bluuebunny/crossref_metadata_2025_split huggingface dataset:
Macrophage Deletion of p38α Partially Impairs Lipopolysaccharide-Induced Cellular Activation
Authors: Kang Young Jun , Chen Jianming , Otsuka Motoyuki , Mols Johann , Ren Shuxun , Wang Yinbin , Han Jiahuai 
Published: April 2014

AbstractThe activation of p38α, a MAPK family member, is associated with macrophage activation by microbial pattern molecules, such as LPS. The requirement of p38α in inflammatory responses has been shown in a number of studies using chemical inhibitors, though the inhibitors also inhibit p38β and perhaps some other enzymes. In this study, we used conditional knockout of p38α in macrophages to address the role of p38α in macrophage activation. We found that p38α deficiency causes a significant inhibition in the production of LPS-induced TNF-α, IL-12, and IL-18, but it has little or no effect on IL-6 or IFN-β production. Knockout of p38α in macrophages did not affect LPS-induced activation of the other major signaling pathways (NF-κB, Jnk, and Erk), nor did it affect the transcriptional activity of NF-κB. It had little inhibitory effect on LPS-induced AP-1 activity, but it significantly inhibited LPS-induced C/EBP-β and CREB activation, indicating that the role of p38α in cytokine production in macrophages is at least in part through its regulation of C/EBP-β and CREB activation. In addition, we also confirmed that p38α is important for phagocytosis of bacteria by macrophages. Our in vivo studies with two murine models showed that p38α is involved in sepsis. Collectively, our data demonstrate that p38α is an important player in inflammatory responses.
A Novel Type I IFN-Producing Cell Subset in Murine Lupus
Authors: Lee Pui Y. , Weinstein Jason S. , Nacionales Dina C. , Scumpia Philip O. , Li Yi , Butfiloski Edward , van Rooijen Nico , Moldawer Lyle , Satoh Minoru , Reeves Westley H. 
Published: April 2014

AbstractExcess type I IFNs (IFN-I) have been linked to the pathogenesis of systemic lupus erythematosus (SLE). Therapeutic use of IFN-I can trigger the onset of SLE and most lupus patients display up-regulation of a group of IFN-stimulated genes (ISGs). Although this “IFN signature” has been linked with disease activity, kidney involvement, and autoantibody production, the source of IFN-I production in SLE remains unclear. 2,6,10,14-Tetramethylpentadecane-induced lupus is at present the only model of SLE associated with excess IFN-I production and ISG expression. In this study, we demonstrate that tetramethylpentadecane treatment induces an accumulation of immature Ly6Chigh monocytes, which are a major source of IFN-I in this lupus model. Importantly, they were distinct from IFN-producing dendritic cells (DCs). The expression of IFN-I and ISGs was rapidly abolished by monocyte depletion whereas systemic ablation of DCs had little effect. In addition, there was a striking correlation between the numbers of Ly6Chigh monocytes and the production of lupus autoantibodies. Therefore, immature monocytes rather than DCs appear to be the primary source of IFN-I in this model of IFN-I-dependent lupus.
CXCL13, CCL21, and CXCL12 Expression in Salivary Glands of Patients with Sjögren’s Syndrome and MALT Lymphoma: Association with Reactive and Malignant Areas of Lymphoid Organization
Authors: Barone Francesca , Bombardieri Michele , Rosado Manuela Maria , Morgan Peter Roger , Challacombe Stephen J. , De Vita Salvatore , Carsetti Rita , Spencer Jo , Valesini Guido , Pitzalis Costantino 
Published: April 2014

Abstract
The chemokines (CKs) CXCL13, CCL21, and CXCL12 are known to play differential roles in the organization of the lymphoid tissues and the development of lymphoid malignancies. We investigated the expression of these CKs and their receptors in the salivary glands of Sjogren’s syndrome patients with lymphoepithelial lesions (lymphoepithelial sialadenitis or LESA) and in MALT lymphoma to understand their involvement in salivary gland lymphomagenesis. We demonstrate that within salivary glands with LESA and MALT lymphoma the lymphoid CKs CXCL13 and CCL21 are selectively associated with areas of reactive lymphoid proliferation, whereas no significant expression of these molecules was detected in the malignant lymphoid aggregate. Conversely, CXCL12 was observed predominantly in infiltrated ducts and malignant B cells. Accordingly, CXCL13 and CCL21 transcript levels were significantly increased in LESA samples while CXCL12 levels were increased in MALT lymphoma and isolated tumor cells. Low levels of CK receptors were detected on lymphoma-extracted lymphocytes, suggesting down-regulation in the abundance of ligands. Our findings suggest that in salivary gland MALT lymphoma the lymphoid CKs CXCL13 and CCL21 are directly implicated in the organization of ectopic reactive lymphoid tissue, whereas CXCL12 is associated with the infiltrated epithelium and malignant B cell component and is possibly involved in the regulation of malignant B cell survival.
The Presence of Activated CD4+ T Cells Is Essential for the Formation of Colony-Forming Unit-Endothelial Cells by CD14+ Cells
Authors: van Beem Rachel T. , Noort Willy A. , Voermans Carlijn , Kleijer Marion , ten Brinke Anja , van Ham S. Marieke , van der Schoot C. Ellen , Zwaginga Jaap Jan 
Published: April 2014

