bluuebunny/crossref_metadata_2025_split huggingface dataset:
Host Dendritic Cells Alone Are Sufficient to Initiate Acute Graft-versus-Host Disease
Authors: Duffner Ulrich A. , Maeda Yoshinobu , Cooke Kenneth R. , Reddy Pavan , Ordemann Rainer , Liu Chen , Ferrara James L. M. , Teshima Takanori 
Published: April 2014

Abstract
Alloantigen expression on host APCs is essential to initiate graft-vs-host disease (GVHD); however, critical APC subset remains to be elucidated. We compared the ability of dendritic cells (DCs) and B cells to initiate acute GVHD by an add-back study of MHC class II-expressing APCs (II+/+) into MHC class II-deficient (II−/−) mice that were resistant to CD4-dependent GVHD. Injection of host-derived, but not donor-derived, II+/+ DCs or host-derived II+/+ B cells, was sufficient to break GVHD resistance of II−/− mice and induced lethal acute GVHD. By contrast, host-derived II+/+ B cells, both naive and LPS stimulated, failed to induce activation or tolerance of donor CD4+ T cells. Similarly, in a model of CD8-dependent GVHD across MHC class I mismatch injection of allogeneic DCs, but not B cells, induced robust proliferation of donor CD8+ T cells and broke GVHD resistance of chimeric recipients in which APCs were syngeneic to donors. These results demonstrate that host-derived DCs are critical in priming donor CD4+ and CD8+ T cells to cause GVHD, and selective targeting of host DCs may be a promising strategy to prevent GVHD.
Activation of Naive CD4+ T Cells In Vivo by a Self-Peptide Mimic: Mechanism of Tolerance Maintenance and Preservation of Immunity
Authors: Choi Jin-Young , Craft Joe 
Published: April 2014

Abstract
Intrathymic selection generates a peripheral repertoire of CD4+ T cells with receptors that retain low affinity for self-peptide MHC complexes. Despite self-recognition, T cells remain tolerant even in the setting of microbial challenge and resultant costimulatory signals. We demonstrate here a novel mechanism for tolerance maintenance under conditions of self-recognition and strong costimulation. TCR engagement in vivo with a low-avidity peptide, as a mimic of self, provided with poly(I:C) (dsRNA) led to division of naive T cells that was dependent upon costimulatory signals; however, the dividing cells rapidly underwent deletion. By contrast, the surviving cells that were activated as evidenced by up-regulation of CD69 did not become effectors upon restimulation with the same ligand and maintained an effective response against agonist peptide. We suggest TCR engagement with self-peptide MHC complexes promotes tolerance maintenance during pathogen challenge, while preserving efficient reactivity for subsequent encounter with foreign Ags.
Increased and Long-Term Generation of Dendritic Cells with Reduced Function from IL-6-Deficient Bone Marrow
Authors: Bleier Joshua I. , Pillarisetty Venu G. , Shah Alaap B. , DeMatteo Ronald P. 
Published: April 2014

Abstract
The importance of IL-6 in dendritic cell (DC) development and function has not been well defined. To establish the role of IL-6, we studied bone marrow-derived DC (BMDC) and freshly isolated splenic DC from IL-6−/−-transgenic mice. We found that although IL-6−/− bone marrow had a similar composition to that of wild-type (WT) mice, it generated up to 10 times more DC when cultured in GM-CSF. The difference persisted even when IL-6−/− and WT bone marrow were cultured together, excluding the possibility that the effects were simply due to different cytokine microenvironments. In comparison to WT BMDC, IL-6−/− BMDC captured at least as much Ag, had an equivalent surface phenotype, and matured similarly in response to LPS or CpG. However, IL-6−/− BMDC induced less T cell allostimulation and Ag-specific T cell activation, but only the former was related to their inability to generate IL-6. Although WT bone marrow cultures died within 4 wk, IL-6−/− cultures continued to generate BMDC for &gt;120 days, although the BMDC became immature and less functional. In vivo, we found that IL-6−/− mice had similar numbers and types of splenic DC as WT mice, both normally and after treatment with either Flt-3 ligand or GM-CSF. These findings demonstrate that IL-6 has profound effects on DC development in vitro, although the number and subtype composition of DC are unaffected by the absence of IL-6 in vivo. Furthermore, secretion of IL-6 is critical to certain DC functions.
Transcriptional Regulation of Human CD5: Important Role of Ets Transcription Factors in CD5 Expression in T Cells
Authors: Arman Mònica , Calvo Javier , Trojanowska Maria E. , Cockerill Peter N. , Santana Mónica , López-Cabrera Manuel , Vives Jordi , Lozano Francisco 
Published: April 2014

