bluuebunny/crossref_metadata_2025_split huggingface dataset:
ICAM-1–Dependent Homotypic Aggregates Regulate CD8 T Cell Effector Function and Differentiation during T Cell Activation
Authors: Zumwalde Nicholas A. , Domae Eisuke , Mescher Matthew F. , Shimizu Yoji 
Published: August 2013

AbstractA hallmark of T cell activation in vitro and in vivo is the clustering of T cells with each other via interaction of the LFA-1 integrin with ICAM-1. The functional significance of these homotypic aggregates in regulating T cell function remains unknown. We used an APC-free in vitro activation system to demonstrate that stimulation of purified naive CD8 T cells results in enhanced expression of ICAM-1 on T cells that is sustained by the inflammatory cytokine IL-12 and associated with robust T cell aggregates. ICAM-1–deficient CD8 T cells proliferate normally but demonstrate a striking failure to aggregate. Interestingly, loss of ICAM-1 expression results in elevated levels of IFN-γ and granzyme B, as well as enhanced cytotoxicity. Similar results were obtained when anti–LFA-1 Ab was used to block the clustering of wild-type T cells. ICAM-1 ligation is not required for IFN-γ regulation, as clustering of ICAM-1–deficient CD8 T cells with wild-type T cells reduces IFN-γ expression. Analysis using a fluorescent reporter that monitors TCR signal strength indicates that T cell clustering limits T cell exposure to Ag during activation. Furthermore, T cell clustering promotes the upregulation of the CTLA-4 inhibitory receptor and the downregulation of eomesodermin, which controls effector molecule expression. Activation of ICAM-1–deficient CD8 T cells in vivo results in an enhanced percentage of KLRG-1+ T cells indicative of short-lived effectors. These results suggest that T cell clustering represents a mechanism that allows continued proliferation but regulates T cell effector function and differentiation.
Inhibition of Endogenous Activated Protein C Attenuates Experimental Autoimmune Encephalomyelitis by Inducing Myeloid-Derived Suppressor Cells
Authors: Alabanza Leah M. , Esmon Naomi L. , Esmon Charles T. , Bynoe Margaret S. 
Published: August 2013

AbstractActivated protein C (PC) is an anticoagulant involved in the interactions between the coagulation and immune systems. Activated PC has broad anti-inflammatory effects that are mediated through its ability to modulate leukocyte function and confer vascular barrier protection. We investigated the influence of activated PC on the pathogenesis of experimental autoimmune encephalomyelitis (EAE), the animal model for multiple sclerosis. We modulated activated PC levels in the circulation during EAE induction through systemic administration of a mAb against PC/activated PC (anti-PC). We initially hypothesized that inhibition of activated PC may result in a heightened inflammatory environment, leading to increased EAE pathogenesis. Contrary to this hypothesis, mice treated with anti-PC Ab (anti-PC mice) exhibited attenuated EAE. Interestingly, despite reduced disease severity and minimal pathogenic conditions in the CNS, anti-PC mice exhibited considerable leukocyte infiltration in the brain, comparable to control mice with severe EAE. Furthermore, CD4+ T cells were diminished in the periphery of anti-PC mice, whereas various CD11b+ populations were increased, notably the myeloid-derived suppressor cells (MDSCs), a CD11b+ subset characterized as potent T cell suppressors. MDSCs from anti-PC mice exhibited increased expression of T cell suppressive factors and effectively inhibited T cell proliferation. Overall, our findings show that activated PC inhibition affected EAE pathogenesis at multiple fronts, specifically increasing vascular barrier permeability, as evidenced by considerable leukocyte infiltration in the brain. Additionally, inhibition of activated PC modulated the functional responses of CD11b+ cells, leading to the expansion and increased activation of MDSCs, which are suppressive to the CD4+ T cells required for EAE progression, thereby resulting in attenuated EAE.
Multiple Checkpoint Breach of B Cell Tolerance in Rasgrp1-Deficient Mice
Authors: Bartlett Amber , Buhlmann Janet E. , Stone James , Lim Bing , Barrington Robert A. 
Published: August 2013