Abstract
The number of colony forming unit-endothelial cells (CFU-EC) in human peripheral blood was found to be a biological marker for several vascular diseases. In this study, the heterogeneous composition of immune cells in the CFU-ECs was investigated. We confirmed that monocytes are essential for the formation of CFU-ECs. Also, however, CD4+ T cells were found to be indispensable for the induction of CFU-EC colonies, mainly through cell-cell contact. By blocking or activating CD3 receptors on CD4+ T cells or blocking MHC class II molecules on monocytes, it was shown that TCR-MHCII interactions are required for induction of CFU-EC colonies. Because the supernatant from preactivated T cells could also induce colony formation from purified monocytes, the T cell support turned out to be cytokine mediated. Gene expression analysis of the endothelial-like colonies formed by CD14+ cells showed that colony formation is a proangiogenic differentiation and might reflect the ability of monocytes to facilitate vascularization. This in vitro study is the first to reveal the role of TCR-MHC class II interactions between T cells and monocytes and the subsequent inflammatory response as stimulus of monocytic properties that are associated with vascularization.
Cutting Edge: Broad Expression of the FoxP3 Locus in Epithelial Cells: A Caution against Early Interpretation of Fatal Inflammatory Diseases following In Vivo Depletion of FoxP3-Expressing Cells
Authors: Chen Guo-Yun , Chen Chong , Wang Lizhong , Chang Xing , Zheng Pan , Liu Yang 
Published: April 2014

Abstract
Dogma that the regulatory T cell (Treg) prevents catastrophic autoimmunity throughout the lifespan relies on the assumption that the FoxP3 locus is transcribed exclusively in Treg. To test the assumption, we used the Rag2−/− and the Rag2−/− mice with the Scurfy (sf) mutation (FoxP3sf/Y or FoxP3sf/sf) to evaluate FoxP3 expression outside of the lymphoid system. Immunohistochemistry and real-time PCR revealed FoxP3 expression in breast epithelial cells, lung respiratory epithelial cells, and prostate epithelial cells, although not in liver, heart, and intestine. The specificity of the assays was confirmed, as the signals were ablated by the Scurfy mutation of the FoxP3 gene. Using mice with a green fluorescence protein open reading frame knocked into the 3′ untranslated region of the FoxP3 locus, we showed that the locus is transcribed broadly in epithelial cells of multiple organs. These results refute an essential underlying assumption of the dogma and question the specificity of FoxP3-based Treg depletion.
Differential Regulation of Human IL-7 Receptor α Expression by IL-7 and TCR Signaling
Authors: Alves Nuno L. , van Leeuwen Ester M. M. , Derks Ingrid A. M. , van Lier René A. W. 
Published: April 2014

