or OX40 ligand in this model reduces human skin allograft injury and T cell effector molecule expression. These data demonstrate that human memory T cells respond to microvascular endothelial cells and can injure allografts in vivo without priming. Furthermore, several recently described costimulators contribute to these processes.
Modulation of CD4 Th Cell Differentiation by Ganglioside GD1a In Vitro
Authors: Shen Weiping , Falahati Rustom , Stark Ryan , Leitenberg David , Ladisch Stephan 
Published: April 2014

Abstract
Cell surface gangliosides are shed by tumors into their microenvironment. In this study they inhibit cellular immune responses, including APC development and function, which is critical for Th1 and Th2 cell development. Using human dendritic cells (DCs) and naive CD4+ T cells, we separately evaluated Th1 and Th2 development under the selective differentiating pressures of DC1-inducing pertussis toxin (PT) and DC2-inducing cholera toxin (CT). High DC IL-12 production after PT exposure and high DC IL-10 production after CT exposure were observed, as expected. However, when DCs were first preincubated with highly purified GD1a ganglioside, up-regulation of costimulatory molecules was blunted, and PT-induced IL-12 production was reduced, whereas CT-induced IL-10 production was increased. The combination of these effects could contribute to a block in the Th1 response. In fact, when untreated naive T cells were coincubated with ganglioside-preincubated, Ag-exposed DCs, naive Th cell differentiation into Th effector cells was reduced. Both the subsequent DC1-induced T cell production of IFN-γ (Th1 marker) and DC2-induced T cell IL-4 production (Th2) were inhibited. Thus, ganglioside exposure of DC impairs, by at least two distinct mechanisms, the ability to induce Th differentiation, which could adversely affect the development of an effective cellular antitumor immune response.
Conformational Variation of Surface Class II MHC Proteins during Myeloid Dendritic Cell Differentiation Accompanies Structural Changes in Lysosomal MIIC
Authors: Potolicchio Ilaria , Chitta Sriram , Xu Xiaonan , Fonseca Dora , Crisi Giovanna , Horejsi Vaclav , Strominger Jack L. , Stern Lawrence J. , Raposo Graca , Santambrogio Laura 
Published: April 2014

Abstract
Dendritic cells (DC), uniquely among APC, express an open/empty conformation of MHC class II (MHC-II) proteins (correctly folded molecules lacking bound peptides). Generation and trafficking of empty HLA-DR during DC differentiation are investigated here. HLA-DR did not fold as an empty molecule in the endoplasmic reticulum/trans-Golgi network, did not derived from MHC/Ii complexes trafficking to the cell surface, but was generated after invariant chain degradation within lysosomal-like MHC-II rich compartments (MIIC). In pre-DC, generated from monocytes cultured in the presence of GM-CSF, Lamp-1+MHC-II+ compartments are predominantly electron dense and, in these cells, empty MHC-II molecules accounts for as much as 20% of total surface HLA-DR. In immature DC, generated in presence of GM-CSF and IL-4, empty HLA-DR reside in multilamellar MIIC, but are scarcely observed at the cell surface. Thus, the morphology/composition of lysosomal MIIC at different DC maturational stages appear important for surface egression or intracellular retention of empty HLA-DR. Ag loading can be achieved for the fraction of empty HLA-DR present in the “peptide-receptive” form. Finally, in vivo, APC-expressing surface empty HLA-DR were found in T cell areas of secondary lymphoid organs.
Proinflammatory Stimulation and Pioglitazone Treatment Regulate Peroxisome Proliferator-Activated Receptor γ Levels in Peripheral Blood Mononuclear Cells from Healthy Controls and Multiple Sclerosis Patients
Authors: Klotz Luisa , Schmidt Martina , Giese Thomas , Sastre Magdalena , Knolle Percy , Klockgether Thomas , Heneka Michael T. 
Published: April 2014

