bluuebunny/crossref_metadata_2025_split huggingface dataset:
Wnt Target Genes Identified by DNA Microarrays in Immature CD34+ Thymocytes Regulate Proliferation and Cell Adhesion
Authors: Staal Frank J. T. , Weerkamp Floor , Baert Miranda R. M. , van den Burg Caroline M. M. , van Noort Mascha , de Haas Edwin F. E. , van Dongen Jacques J. M. 
Published: April 2014

Abstract
The thymus is seeded by very small numbers of progenitor cells that undergo massive proliferation before differentiation and rearrangement of TCR genes occurs. Various signals mediate proliferation and differentiation of these cells, including Wnt signals. Wnt signals induce the interaction of the cytoplasmic cofactor β-catenin with nuclear T cell factor (TCF) transcription factors. We identified target genes of the Wnt/β-catenin/TCF pathway in the most immature (CD4−CD8−CD34+) thymocytes using Affymetrix DNA microarrays in combination with three different functional assays for in vitro induction of Wnt signaling. A relatively small number (∼30) of genes changed expression, including several proliferation-inducing transcription factors such as c-fos and c-jun, protein phosphatases, and adhesion molecules, but no genes involved in differentiation to mature T cell stages. The adhesion molecules likely confine the proliferating immature thymocytes to the appropriate anatomical sites in the thymus. For several of these target genes, we validated that they are true Wnt/β-catenin/TCF target genes using real-time quantitative PCR and reporter gene assays. The same core set of genes was repressed in Tcf-1-null mice, explaining the block in early thymocyte development in these mice. In conclusion, Wnt signals mediate proliferation and cell adhesion, but not differentiation of the immature thymic progenitor pool.
The Epidermal Growth Factor-Seven Transmembrane (EGF-TM7) Receptor CD97 Is Required for Neutrophil Migration and Host Defense
Authors: Leemans Jaklien C. , te Velde Anje A. , Florquin Sandrine , Bennink Roelof J. , de Bruin Kora , van Lier René A. W. , van der Poll Tom , Hamann Jörg 
Published: April 2014

Abstract
The epidermal growth factor-seven transmembrane (EGF-TM7) family is a group of seven-span transmembrane receptors predominantly expressed by cells of the immune system. Family members CD97, EGF module-containing mucin-like receptor (EMR) 1, EMR2, EMR3, EMR4, and EGF-TM7-latrophilin-related protein are characterized by an extended extracellular region with a variable number of N-terminal EGF-like domains. EGF-TM7 receptors bind cellular ligands as demonstrated by the interaction of CD97 with decay accelerating factor (CD55) and dermatan sulfate. Investigating the effect of newly generated mAb on the migration of neutrophilic granulocytes, we here report for the first time in vivo data on the function of CD97. In dextran sulfate sodium-induced experimental colitis, we show that homing of adoptively transferred neutrophils to the colon was significantly delayed when cells were preincubated with CD97 mAb. The consequences of this defect in neutrophil migration for host defense are demonstrated in a murine model of Streptococcus pneumoniae-induced pneumonia. Mice treated with CD97 mAb to EGF domain 1 (1B2) and EGF domain 3 (1C5) displayed a reduced granulocytic inflammatory infiltrate at 20 h after inoculation. This was associated with a significantly enhanced outgrowth of bacteria in the lungs at 44 h and a strongly diminished survival. Together, these findings indicate an essential role for CD97 in the migration of neutrophils.
The Cationic Antimicrobial Peptide LL-37 Modulates Dendritic Cell Differentiation and Dendritic Cell-Induced T Cell Polarization
Authors: Davidson Donald J. , Currie Andrew J. , Reid Gregor S. D. , Bowdish Dawn M. E. , MacDonald Kelly L. , Ma Rebecca C. , Hancock Robert E. W. , Speert David P. 
Published: April 2014

Abstract
Dendritic cells (DC) are instrumental in orchestrating an appropriately polarized Th cell response to pathogens. DC exhibit considerable phenotypic and functional plasticity, influenced by lineage, Ag engagement, and the environment in which they develop and mature. In this study, we identify the human cationic peptide LL-37, found in abundance at sites of inflammation, as a potent modifier of DC differentiation, bridging innate and adaptive immune responses. LL-37-derived DC displayed significantly up-regulated endocytic capacity, modified phagocytic receptor expression and function, up-regulated costimulatory molecule expression, enhanced secretion of Th-1 inducing cytokines, and promoted Th1 responses in vitro. LL-37 may be an attractive therapeutic candidate for manipulating T cell polarization by DC.
Mice Deficient in LRG-47 Display Increased Susceptibility to Mycobacterial Infection Associated with the Induction of Lymphopenia
Authors: Feng Carl G. , Collazo-Custodio Carmen M. , Eckhaus Michael , Hieny Sara , Belkaid Yasmine , Elkins Karen , Jankovic Dragana , Taylor Gregory A. , Sher Alan 
Published: April 2014