Abstract
IL-7Rα is essential for the development and homeostatic maintenance of mature T cells. Studies in humans and mice have shown that IL-7Rα expression is reduced by its cognate cytokine, IL-7, and Ag, suggesting that active regulation of IL-7 responsiveness is necessary to balance T cell numbers. We show that IL-7- or TCR/CD28-mediated signaling induced a rapid down-regulation of IL-7Rα expression on naive T cells on the mRNA and protein level, with a mild (10-fold) or strong (50-fold) gene suppression, respectively. In both situations, the down-regulation of IL-7Rα was blocked by cyclohexamide and actinomycin D, indicating the involvement of an active mechanism dependent on new transcription and protein synthesis. Upon IL-7 withdrawal, IL-7Rα mRNA and surface protein reappeared in a transcription-dependent manner within 7 h. Yet, IL-7Rα was hardly re-expressed during the same period after TCR/CD28-activation. Likewise, T cells that were activated through CMV in vivo did not re-express IL-7Rα after in vitro culture. Functionally, IL-7-induced down-regulation of IL-7Rα did not hinder the responsiveness of naive T cells to IL-7. Conversely, down-regulation of IL-7Rα on TCR/CD28-activated cells limited IL-7 responsiveness. Strikingly, ectopic expression of IL-7Rα cells on TCR/CD28-activated cells conferred a selective advantage in the response to IL-7. In conclusion, our data show that IL-7- and TCR/CD28-mediated signaling differentially regulate IL-7Rα expression on human T cells with a transient and chronic effect, respectively. The stringent and active regulation of IL-7Rα may constitute a homeostatic mechanism to curtail unwarranted T cell expansion.
Down-Regulation of ICOS Ligand by Interaction with ICOS Functions as a Regulatory Mechanism for Immune Responses
Authors: Watanabe Masashi , Takagi Yuri , Kotani Motoko , Hara Yasushi , Inamine Ayako , Hayashi Katsuhiko , Ogawa Shuhei , Takeda Kei , Tanabe Kazunari , Abe Ryo 
Published: April 2014

Abstract
Although it is well-known that the ICOS-ICOS ligand (ICOSL) costimulatory pathway is important for many immune responses, recent accumulated evidence suggests that dysregulation of this pathway may lead to and/or exaggerate autoimmune responses. ICOS is induced on the cell surface after T cell activation. Similarly, ICOSL is up-regulated on APCs by several mitogenic stimuli. However, the mechanism regulating expression of the ICOS-ICOSL pair, and the significance of controlling their expression for an appropriate immune response, is largely unknown. To gain a better understanding of the importance of fine control of the ICOS-ICOSL costimulatory pathway, we generated ICOS-transgenic (Tg) mice that have high constitutive expression of ICOS in all T cells. Using ICOS-Tg mice, we studied whether in vivo immune responses were affected. Unexpectedly, we first found that ICOS-Tg mice exhibited a phenotype resembling ICOS-deficient mice in their Ag-specific Ab response, such as a defect in class switch recombination. Further examination revealed that ICOSL expression of APCs was significantly suppressed in ICOS-Tg mice. Interestingly, suppression of ICOSL was induced by interaction of ICOSL with ICOS, and it seemed to be regulated at the posttranscriptional level. The suppressive effect of the ICOS-ICOSL interaction overcame the positive effect of CD40 or B cell activation factor of the TNF family (BAFF) stimulation on ICOSL expression. Together, our studies demonstrate a novel mechanism for the regulation of ICOSL expression in vivo and suggest that the ICOS costimulatory pathway is subject to negative feedback regulation by ICOSL down-regulation in response to ICOS expression.
CD137 Costimulation of CD8+ T Cells Confers Resistance to Suppression by Virus-Induced Regulatory T Cells
Authors: Robertson Shelly J. , Messer Ronald J. , Carmody Aaron B. , Mittler Robert S. , Burlak Christopher , Hasenkrug Kim J. 
Published: April 2014

AbstractChronic viral infections cause high levels of morbidity and mortality worldwide, making the development of effective therapies a high priority for improving human health. We have used mice infected with Friend virus as a model to study immunotherapeutic approaches to the cure of chronic retroviral infections. In chronic Friend virus infections CD4+ T regulatory (Treg) cells suppress CD8+ T cell effector functions critical for virus clearance. In this study, we demonstrate that immunotherapy with a combination of agonistic anti-CD137 Ab and virus-specific, TCR-transgenic CD8+ T cells produced greater than 99% reductions of virus levels within 2 wk. In vitro studies indicated that the CD137-specific Ab rendered the CD8+ T cells resistant to Treg cell-mediated suppression with no direct effect on the suppressive function of the Treg cells. By 2 weeks after transfer, the adoptively transferred CD8+ T cells were lost, likely due to activation-induced cell death. The highly focused immunological pressure placed on the virus by the single specificity CD8+ T cells led to the appearance of escape variants, indicating that broader epitope specificity will be required for long-term virus control. However, the results demonstrate a potent strategy to potentiate the function of CD8+ T cells in the context of immunosuppressive Treg cells.
Aging Down-Regulates the Transcription Factor E2A, Activation-Induced Cytidine Deaminase, and Ig Class Switch in Human B Cells
Authors: Frasca Daniela , Landin Ana Marie , Lechner Suzanne C. , Ryan John G. , Schwartz Robert , Riley Richard L. , Blomberg Bonnie B. 
Published: April 2014