Abstract
CD5 is a surface receptor constitutively expressed on thymocytes and mature T and B-1a cells. CD5 expression is tightly regulated during T and B cell development and activation processes. In this study we shown that the constitutive expression of CD5 on human T cells correlates with the presence of a DNase I-hypersensitive (DH) site at the 5′-flanking region of CD5. Human CD5 is a TATA-less gene for which 5′-RACE analysis shows multiple transcriptional start sites, the most frequent of which locates within an initiator sequence. Luciferase reporter assays indicate that a 282-bp region upstream of the initiation ATG displays full promoter activity in human T cells. Two conserved Ets-binding sites (at positions −239 and −185) were identified as functionally relevant to CD5 expression by site-directed mutagenesis, EMSAs, and cotransfection experiments. A possible contribution of Sp1 (−115 and −95), c-Myb (−177), and AP-1-like (−151) motifs was also detected. Further DH site analyses revealed an inducible DH site 10 kb upstream of the human CD5 gene in both T and B CD5+ cells. Interestingly, a 140-bp sequence showing high homology with a murine inducible enhancer is found within that site. The data presented indicate that the 5′-flanking region of human CD5 is transcriptionally active in T cells, and that Ets transcription factors in conjunction with other regulatory elements are responsible for constitutive and tissue-specific CD5 expression.
CD200 Is a Ligand for All Members of the CD200R Family of Immunoregulatory Molecules
Authors: Gorczynski Reginald , Chen Zhiqi , Kai Yu , Lee Lydia , Wong Simon , Marsden Philip A. 
Published: April 2014

Abstract
CD200Fc, a chimeric molecule including the extracellular domain of CD200 and a murine IgG2a Fc region, regulates immune responses following engagement of a cell surface receptor, CD200R, expressed on cells of the myeloid and T cell lineage. A recent report focused attention on a family of CD200Rs, but concluded that only one member used CD200 as its ligand. We have also cloned and sequenced a family of CD200Rs, but identify an amino terminus to two of the three isoforms not recognized by previous researchers. We show by FACS, using FITC-labeled CD200Fc, that COS7 cells transfected with all CD200R isoforms bind CD200 as ligand, although the functional consequences of this binding likely differs between the different isoforms. mAbs directed against the CD200 R1/R4 isoforms altered IL-2/IL-4 cytokine production and suppressed CTL responses in a fashion comparable to CD200Fc, with a significantly lesser effect seen following addition of anti-CD200 R2/R3.
Activation of Phosphoinositide 3-Kinases by the CCR4 Ligand Macrophage-Derived Chemokine Is a Dispensable Signal for T Lymphocyte Chemotaxis
Authors: Cronshaw Darran G. , Owen Charles , Brown Zarin , Ward Stephen G. 
Published: April 2014