Abstract
Although IFN-γ is essential for host control of mycobacterial infection, the mechanisms by which the cytokine restricts pathogen growth are only partially understood. LRG-47 is an IFN-inducible GTP-binding protein previously shown to be required for IFN-γ-dependent host resistance to acute Listeria monocytogenes and Toxoplasma gondii infections. To examine the role of LRG-47 in control of mycobacterial infection, LRG-47−/− and wild-type mice were infected with Mycobacterium avium, and host responses were analyzed. LRG-47 protein was strongly induced in livers of infected wild-type animals in an IFN-γ-dependent manner. LRG-47−/− mice were unable to control bacterial replication, but survived the acute phase, succumbing 11–16 wk postinfection. IFN-γ-primed, bone marrow-derived macrophages from LRG-47−/− and wild-type animals produced equivalent levels of TNF and NO upon M. avium infection in vitro and developed similar intracellular bacterial loads. In addition, priming for IFN-γ production was observed in T cells isolated from infected LRG-47−/− mice. Importantly, however, mycobacterial granulomas in LRG-47−/− mice showed a marked lymphocyte deficiency. Further examination of these animals revealed a profound systemic lymphopenia and anemia triggered by infection. As LRG47−/− T lymphocytes were found to both survive and confer resistance to M. avium in recipient recombinase-activating gene-2−/− mice, the defect in cellular response and bacterial control in LRG-47−/− mice may also depend on a factor(s) expressed in a nonlymphocyte compartment. These findings establish a role for LRG-47 in host control of mycobacteria and demonstrate that in the context of the IFN-γ response to persistent infection, LRG-47 can have downstream regulatory effects on lymphocyte survival.
Prostaglandin E2 Induces Degranulation-Independent Production of Vascular Endothelial Growth Factor by Human Mast Cells
Authors: Abdel-Majid Raja M. , Marshall Jean S. 
Published: April 2014

Abstract
Mast cells accumulate in large numbers at angiogenic sites, where they have been shown to express a number of proangiogenic factors, including vascular endothelial growth factor (VEGF-A). PGE2 is known to strongly promote angiogenesis and is found in increased levels at sites of chronic inflammation and around solid tumors. The expression pattern of VEGF and the regulation of VEGF-A by PGE2 were examined in cord blood-derived human mast cells (CBMC). CBMC expressed mRNA for five isoforms of VEGF-A and other members of the VEGF family (VEGF-B, VEGF-C, and VEGF-D) with strong expression of the most potent secretory isoforms. PGE2 was a very strong inducer of VEGF-A121/165 production by CBMC and also elevated VEGF-A mRNA expression. The amount of VEGF-A121/165 protein production induced by PGE2 was 4-fold greater than that induced by IgE-mediated activation of CBMC. Moreover, the response to PGE2 as well as to other cAMP-elevating agents such as forskolin and salbutamol was observed under conditions that were not associated with mast cell degranulation. CBMC expressed substantial levels of the EP2 receptor, but not the EP4 receptor, when examined by flow cytometry. In contrast to other reported PGE2-mediated effects on mast cells, VEGF-A121/165 production occurred via activation of the EP2 receptor. These data suggest a role for human mast cells as a potent source of VEGF121/165 in the absence of degranulation, and may provide new opportunities to regulate angiogenesis at mast cell-rich sites.
CXCR2−/− Mice Show Enhanced Susceptibility to Herpetic Stromal Keratitis: A Role for IL-6-Induced Neovascularization
Authors: Banerjee Kaustuv , Biswas Partha S. , Kim Bumseok , Lee Sujin , Rouse Barry T. 
Published: April 2014