Abstract
The peroxisome proliferator-activated receptor γ (PPAR-γ) belongs to a receptor superfamily of ligand-activated transcription factors involved in the regulation of metabolism and inflammation. Oral administration of PPAR-γ agonists ameliorates the clinical course and histopathological features in experimental autoimmune encephalomyelitis, an animal model for multiple sclerosis (MS), and PPAR-γ agonist treatment of PBMCs from MS patients suppresses PHA-induced cell proliferation and cytokine secretion. These effects are pronounced when cells are preincubated with the PPAR-γ agonists and reexposed at the time of stimulation, indicating a sensitizing effect. To characterize the mechanisms underlying this sensitizing effect, we analyzed PPAR-γ expression in PMBCs of MS patients and healthy controls. Surprisingly, MS patients exhibited decreased PPAR-γ levels compared with controls. PHA stimulation of PBMCs from healthy controls resulted in a significant loss of PPAR-γ, which was prevented by in vitro preincubation of the cells or in vivo by long-term oral medication with the PPAR-γ agonist pioglitazone. Differences in PPAR-γ expression were accompanied by changes in PPAR-γ DNA-binding activity, as preincubation with pioglitazone increased DNA binding of PPAR-γ. Additionally, preincubation decreased NF-κB DNA-binding activity to control levels, whereas the inhibitory protein IκBα was increased. In MS patients, pioglitazone-induced increase in PPAR-γ DNA-binding activity and decrease in NF-κB DNA-binding activity was only observed in the absence of an acute MS relapse. These results suggest that the sensitizing effect observed in the preincubation experiments is mediated by prevention of inflammation-induced suppression of PPAR-γ expression with consecutive increase in PPAR-γ DNA-binding activity.
Prevention of Allergen-Specific, Th2-Biased Immune Responses In Vivo: Role of Increased IL-12 and IL-18 Responsiveness
Authors: Lewkowich Ian P. , Rempel Julia D. , HayGlass Kent T. 
Published: April 2014

Abstract
The factors that control development of adaptive responses to exogenous Ag remain incompletely understood. An ability to selectively direct immunity toward a specific phenotype would be of clinical benefit in numerous immunological disorders. Administration of chemically modified allergen glutaraldehyde-polymerized OVA (OA-POL) leads to &gt;90% reductions in murine IgE and &gt;500-fold increases in IgG2c responses that develop upon subsequent immunization with native Ag. In the present study, we examine the mechanisms underlying this reorientation of the type 2 dominant response that would normally develop. Lack of endogenous IL-12 or IFN-γ results in markedly reduced induction of IgG2c responses following OA-POL treatment, but only IFN-γ−/− mice demonstrate reduced capacity to prevent IgE induction. This indicates that while both IL-12 and IFN-γ are critical promoters of type 1 immunity, only IFN-γ is required to maximally inhibit development of type 2 immune responses. Compared with OVA-immunized mice, CD69+ T cells from OA-POL-immunized mice demonstrate elevated IL-12Rβ2, IL-18Rα, and IL-18Rβ mRNA levels, as well as increased IFN-γ production in response to rIL-12 or rIL-18 stimulation. Collectively, these data indicate that preventing induction of type 2 immune responses is critically dependent on altered T cell responsiveness to these cytokines. The finding that targeted, Ag-specific manipulation of IL-12 and IL-18 responsiveness can be used to shape the phenotype of the dominant immune response that develops suggests that specifically targeting IL-12 and IL-18 receptor expression may offer clinical options for clinical prophylaxis or intervention.
Severe Impairment of Dendritic Cell Allostimulatory Activity by Sendai Virus Vectors Is Overcome by Matrix Protein Gene Deletion
Authors: Armeanu Sorin , Bitzer Michael , Smirnow Irina , Bossow Sascha , Appel Silke , Ungerechts Guy , Bernloehr Christian , Neubert Wolfgang J. , Lauer Ulrich M. , Brossart Peter 
Published: April 2014