Abstract
Lymphopenic hosts offer propitious microenvironments for expansion of autoreactive B and T cells. Despite this, many lymphopenic hosts do not develop autoimmune disease, suggesting that additional factors are required for breaching self-tolerance in the setting of lymphopenia. Mice deficient in guanine nucleotide exchange factor Rasgrp1 develop a lymphoproliferative disorder with features of human systemic lupus erythematosus. Early in life, Rasgrp1-deficient mice have normal B cell numbers but are T lymphopenic, leading to defective homeostatic expansion of CD4 T cells. To investigate whether B cell–intrinsic mechanisms also contribute to autoimmunity, Rasgrp1-deficient mice were bred to mice containing a knockin autoreactive BCR transgene (564Igi), thereby allowing the fate of autoreactive B cells to be assessed. During B cell development, the frequency of receptor-edited 564Igi B cells was reduced in Rasrp1-deficient mice compared with Rasgrp1-sufficient littermate control mice, suggesting that tolerance was impaired. In addition, the number of 564Igi transitional B cells was increased in Rasgrp1-deficient mice compared with control mice. Immature 564Igi B cells in bone marrow and spleen lacking RasGRP1 expressed lower levels of Bim mRNA and protein, suggesting that autoreactive B cells elude clonal deletion during development. Concomitant with increased serum autoantibodies, Rasgrp1-deficient mice developed spontaneous germinal centers at 8–10 wk of age. The frequency and number of 564Igi B cells within these germinal centers were significantly increased in Rasgrp1-deficient mice relative to control mice. Taken together, these studies suggest that autoreactive B cells lacking Rasgrp1 break central and peripheral tolerance through both T cell–independent and –dependent mechanisms.
Lectin-like Receptor Ly49s3 on Dendritic Cells Contributes to the Differentiation of Regulatory T Cells in the Rat Thymus
Authors: Yamada Toshiyuki , Nanashima Naoki , Akita Miki , Shimizu Takeshi , Miura Takuya , Yamana Daisuke , Sawano Takeyuki , Sakurai Takuya , Tsuchida Shigeki 
Published: August 2013

Abstract
Naturally occurring regulatory T cells (nTregs), important for immune regulation and the maintenance of self-tolerance, develop in the thymus. The Hirosaki hairless rat (HHR), derived from the Sprague–Dawley rat (SDR), was shown to have decreased peripheral lymphocyte number, small thymus, and leukocyte infiltration in its dermis. In the HHR thymus, the medulla was underdeveloped and nTreg number was decreased. Array comparative genome hybridization revealed the deletion of an NK cell lectin-like receptor gene, Ly49s3, detecting MHC class I molecules on target cells, in the chromosome 4q42 region in HHRs. The gene was expressed in thymic conventional dendritic cells (cDCs) in SDRs, but not in HHRs. When CD4–single-positive or CD4+CD8−CD25− thymocytes were cultured with thymic cDCs, the expression of nTreg marker genes was lower when these cells were from HHRs than from SDRs, suggesting that HHR cDCs are deficient in the ability to induce and maintain nTreg differentiation. Expression of the genes was recovered when Ly49s3 was expressed on HHR thymic cDCs. Expression levels of MHC class II genes, presumably from cDCs, were parallel to those of nTreg marker genes in mixed-cell cultures. However, in the presence of an anti-MHC class I Ab, blocking interaction between Ly49s3 and MHC class I molecules, the expression of the former genes was upregulated, whereas the latter was downregulated. These results suggest that Ly49s3 contributes to nTreg regulation along with MHC class II molecules, whose effects alone are insufficient, and loss of Ly49s3 from thymic cDCs is the reason for the nTreg deficiency in HHRs.
Integrin-α FG-GAP Repeat-Containing Protein 2 Is Critical for Normal B Cell Differentiation and Controls Disease Development in a Lupus Model
Authors: Al-Shami Amin , Crisostomo Jeannette , Wilkins Carrie , Xu Nianhua , Humphries Juliane , Chang Wei C. , Anderson Stephen J. , Oravecz Tamas 
Published: August 2013

Abstract
The phenylalanyl-glycyl–glycyl-alanyl-prolyl (FG-GAP) domain plays an important role in protein–protein interactions, including interaction of integrins with their ligands. Integrin-α FG-GAP repeat-containing protein 2 (Itfg2) is a highly conserved protein in vertebrates that carries two FG-GAP domains, but its role in mammalian physiology is unknown. In this article, we show that Itfg2 is an intracellular protein and it plays a critical role in B cell differentiation and development of autoimmunity. Itfg2-deficient mice displayed a phenotype consistent with retention of B cells in the spleen and had a lower concentration of IgG in the blood when compared with wild-type littermates. Itfg2-deficient splenocytes also showed a defect in cell migration in vitro. After immunization with a thymus-dependent Ag, the absence of Itfg2 caused a shift in B cell maturation from the germinal centers to the extrafollicular regions of the spleen and blocked deposition of Ag-specific plasma cells in the bone marrow. In support of hematopoietic cell intrinsic activity of Itfg2, bone marrow transplantation of Itfg2-deficient cells was sufficient to impair germinal center development in wild-type mice. Furthermore, Itfg2 deficiency exacerbated development of autoimmune disease in MRL/lpr lupus-prone mice. These results identify Itfg2 as a novel contributor to B cell differentiation and a negative regulator of the autoimmune response during lupus.
Suppression of IL-12 Production by Tristetraprolin through Blocking NF-кB Nuclear Translocation
Authors: Gu Ling , Ning Huan , Qian Xuesong , Huang Qi , Hou Rong , Almourani Rajaa , Fu Mingui , Blackshear Perry J. , Liu Jianguo 
Published: August 2013