Abstract
Ocular infection with HSV results in a blinding immunoinflammatory lesion known as herpetic stromal keratitis (HSK). Early preclinical events include inflammatory cell, mainly neutrophils, infiltration of the stroma, and neovascularization. To further evaluate the role of neutrophils in pathogenesis, HSV infection was compared in BALB/c and mice of the same background, but lacking CXCR2, the receptor for chemokines involved in neutrophil recruitment. Our results show clear differences in the outcome of ocular HSV infection in CXCR2−/− compared with control BALB/c mice. Thus, CXCR2−/− animals had minimal PMN influx during the first 7 days postinfection, and this correlated with a longer duration of virus infection in the eye compared with BALB/c mice. The CXCR2−/− mice were also more susceptible to HSV-induced lesions and developed HSK upon exposure to a dose of HSV that was minimally pathogenic to BALB/c mice. The basis for the greater HSK lesion susceptibility of CXCR2−/− mice was associated with an elevated IL-6 response, which appeared in turn to induce the angiogenic factor, vascular endothelial growth factor. Our results serve to further demonstrate the critical role of angiogenesis in the pathogenesis of ocular lesions.
Defective Control of Latent Epstein-Barr Virus Infection in Systemic Lupus Erythematosus
Authors: Kang Insoo , Quan Timothy , Nolasco Helena , Park Sung-Hwan , Hong Myung Sun , Crouch Jill , Pamer Eric G. , Howe John Greg , Craft Joe 
Published: April 2014

Abstract
EBV infection is more common in patients with systemic lupus erythematosus (SLE) than in control subjects, suggesting that this virus plays an etiologic role in disease and/or that patients with lupus have impaired EBV-specific immune responses. In the current report we assessed immune responsiveness to EBV in patients with SLE and healthy controls, determining virus-specific T cell responses and EBV viral loads using whole blood recall assays, HLA-A2 tetramers, and real-time quantitative PCR. Patients with SLE had an ∼40-fold increase in EBV viral loads compared with controls, a finding not explained by disease activity or immunosuppressive medications. The frequency of EBV-specific CD69+ CD4+ T cells producing IFN-γ was higher in patients with SLE than in controls. By contrast, the frequency of EBV-specific CD69+ CD8+ T cells producing IFN-γ in patients with SLE appeared lower than that in healthy controls, although this difference was not statistically significant. These findings suggest a role for CD4+ T cells in controlling, and a possible defect in CD8+ T cells in regulating, increased viral loads in lupus. These ideas were supported by correlations between viral loads and EBV-specific T cell responses in lupus patients. EBV viral loads were inversely correlated with the frequency of EBV-specific CD69+ CD4+ T cells producing IFN-γ and were positively correlated with the frequencies of CD69+ CD8+ T cells producing IFN-γ and with EBV-specific, HLA-A2 tetramer-positive CD8+ T cells. These results demonstrate that patients with SLE have defective control of latent EBV infection that probably stems from altered T cell responses against EBV.
Periportal Fibrosis in Human Schistosoma mansoni Infection Is Associated with Low IL-10, Low IFN-γ, High TNF-α, or Low RANTES, Depending on Age and Gender
Authors: Booth Mark , Mwatha Joseph K. , Joseph Sarah , Jones Frances M. , Kadzo Hilda , Ireri Edmund , Kazibwe Frances , Kemijumbi Jovanice , Kariuki Curtis , Kimani Gachuhi , Ouma John H. , Kabatereine Narcis B. , Vennervald Birgitte J. , Dunne David W. 
Published: April 2014

Abstract
Schistosoma mansoni infection is highly endemic in parts of Uganda, and periportal fibrosis is common in communities along the shore of Lake Albert. In this study, we have identified cellular immune responses associated with fibrosis. A cohort of 199 individuals aged 6–50, resident in the village for at least 10 years or since birth, were examined for evidence of periportal fibrosis by ultrasound using the Niamey protocol. Whole-blood samples were assayed for levels of nine cellular immune molecules (IL-3, IL-4, IL-5, IL-10, IL-13, TNF-α, IFN-γ, IL-1β, and RANTES) in the absence of in vitro Ag stimulation, and after stimulation with egg and worm Ags. A lack of Ag specificity allowed the number of variables in the analysis to be reduced by factor analysis. The resulting factor scores were then entered into a risk analysis using a classification tree algorithm. Children, adult males, and adult females had different factors associated with fibrosis. Most cases of fibrosis in children (eight of nine) were associated with low (&lt;47th percentile) IL-10 factor scores. Adult females at lowest risk had relatively high IFN-γ factor scores (&gt;83rd percentile), whereas those at highest risk had a combination of intermediate (32nd to 83rd percentile) IFN-γ and relatively high (&gt;60th percentile) TNF-α factor scores. Adult males at lowest risk of fibrosis had moderate TNF-α factor scores (55th to 82nd percentile), and a high risk was associated with either high TNF-α factor scores (&gt;82nd percentile), or intermediate TNF-α combined with low RANTES factor scores (&lt;58th percentile). These results demonstrate that periportal fibrosis is associated with cytokine production profiles that vary with both age and gender.
Cutting Edge: BAFF Regulates CD21/35 and CD23 Expression Independent of Its B Cell Survival Function
Authors: Gorelik Leonid , Cutler Anne H. , Thill Greg , Miklasz Steven D. , Shea Dianna E. , Ambrose Christine , Bixler Sarah A. , Su Lihe , Scott Martin L. , Kalled Susan L. 
Published: April 2014