AbstractElderly humans have compromised humoral and cellular immune responses, which lead to reduced protection to infectious agents and to vaccines. Currently, available vaccines suboptimally protect the elderly population. The capacity to class switch the Ig H chain is critical to the effectiveness of humoral immune responses in mice and humans. We have previously shown in mice that the E2A-encoded transcription factor E47, which regulates many B cell functions, is down-regulated in old splenic B cells. This leads to a reduction in the activation-induced cytidine deaminase (AID), which is known to induce class switch recombination and Ig somatic hypermutation. The old activated murine B cells also have less AID and less switched Abs. We have extended our study here to investigate whether aging also affects Ab production and E47 and AID expression in B cells isolated from the peripheral blood of human subjects (18–86 years). Our results obtained with activated CD19+ B cells show that the expression of E47, AID, and Igγ1 circle transcripts progressively decrease with age. We also show an age-related decline in the percentage of switch memory B cells (IgG+/IgA+), an increase in that of naive B cells (IgG−/IgA−/CD27−) for most individuals, and no decrease in that of IgM memory cells in peripheral blood, consistent with our data on the decrease seen in class switch recombination in vitro. Our results provide a possible molecular mechanism for a B cell intrinsic defect in the humoral immune response with aging and suggest avenues for improvement of vaccine response in elderly humans.
Derivation and Fluidity of Acutely Induced Dysfunctional CD8+ T Cells
Authors: Plesa Gabriela , Snook Adam E. , Waldman Scott A. , Eisenlohr Laurence C. 
Published: April 2014

AbstractDysfunctional CD8+ T (TCD8+) cells lacking cytokine production have been identified in many viral infections, but their genesis is not well understood. Established results indicate that such cells could be either high avidity that enter a refractory state due to overstimulation or low avidity that are only partially stimulated. Using an acute, resolving infection model that results in rapid production of dysfunctional cells, we show that this IL2 unresponsive phenotype emerges from the low end of the avidity spectrum and is characterized by broad TCR usage and a reduced proliferation rate. Furthermore, the dysfunctional population is extremely fluid, being sustained by high Ag dose but virtually eliminated following low dose boosting. Together, these results suggest that persistence of dysfunctional cells generated in this manner depends upon continual exposure to high Ag levels and that such cells may ultimately predominate if functional cells become exhausted.
The Lymphopenic Environment of CD132 (Common γ-Chain)-Deficient Hosts Elicits Rapid Homeostatic Proliferation of Naive T Cells via IL-15
Authors: Ramsey Chris , Rubinstein Mark P. , Kim David M. , Cho Jae-Ho , Sprent Jonathan , Surh Charles D. 
Published: April 2014

Abstract
Homeostatic proliferation for naive T cells is observed readily only under lymphopenic conditions in response to elevated levels of IL-7 and contact with self-MHC/peptide ligands. Homeostatic proliferation occurs at a slow pace and gradually induces the dividing cells to acquire characteristics of memory cells. We describe a novel type of homeostatic proliferation whereby naive T cells proliferate at a significantly faster rate, resembling the proliferation speed induced by foreign Ags, and the expanding cells rapidly differentiate into central memory cells. Remarkably, such rapid homeostatic proliferation is driven by a combination of IL-2 and IL-15, with IL-15 playing a bigger role, and applies for a wide repertoire of CD8+ naive T cells, including many TCR-transgenic lines, even those that fail to undergo IL-7-driven homeostatic proliferation. Thus, naive T cells can be induced to undergo homeostatic proliferation of variable speed with a few members of the common γ-chain (CD132) family of cytokines, the speed of proliferation depending on the levels of the particular cytokine involved.
Neural Crest Origin of Perivascular Mesenchyme in the Adult Thymus
Authors: Müller Susanna M. , Stolt Claus C. , Terszowski Grzegorz , Blum Carmen , Amagai Takashi , Kessaris Nicoletta , Iannarelli Palma , Richardson William D. , Wegner Michael , Rodewald Hans-Reimer 
Published: April 2014