Abstract
Macrophage-derived chemokine (MDC/CC chemokine ligand 22 (CCL22)) mediates its cellular effects principally by binding to its receptor CCR4, and together they constitute a multifunctional chemokine/receptor system with homeostatic and inflammatory roles in the body. We report the CCL22-induced accumulation of phosphatidylinositol-(3,4,5)-trisphosphate (PI(3,4,5)P3) in the leukemic T cell line CEM. CCL22 also had the ability to chemoattract human Th2 cells and CEM cells in a pertussis toxin-sensitive manner. Although the PI(3,4,5)P3 accumulation along with the pertussis toxin-susceptible phosphorylation of protein kinase B were sensitive to the two phosphoinositide 3-kinase inhibitors, LY294002 and wortmannin, cell migration was unaffected. However, cell migration was abrogated with the Rho-dependent kinase inhibitor, Y-27632. These data demonstrate that although there is PI(3,4,5)P3 accumulation downstream of CCR4, phosphoinositide 3-kinase activity is a dispensable signal for CCR4-stimulated chemotaxis of Th2 cells and the CEM T cell line.
Alterations in Lipid Raft Composition and Dynamics Contribute to Abnormal T Cell Responses in Systemic Lupus Erythematosus
Authors: Krishnan Sandeep , Nambiar Madhusoodana P. , Warke Vishal G. , Fisher Carolyn U. , Mitchell Jeanne , Delaney Nancy , Tsokos George C. 
Published: April 2014

Abstract
In response to appropriate stimulation, T lymphocytes from systemic lupus erythematosus (SLE) patients exhibit increased and faster intracellular tyrosine phosphorylation and free calcium responses. We have explored whether the composition and dynamics of lipid rafts are responsible for the abnormal T cell responses in SLE. SLE T cells generate and possess higher amounts of ganglioside-containing lipid rafts and, unlike normal T cells, SLE T cell lipid rafts include FcRγ and activated Syk kinase. IgM anti-CD3 Ab-mediated capping of TCR complexes occurs more rapidly in SLE T cells and concomitant with dramatic acceleration of actin polymerization kinetics. The significance of these findings is evident from the observation that cross-linking of lipid rafts evokes earlier and higher calcium responses in SLE T cells. Thus, we propose that alterations in the lipid raft signaling machinery represent an important mechanism that is responsible for the heightened and accelerated T cell responses in SLE.
Shortening the Infectious Period Does Not Alter Expansion of CD8 T Cells but Diminishes Their Capacity to Differentiate into Memory Cells
Authors: Williams Matthew A. , Bevan Michael J. 
Published: April 2014

Abstract
Following a primary immune response, a portion of effector T cells gives rise to long-lived memory cells. Although primary expansion and differentiation of effector CD8 T cells is dictated by a brief exposure to Ag, it is unclear whether full memory differentiation is also programmed within the same short window. By carefully modulating the kinetics of Listeria monocytogenes infection, we analyzed the requirements for the programming of effector and memory T cell development in vivo. We find that although limiting the infectious period to the first 24–48 h does not impact the size of the primary CD8 response, the ensuing memory population is significantly diminished. This effect is particularly pronounced in the development of tissue-homing memory cells and is inversely proportional to the initial infectious dose. In contrast to CD8 responses, the differentiation of primary CD4 responses was highly dependent on the continued presence of the infection. Shortening the duration of the infection greatly reduced the development of CD4 effector responses in the spleen and prevented their trafficking to peripheral sites of infection. We propose that the stimulus received by CD8 T cells during the early stages of infection largely contribute to the differentiation of CD8 effector cells, whereas continued or distinct signals received at later stages influence their ability to differentiate into memory cells.
Recruitment of Uterine NK Cells: Induction of CXC Chemokine Ligands 10 and 11 in Human Endometrium by Estradiol and Progesterone
Authors: Sentman Charles L. , Meadows Sarah K. , Wira Charles R. , Eriksson Mikael 
Published: April 2014