Abstract
Delivery of Ags to dendritic cells (DCs) plays a pivotal role in the induction of efficient immune responses ranging from immunity to tolerance. The observation that certain viral pathogens are able to infect DCs has led to a concept in which applications of recombinant viruses are used for Ag delivery with the potential benefit of inducing potent Ag-specific T cell responses directed against multiple epitopes. As a prerequisite for such an application, the infection of DCs by recombinant viruses should not interfere with their stimulatory capacity. In this context, we could show that an emerging negative-strand RNA viral vector system based on the Sendai virus (SeV) is able to efficiently infect monocyte-derived human DCs (moDCs). However, after infection with SeV wild type, both the response of DCs to bacterial LPS as a powerful mediator of DC maturation and the allostimulatory activity were severely impaired. Interestingly, using various recombinant SeV vectors that were devoid of single viral genes, we were able to identify the SeV matrix (M) protein as a key component in moDC functional impairment after viral infection. Consequently, use of M-deficient SeV vectors preserved the allostimulatory activity in infected moDCs despite an efficient expression of all other virally encoded genes, thereby identifying M-deficient vectors as a highly potent tool for the genetic manipulation of DCs.
Conjugated Linoleic Acid Suppresses NF-κB Activation and IL-12 Production in Dendritic Cells through ERK-Mediated IL-10 Induction
Authors: Loscher Christine E. , Draper Eve , Leavy Olive , Kelleher Dermot , Mills Kingston H. G. , Roche Helen M. 
Published: April 2014

Abstract
Polyunsaturated fatty acids (PUFA) have been shown to modulate immune responses and have therapeutic effects in inflammatory disorders. However, the influence of PUFA on dendritic cells (DC), key cells of the innate immune system in shaping adaptive immune responses, has not yet been defined. In this study, we examine the effects of the cis-9, trans-11 isomer of conjugated linoleic acid (c9, t11-CLA), a dietary PUFA found in meat and dairy products, on murine DC activation. Treatment of DC with c9, t11-CLA suppressed LPS-induced IL-12, enhanced IL-10R expression, and enhanced IL-10 production at the transcriptional and protein level. The suppression of IL-12 by c9, t11-CLA was found to be IL-10 dependent. We investigated the involvement of the MAPK, ERK, and the transcription factor, NF-κB, in this IL-10-mediated effect. c9, t11-CLA enhanced ERK activation after LPS stimulation, and inhibition of ERK resulted in abrogation of IL-10 and recovery of IL-12 production. c9, t11-CLA decreased NF-κB:DNA binding after LPS stimulation, which was concomitant with delayed translocation of NF-κBp65 into the nucleus and an increase in IκBα. These effects were reversed by addition of a neutralizing anti-IL-10 Ab. Our findings demonstrate that c9, t11-CLA suppresses IL-12 production by LPS-stimulated DC by ERK mediated IL-10-induction. Furthermore, these IL-10-mediated effects are dependent on inhibition of NF-κB activation. This is the first study to demonstrate that c9, t11-CLA can enhance transcription and production of the anti-inflammatory cytokine IL-10, while inhibiting the Th1-promoting cytokine IL-12, and may explain certain of its immunosuppressive properties.
Human Invariant NKT Cells Are Required for Effective In Vitro Alloresponses
Authors: Patterson Scott , Kotsianidis Ioannis , Almeida Antonio , Politou Marianna , Rahemtulla Amin , Matthew Bini , Schmidt Richard R. , Cerundolo Vincenzo , Roberts Irene A. G. , Karadimitris Anastasios 
Published: April 2014

Abstract
NKT cells are a small subset of regulatory T cells conserved in humans and mice. In humans they express the Vα24Jα18 invariant chain (hence invariant NKT (iNKT) cells) and are restricted by the glycolipid-presenting molecule CD1d. In mice, iNKT cells may enhance or inhibit anti-infectious and antitumor T cell responses but suppress autoimmune and alloreactive responses. We postulated that iNKT cells might also modulate human alloreactive responses. Using MLR assays we demonstrate that in the presence of the CD1d-presented glycolipid α-galactosylceramide (αGC) alloreactivity is enhanced (37 ± 12%; p &lt; 0.001) in an iNKT cell-dependent manner. iNKT cells are activated early during the course of the MLR, presumably by natural ligands. In MLR performed without exogenous ligands, depletion of iNKT cells significantly diminished the alloresponse in terms of proliferation (58.8 ± 24%; p &lt; 0.001) and IFN-γ secretion (43.2 ± 15.2%; p &lt; 0.001). Importantly, adding back fresh iNKT cells restored the reactivity of iNKT cell-depleted MLR to near baseline levels. CD1d-blocking mAbs equally reduced the reactivity of the iNKT cell-replete and -depleted MLR compared with IgG control, indicating that the effect of iNKT cells in the in vitro alloresponse is CD1d-dependent. These findings suggest that human iNKT cells, although not essential for its development, can enhance the alloreactive response.
Estrogen Selectively Promotes the Differentiation of Dendritic Cells with Characteristics of Langerhans Cells
Authors: Mao Allen , Paharkova-Vatchkova Vladislava , Hardy John , Miller Marcia M. , Kovats Susan 
Published: April 2014