Abstract
Herein we demonstrate that B cell-activating factor of the TNF family (BAFF), a B cell survival factor, also regulates CD21/35 and CD23 expression. BAFF blockade in wild-type mice down-modulates CD21/35 and CD23 on B cells while survival remains intact, and BAFF exposure causes elevated CD21/35 and CD23 expression. Similar down-modulation is observed in bcl-2-transgenic mice treated with a BAFF inhibitor. This is the first evidence that BAFF has a function independent of B cell survival. Reports using CD21/35 and CD23 expression to assess splenic B cell subsets in BAFF-null mice concluded a lack of B cells beyond the immature stage. Since CD21/35 and CD23 are inadequate for delineating B cell subpopulations in BAFF-null mice, we used expression of BAFF-R and several B cell markers to identify more mature splenic B cells in these mice. These data broaden our understanding of BAFF function and correct the view that BAFF-null mice lack mature B cells.
TNF Deficiency Fails to Protect BAFF Transgenic Mice against Autoimmunity and Reveals a Predisposition to B Cell Lymphoma
Authors: Batten Marcel , Fletcher Carrie , Ng Lai Guan , Groom Joanna , Wheway Julie , Laâbi Yacine , Xin Xiaoguan , Schneider Pascal , Tschopp Jurg , Mackay Charles R. , Mackay Fabienne 
Published: April 2014

AbstractTNF is well characterized as a mediator of inflammatory responses. TNF also facilitates organization of secondary lymphoid organs, particularly B cell follicles and germinal centers, a hallmark of T-dependent Ab responses. TNF also mediates defense against tumors. We examined the role of TNF in the development of inflammatory autoimmune disorders resembling systemic lupus erythematosus and Sjögren’s syndrome induced by excess B cell-activating factor belonging to the TNF family (BAFF), by generating BAFF-transgenic (Tg) mice lacking TNF. TNF−/− BAFF-Tg mice resembled TNF−/− mice, in that they lacked B cell follicles, follicular dendritic cells, and germinal centers, and have impaired responses to T-dependent Ags. Nevertheless, TNF−/− BAFF-Tg mice developed autoimmune disorders similar to that of BAFF-Tg mice. Disease in TNF−/− BAFF-Tg mice correlates with the expansion of transitional type 2 and marginal zone B cell populations and enhanced T-independent immune responses. TNF deficiency in BAFF-Tg mice also led to a surprisingly high incidence of B cell lymphomas (&gt;35%), which most likely resulted from the combined effects of BAFF promotion of neoplastic B cell survival, coupled with lack of protective antitumor defense by TNF. Thus, TNF appears to be dispensable for BAFF-mediated autoimmune disorders and may, in fact, counter any proneoplastic effects of high levels of BAFF in diseases such as Sjögren’s syndrome, systemic lupus erythematosus, and rheumatoid arthritis.
Central Tolerance to Self-Antigen Expressed by Cortical Epithelial Cells
Authors: Mayerova Dita , Hogquist Kristin A. 
Published: April 2014

Abstract
The exposure of developing thymocytes to high-affinity self-Ag results in T cell tolerance. A predominant mechanism for this is clonal deletion; though receptor editing, anergy induction, and positive selection of regulatory T cells have also been described. It is unclear what signals are involved in determining different tolerance mechanisms. In particular, OT-I mice displayed receptor editing when the high-affinity self-Ag was expressed in cortical epithelial cells (cEC) using the human keratin 14 promoter. To test the hypothesis that receptor editing is a consequence of a unique instruction given by cEC presenting self-Ag, we created mice expressing the 2C and HY ligands under control of the keratin 14 promoter. Alternatively, we studied the fate of developing T cells in OT-I mice where Ag was presented by all thymic APC. Surprisingly, we found that the tolerance mechanism was not influenced by the APC subset involved in presentation. Clonal deletion was observed in 2C and HY models even when Ag was presented only by cEC; and receptor editing was observed in OT-I mice even when Ag was presented by all thymic APC. These results suggest that different TCRs show intrinsic differences in thymic tolerance mechanism.
Turnover and Proliferation of NK Cells in Steady State and Lymphopenic Conditions
Authors: Jamieson Amanda M. , Isnard Patricia , Dorfman Jeffrey R. , Coles Mark C. , Raulet David H. 
Published: April 2014