Abstract
Uterine NK (uNK) cells express a unique set of markers compared with blood NK cells. However, recent studies suggest that uNK cells may be derived from the recruitment of blood NK cells into the endometrium. In this study, we used an in vitro organ culture system to demonstrate that estradiol induces expression of chemokines CXCL10 and/or CXCL11 within human endometrium in 85% of patient samples tested. The average increase in gene expression after 10−9 M estradiol treatment was 8.5-fold for CXCL10 and 7.7-fold for CXCL11 compared with medium alone. We observed that a specific estrogen receptor antagonist (ICI182780) was able to prevent chemokine gene induction, indicating that the effect of estradiol was receptor mediated. Moreover, our study showed that progesterone induced CXCL10 and CXCL11 expression in 83% of endometrial samples tested. We have also found that uNK cells and blood NK cells express the receptor for CXCL10 and CXCL11, CXCR3, with the highest expression found on uNK cells and CD56bright blood NK cells. These data indicate that sex hormones induce specific chemokines in nonpregnant human endometrium that can activate NK cell migration, and suggest that this mechanism may account for the increased NK cell numbers in endometrium during the menstrual cycle.
Antibody Repertoire Development in Fetal and Neonatal Pigs. VII. Characterization of the Preimmune κ Light Chain Repertoire
Authors: Butler John E. , Wertz Nancy , Sun Jishan , Wang Huang , Chardon Patrick , Piumi Francois , Wells Kevin 
Published: April 2014

AbstractCombinatorial diversity is highly restricted in the preimmune porcine H chain repertoire compared with that in humans and mice. This raised the question of whether similar restriction characterized the preimmune L chain repertoire. In this study we present evidence that &gt;90% of all expressed Vκ genes in the porcine preimmune repertoire belong to three subfamilies of Vκ genes that share 87% sequence similarity with human IGKV2. This porcine Vκ family also shares sequence similarity with some, but not all, Vκ genes from sheep. Hybridization with sperm DNA and sequence analyses of polynucleotides from overlapping bacterial artificial chromosome clones suggest swine possess ∼60 IGVK2 genes. The latter method also revealed that certain IGKV2 subfamilies are not expressed in the preimmune repertoire. Six members of an IGVK1 family were also expressed as part of the preimmune repertoire, and these shared 87% sequence similarity with human IGVK1. Five Jκ segments, complete with recombination signal sequences and separated by ∼300 nt, were identified ∼3 kb upstream of a single Cκ. Surprisingly, Jκ2 accounted for &gt;90% of all framework region 4 sequences in the preimmune repertoire. These findings show that swine use ∼10 IGVK2 genes from three of six subfamilies and preferentially one Jκ segment to generate their preimmune κ repertoire. These studies, like those of porcine Ig constant regions and MHC genes, also indicate unexpected high sequence similarity with their human counterparts despite differences in phylogeny and the mechanism of repertoire diversification.
Human CD8+ T Cells Recognize the 60-kDa Cysteine-Rich Outer Membrane Protein fromChlamydia trachomatis
Authors: Gervassi Ana L. , Grabstein Kenneth H. , Probst Peter , Hess Bruce , Alderson Mark R. , Fling Steven P. 
Published: April 2014

AbstractThe intracellular bacterial pathogen Chlamydia is sequestered from the host cell cytoplasm by remaining within an inclusion body during its replication cycle. Nevertheless, CD8+ T cells recognizing Chlamydia Ags in the context of MHC class I molecules are primed during infection. We have recently described derivation of Chlamydia-specific human CD8+ T cells by using infected dendritic cells as a surrogate system to reflect Chlamydia-specific CD8+ T cell responses in vivo. These CD8+ T cell clones recognize chlamydial Ags processed via the conventional class Ia processing pathway, as assessed by treatment of infected APC with lactacystin and brefeldin A, suggesting that the Ags are translocated from the chlamydial inclusion into the host cell cytosol. In this study, outer membrane protein 2 (OmcB) was identified as the Ag recognized by one of these Chlamydia-specific human CD8+ T cells, and we defined the HLA*A0101-restricted epitope from this Ag. CD8+ T cell responses to this epitope were present at high frequencies in the peripheral blood of both of two HLA*A0101 donors tested. In vitro chlamydial growth was completely inhibited by the OmcB-specific CD8+ T cell clone independently of lytic mechanisms. OmcB is a 60-kDa protein that has been postulated to be associated with the Chlamydia outer membrane complex. The subcellular localization of OmcB to the cytosol of infected cells, as determined by conventional MHC class I Ag processing and presentation, suggests the possibility of an additional, cytosolic-associated function for this protein.
CCR1 and CC Chemokine Ligand 5 Interactions Exacerbate Innate Immune Responses during Sepsis
Authors: Ness Traci L. , Carpenter Kristin J. , Ewing Jillian L. , Gerard Craig J. , Hogaboam Cory M. , Kunkel Steven L. 
Published: April 2014