Abstract
The steroid hormone estrogen regulates the differentiation, survival, or function of diverse immune cells. Previously, we found that physiological amounts of 17β-estradiol act via estrogen receptors (ER) to promote the GM-CSF-mediated differentiation of dendritic cells (DC) from murine bone marrow progenitors in ex vivo cultures. Of the two major subsets of CD11c+ DC that develop in these cultures, estrogen is preferentially required for the differentiation of a CD11bintLy6C− population, although it also promotes increased numbers of a CD11bhighLy6C+ population. Although both DC subsets express ERα, only the CD11bhighLy6C+ DC express ERβ, perhaps providing a foundation for the differential regulation of these two DC types by estrogen. The two DC populations exhibit distinct phenotypes in terms of capacity for costimulatory molecule and MHC expression, and Ag internalization, which predict functional differences. The CD11bintLy6C− population shows the greatest increase in MHC and CD86 expression after LPS activation. Most notably, the estrogen-dependent CD11bintLy6C− DC express langerin (CD207) and contain Birbeck granules characteristic of Langerhans cells. These data show that estrogen promotes a DC population with the unique features of epidermal Langerhans cells and suggest that differentiation of Langerhans cells in vivo will be dependent upon local estrogen levels and ER-mediated signaling events in skin.
Protein Acetylation Regulates Both PU.1 Transactivation and Igκ 3′ Enhancer Activity
Authors: Bai Yuchen , Srinivasan Lakshmi , Perkins Leslie , Atchison Michael L. 
Published: April 2014

Abstract
Igκ gene expression and chromatin structure change during B cell development. At the pre-B cell stage, the locus is relatively hypoacetylated on histone H3, whereas it is hyperacetylated at the plasma cell stage. We find in this study that the histone deacetylase inhibitor, trichostatin A (TSA) stimulated 3′ enhancer activity through the PU.1 binding site. TSA also stimulated PU.1 transactivation potential. PU.1 activity was increased by the coactivator acetyltransferase protein, p300, and p300 physically interacted with PU.1 residues 7–30. PU.1 served as a substrate for p300 and was acetylated on lysine residues 170, 171, 206, and 208. Mutation of PU.1 lysines 170 and 171 did not affect PU.1 DNA binding, but did lower the ability of PU.1 to activate transcription in association with p300. Lysine 170 was acetylated in pre-B cells and plasmacytoma cells, but TSA treatment did not stimulate PU.1 acetylation at this residue arguing that a second mechanism can stimulate 3′ enhancer activity. Using chromatin immunoprecipitation assays we found that TSA caused preferential acetylation of histone H3 at the 3′ enhancer. The relevance of these studies for PU.1 function in transcription and hemopoietic development is discussed.
KIR3DL1 Polymorphisms That Affect NK Cell Inhibition by HLA-Bw4 Ligand
Authors: Carr William Henry , Pando Marcelo Jorge , Parham Peter 
Published: April 2014

Abstract
The killer cell Ig-like receptor (KIR) gene family encodes MHC class I receptors expressed by NK cells and several T cell subpopulations. Factors contributing to human KIR haplotype diversity are differences in gene number, gene content, and allelic polymorphism. Whereas functional and clinical consequences of the first two factors are established, knowledge of the effects of KIR gene polymorphism is limited to special cases in which signaling function is reversed or cell surface expression lost. In this study we use retrovirally transduced human cell lines to show that 3DL1*002 is a stronger inhibitory receptor for HLA-Bw4 ligands than 3DL1*007. Analysis of mutant 3DL1*002 and 3DL1*007 molecules demonstrates that residue 238 in the D2 domain and 320 in the transmembrane region contribute to the difference in receptor strength. Neither position 238 nor 320 is predicted to interact directly with HLA-Bw4 ligand. This study also revealed that KIR3DL1 and LILRB1 both contribute to developing an inhibitory response to HLA-Bw4 ligands.