Abstract
To gain insight into NK cell dynamics, we investigated the turnover and proliferation rates of NK cells in normal and lymphopenic conditions. In contrast to previous reports suggesting a very rapid turnover of NK cells, continuous 5-bromo-2′-deoxyuridine (BrdU)-labeling studies demonstrated that the time necessary for labeling 50% of splenic NK cells in mature mice was 17 days, similar to the rate of labeling of memory T cells. In contrast, in young mice, splenic NK cells labeled very rapidly with BrdU, although cell cycle analyses and BrdU pulse-labeling studies suggested that most of this proliferation occurred in a precursor population. A somewhat larger percentage of bone marrow NK cells was cycling, suggesting that these proliferating cells are the precursors of the mostly nondividing or slowly dividing splenic NK cells. Splenic NK cells from mature mice also did not proliferate significantly when transferred to normal mice, but did proliferate when transferred to irradiated mice. Thus, NK cells, like T cells, undergo homeostatic proliferation in a lymphopenic environment. Homeostatic proliferation of NK cells was not dependent on host cell class I molecules or host production of IL-15. Nevertheless, the number of recovered NK cells was much lower in IL-15−/− hosts. These results suggest that IL-15 is not essential for homeostatic proliferation of NK cells, but is necessary for survival of the NK cells. Our results provide important basic information concerning the production and replacement of NK cells.
An Altered Self-Peptide with Superagonist Activity Blocks a CD8-Mediated Mouse Model of Type 1 Diabetes
Authors: Hartemann-Heurtier Agnès , Mars Lennart T. , Bercovici Nadège , Desbois Sabine , Cambouris Christophe , Piaggio Eliane , Zappulla Jacques , Saoudi Abdelhadi , Liblau Roland S. 
Published: April 2014

Abstract
T cell tolerance can be experimentally induced through administration of self-peptides with single amino acid substitution (altered peptide ligands or APLs). However, little is known about the effects of APLs on already differentiated autoreactive CD8+ T cells that play a pivotal role in the pathogenesis of autoimmune diabetes. We generated a panel of APLs derived from an influenza virus hemagglutinin peptide exhibiting in vitro functions ranging from antagonism to superagonism on specific CD8+ T cells. A superagonist APL was further characterized for its therapeutic activity in a transgenic mouse model of type 1 diabetes. When injected i.v. 1 day after the transfer of diabetogenic hemagglutinin-specific CD8+ T cells into insulin promoter-hemagglutinin transgenic mice, the superagonist APL proved more effective than the native hemagglutinin peptide in blocking diabetes. This protective effect was associated with an inhibition of CD8+ T cell cytotoxicity in vivo and with a decreased accumulation of these cells in the pancreas, leading to a marked reduction of intrainsulitis. In conclusion, a superagonist “self-peptide” APL was more effective than the native peptide in treating a CD8+ T cell-mediated diabetes model.
Alloantigen-Induced CD25+CD4+ Regulatory T Cells Can Develop In Vivo from CD25−CD4+ Precursors in a Thymus-Independent Process
Authors: Karim Mahzuz , Kingsley Cherry I. , Bushell Andrew R. , Sawitzki Birgit S. , Wood Kathryn J. 
Published: April 2014

Abstract
The capacity of naturally occurring autoreactive CD25+CD4+ regulatory T cells (Treg) to control immune responses both in vivo and in vitro is now well established. It has been demonstrated that these cells undergo positive selection within the thymus and appear to enter the periphery as committed CD25+CD4+ Treg. We have shown previously that CD25+CD4+ Treg with the capacity to prevent skin allograft rejection can be generated by pretreatment with donor alloantigen under the cover of anti-CD4 therapy. Here we demonstrate that this process does not require an intact thymus. Furthermore, generation of these Treg is not dependent on the expansion of CD25+CD4+ thymic emigrants, because depletion of CD25+ cells before pretreatment does not prevent Treg development, and Treg can be generated from CD25−CD4+ precursors. Taken together, these results clearly demonstrate that CD25+CD4+ Treg can be generated in the periphery from CD25−CD4+ precursors in a pathway distinct to that by which naturally occurring autoreactive CD25+CD4+ Treg develop. These observations may have important implications for the design of protocols, both experimental and clinical, for the induction of tolerance to autoantigens or alloantigens in adults with limited thymic function.