AbstractCCR1 has previously been shown to play important roles in leukocyte trafficking, pathogen clearance, and the type 1/type 2 cytokine balance, although very little is known about its role in the host response during sepsis. In a cecal ligation and puncture model of septic peritonitis, CCR1-deficient (CCR1−/−) mice were significantly protected from the lethal effects of sepsis when compared with wild-type (WT) controls. The peritoneal and systemic cytokine profile in CCR1−/− mice was characterized by a robust, but short-lived and regulated antibacterial response. CCR1 expression was not required for leukocyte recruitment, suggesting critical differences extant in the activation of WT and CCR1−/− resident or recruited peritoneal cells during sepsis. Peritoneal macrophages isolated from naive CCR1−/− mice clearly demonstrated enhanced cytokine/chemokine generation and antibacterial responses compared with similarly treated WT macrophages. CCR1 and CCL5 interactions markedly altered the inflammatory response in vivo and in vitro. Administration of CCL5 increased sepsis-induced lethality in WT mice, whereas neutralization of CCL5 improved survival. CCL5 acted in a CCR1-dependent manner to augment production of IFN-γ and MIP-2 to damaging levels. These data illustrate that the interaction between CCR1 and CCL5 modulates the innate immune response during sepsis, and both represent potential targets for therapeutic intervention.
Prostaglandin E2 Promotes the Survival of Bone Marrow-Derived Dendritic Cells
Authors: Vassiliou Evros , Sharma Vikas , Jing Huie , Sheibanie Farzad , Ganea Doina 
Published: April 2014

AbstractSince dendritic cells (DC) participate in both innate and adaptive immunity, their survival and expansion is tightly controlled. Little is known about the mechanisms of DC apoptosis. PGE2, an arachidonic acid metabolite, plays an essential role in DC migration. We propose a novel function for PGE2 as a DC survival factor. Our studies demonstrate that PGE2 protects DC in vitro against apoptosis induced by withdrawal of growth factors or ceramide. DC matured in conditions that inhibit endogenous PGE2 release are highly susceptible to apoptosis and exogenous PGE2 re-establishes the more resistant phenotype. The antiapoptotic effect is mediated through EP-2/EP-4 receptors and involves the PI3K → Akt pathway. PGE2 leads to increased phosphorylation of Akt, protection against mitochondrial membrane compromise, and decreased caspase 3 activity. Macroarray data indicate that PGE2 leads to the down-regulation of a number of proapoptotic molecules, i.e., BAD, several caspases, and granzyme B. In vivo, higher numbers of immature and Ag-loaded CFSE-labeled DC are present in the draining lymph nodes of mice inoculated with PGE2 receptor agonists, compared with animals treated with ibuprofen or controls injected with PBS. This suggests that PGE2 acts as an endogenous antiapoptotic factor for DC and raises the possibility of using PGE2 agonists to increase the survival of Ag-loaded DC following in vivo administration.
Involvement of Eotaxin, Eosinophils, and Pancreatic Predisposition in Development of Type 1 Diabetes Mellitus in the BioBreeding Rat
Authors: Hessner Martin J. , Wang Xujing , Meyer Lisa , Geoffrey Rhonda , Jia Shuang , Fuller Jessica , Lernmark Ake , Ghosh Soumitra 
Published: April 2014