Abstract
The endodermal epithelial thymus anlage develops in tight association with neural crest (NC)-derived mesenchyme. This epithelial-NC interaction is crucial for thymus development, but it is not known how NC supports thymus development or whether NC cells or their progeny make any significant contribution to the adult thymus. By nude mouse blastocyst complementation and by cell surface phenotype, we could previously separate thymus stroma into Foxn1-dependent epithelial cells and a Foxn1-independent mesenchymal cell population. These mesenchymal cells expressed vascular endothelial growth factor-A, and contributed to thymus vascularization. These data suggested a physical or functional association with thymic blood vessels, but the origin, location in the thymus, and function of these stromal cells remained unknown. Using a transgenic mouse expressing Cre recombinase in premigratory NC (Sox10-Cre), we have now fate-mapped the majority of these adult mesenchymal cells to a NC origin. NC-derived cells represent tightly vessel-associated pericytes that are sandwiched between endothelium and epithelium along the entire thymus vasculature. The ontogenetic, phenotypic, and positional definition of this distinct perivascular mesenchymal compartment provides a cellular basis for the role of NC in thymus development and possibly maintenance, and might be useful to address properties of the endothelial-epithelial barrier in the adult thymus.
Equivalent Specificity of Peripheral Blood and Islet-Infiltrating CD8+ T Lymphocytes in Spontaneously Diabetic HLA-A2 Transgenic NOD Mice
Authors: Énée Emmanuelle , Martinuzzi Emanuela , Blancou Philippe , Bach Jean-Marie , Mallone Roberto , van Endert Peter 
Published: April 2014

Abstract
CD8+ T cells play an important role in the initiation of insulitis and in the destructive stage leading to insulin-dependent diabetes mellitus. A string of recent studies has led to the identification of numerous HLA-A2-restricted epitopes derived from pancreatic β cell Ags. It is hoped that assays detecting responses of patient PBMC to such epitopes might be instrumental for early diagnosis of β cell-directed autoimmunity and for monitoring trials of immunointervention. However, it remains unclear whether the results of assays studying PBMC reflect responses of islet-infiltrating lymphocytes, and to what extent they correlate with disease risk and/or activity. We have used female and male humanized NOD mice expressing HLA-A2 in addition to murine MHC class I molecules to study spontaneous responses of islet-infiltrating blood, spleen, and lymph node lymphocytes of various age groups to a panel of 16 epitopes. Twelve of these are restricted by HLA-A2, have previously been shown to be recognized by patient CTL, and have identical sequences in human and murine autoantigens. Using an IFN-γ ELISPOT assay, we find highly similar hierarchies of epitope immunodominance in the different T cell compartments, including peripheral blood and pancreatic islets. Moreover, we demonstrate that most of the epitopes eliciting dominant responses in humans display similar status in the mouse model. These results emphasize the potential of humanized mice as tools for studying spontaneous autoimmune CTL responses, and they provide a strong rationale for the development and use of assays monitoring responses of CD8+ PBMC in human type 1 diabetes.
A 9-Centimorgan Interval of Chromosome 10 Controls the T Cell-Dependent Psoriasiform Skin Disease and Arthritis in a Murine Psoriasis Model
Authors: Wang Honglin , Kess Daniel , Lindqvist Anna-Karin B. , Peters Thorsten , Sindrilaru Anca , Wlaschek Meinhard , Blakytny Robert , Holmdahl Rikard , Scharffetter-Kochanek Karin 
Published: April 2014

Abstract
Psoriasis is a complex genetic disease of unresolved pathogenesis with both heritable and environmental factors contributing to onset and severity. In addition to a disfiguring skin inflammation, approximately 10–40% of psoriasis patients suffer from destructive joint involvement. Previously, we reported that the CD18 hypomorphic PL/J mouse carrying a mutation resulting in reduced expression of the common chain of β2 integrins (CD11/CD18) spontaneously develops a skin disease that closely resembles human psoriasis. In contrast, the same mutation on C57BL/6J background did not demonstrate this phenotype. By a genome-wide linkage analysis, two major loci were identified as contributing to the development of psoriasiform dermatitis under the condition of low CD18 expression. Using a congenic approach, we now demonstrate that the introduction of a 9-centimorgan fragment of chromosome 10 derived from the PL/J strain into the disease-resistant CD18 hypomorphic C57BL/6J was promoting the development of psoriasiform skin disease and notably also arthritis. We therefore designated this locus psoriasiform skin disease-associated locus 1 (PSD1). High numbers of CD4+ T cells and TNF-α producing macrophages were detected both in inflamed skin and joints in these congenic mice, with a complete resolution upon TNF-α inhibitor therapy or depletion of CD4+ T cells. For the first time, we have identified a distinct genetic element that contributes to the T cell-dependent development of both psoriasiform skin disease and associated arthritis. This congenic model will be suitable to further investigations of genetic and molecular pathways that cause psoriasiform dermatitis and arthritis, and it may also be relevant for other autoimmune diseases.