Abstract
Allergy and autoimmunity are both examples of deregulated immunity characterized by inflammation and injury of targeted tissues that have until recently been considered disparate disease processes. However, recent findings have implicated mast cells, in coordination with granulocytes and other immune effector cells, in the pathology of these two disorders. The BioBreeding (BB) DRlyp/lyp rat develops an autoimmune insulin-dependent diabetes similar to human type 1 diabetes mellitus (T1DM), whereas the BBDR+/+ rat does not. To better understand immune processes during development of T1DM, gene expression profiling at day (d) 40 (before insulitis) and d65 (before disease onset) was conducted on pancreatic lymph nodes of DRlyp/lyp, DR+/+, and Wistar-Furth (WF) rats. The eosinophil-recruiting chemokine, eotaxin, and the high-affinity IgE receptor (FcεRI) were up-regulated &gt;5-fold in d65 DRlyp/lyp vs d65 DR+/+ pancreatic lymph nodes by microarray (p &lt; 0.05) and quantitative RT-PCR studies (p &lt; 0.05). DR+/+, WF, and d40 DRlyp/lyp animals possessed normal pancreatic histology; however, d65 DRlyp/lyp animals possessed eosinophilic insulitis. Therefore, immunohistochemistry for pancreatic eotaxin expression was conducted, revealing positive staining of d65 DRlyp/lyp islets. Islets of d65 DR+/+ rats also stained positively, consistent with underlying diabetic predisposition in the BB lineage, whereas WF islets did not. Other differentially expressed transcripts included those associated with eosinophils, mast cells, and lymphocytes. These data support an important role for these inflammatory mediators in BB rat T1DM and suggest that the lymphopenia due to the Ian5/(lyp) mutation may result in a deregulation of cells involved in insulitis and β cell destruction.
Notch Governing Mature T Cell Differentiation
Authors: Tsukumo Shin-ichi , Yasutomo Koji 
Published: April 2014

Abstract
The differentiation of naive T cells to effector/memory T cells is regulated by a variety of factors. The recent advance of the contribution of Notch signaling in this differentiation step has provided a new path to better understand the acquisition or persistence of effector function of mature T cells. In this review, we summarize emerging and, in some points, conflicting evidence for Notch signaling on mature T cell activation and differentiation.
Cutting Edge: TLR4 Activation Mediates Liver Ischemia/Reperfusion Inflammatory Response via IFN Regulatory Factor 3-Dependent MyD88-Independent Pathway
Authors: Zhai Yuan , Shen Xiu-da , O’Connell Ryan , Gao Feng , Lassman Charles , Busuttil Ronald W. , Cheng Genhong , Kupiec-Weglinski Jerzy W. 
Published: April 2014

Abstract
The triggering molecular mechanism of ischemia-reperfusion injury (IRI), which in clinical settings results in excessive and detrimental inflammatory responses, remains unclear. This study analyzes the role of the TLR system in an established murine model of liver warm ischemia followed by reperfusion. By contrasting in parallel TLR knockout mice with their wild-type counterparts, we found that TLR4, but not TLR2, was specifically required in initiating the IRI cascade, as manifested by liver function (serum alanine aminotransferase levels), pathology, and local induction of proinflammatory cytokines/chemokines (TNF-α, IL-6, IFN-inducible protein 10). We then investigated the downstream signaling pathway of TLR4 activation. Our results show that IFN regulatory factor 3, but not MyD88, mediated IRI-induced TLR4 activation leading to liver inflammation and hepatocellular damage. This study documents the selective usage of TLR in a clinically relevant noninfectious disease model, and identifies a triggering molecular mechanism in the pathophysiology of liver IRI.