Abstract
Tristetraprolin (TTP), an mRNA-binding protein, plays a significant role in regulating the expression of adenylate-uridylate–rich elements containing mRNAs. Mice deficient of TTP (TTP−/−) develop a systemic autoimmune inflammatory syndrome characterized by cachexia, conjunctivitis, and dermatitis. IL-12 plays a crucial role in immune defense against infectious and malignant diseases. In this study, we found increased production of IL-12 during endotoxic shock and enhanced Th1 cells in TTP knockout mice. The levels of IL-12 p70 and p40 protein as well as p40 and p35 mRNA were also increased in activated macrophages deficient of TTP. In line with these findings, overexpression of TTP suppressed IL-12 p35 and p40 expression at the mRNA and promoter level, whereas it surprisingly had little effects on their mRNA stability. Our data showed that the inhibitory effects of TTP on p35 gene transcription were completely rescued by overexpression of NF-кB p65 and c-Rel but not by the p50 in activated macrophages. Our data further indicated that TTP acquired its inhibition on IL-12 expression through blocking nuclear translocation of NF-кB p65 and c-Rel while enhancing p50 upon stimulation. In summary, our study reveals a novel pathway through which TTP suppresses IL-12 production in macrophages, resulting in suppression of Th1 cell differentiation. This study may provide us with therapeutic targets for treatment of inflammatory and autoimmune disorders.
Recombinant Human IL-15 Trans-Presentation by B Leukemic Cells from Chronic Lymphocytic Leukemia Induces Autologous NK Cell Proliferation Leading to Improved Anti-CD20 Immunotherapy
Authors: Laprevotte Emilie , Voisin Gregory , Ysebaert Loïc , Klein Christian , Daugrois Camille , Laurent Guy , Fournie Jean-Jacques , Quillet-Mary Anne 
Published: August 2013

Abstract
Recombinant human IL-15 (rhIL-15) is one of the most promising cytokines for antitumor immunotherapy. In physiology IL-15 trans-presentation by accessory cells leads to pleiotropic activities, including activation of immune cells, such as NK cells. NK cells are largely involved in Ab-dependent cellular cytotoxicity mediated by therapeutic mAbs, such as rituximab, in chronic lymphocytic leukemia (CLL). Nevertheless, in CLL, Ab-dependent cellular cytotoxicity is relatively impaired by the low E:T ratio (NK/B leukemic cells). Thus, any strategy leading to an increase in NK cell number and activation status can offer new strategies for CLL treatment. To this end, we evaluated the effect of rhIL-15 on autologous NK cell stimulation in CLL samples. We show that rhIL-15 induces NK cell activation and proliferation, leading to improved B leukemic cell depletion. This phenomenon is significantly increased in the presence of anti-CD20 mAbs. In addition, the greater effect of obinutuzumab versus rituximab suggests a cooperative role between rhIL-15 signaling and CD16 signaling in the induction of NK cell proliferation. Moreover, rhIL-15–induced proliferation of autologous NK cells is strictly dependent on their interaction with B leukemic cells, identified in this study as new accessory cells for rhIL-15 trans-presentation. Thus, rhIL-15 is able to promote NK cell–based activity in Ab immunotherapy of CLL.
Macrophage-Derived IL-33 Is a Critical Factor for Placental Growth
Authors: Fock Valerie , Mairhofer Mario , Otti Gerlinde R. , Hiden Ursula , Spittler Andreas , Zeisler Harald , Fiala Christian , Knöfler Martin , Pollheimer Jürgen 
Published: August 2013

Abstract
IL-33, the most recently discovered member of the IL-1 superfamily and ligand for the transmembrane form of ST2 (ST2L), has been linked to several human pathologies including rheumatoid arthritis, asthma, and cardiovascular disease. Deregulated levels of soluble ST2, the natural IL-33 inhibitor, have been reported in sera of preeclamptic patients. However, the role of IL-33 during healthy pregnancy remains elusive. In the current study, IL-33 was detected in the culture supernatants of human placental and decidual macrophages, identifying them as a major source of secreted IL-33 in the uteroplacental unit. Because flow cytometry and immunofluorescence stainings revealed membranous ST2L expression on specific trophoblast populations, we hypothesized that IL-33 stimulates trophoblasts in a paracrine manner. Indeed, BrdU incorporation assays revealed that recombinant human IL-33 significantly increased proliferation of primary trophoblasts as well as of villous cytotrophoblasts and cell column trophoblasts in placental explant cultures. These effects were fully abolished upon addition of soluble ST2. Interestingly, Western blot and immunofluorescence analyses demonstrated that IL-33 activates AKT and ERK1/2 in primary trophoblasts and placental explants. Inhibitors against PI3K (LY294002) and MEK1/2 (UO126) efficiently blocked IL-33–induced proliferation in all model systems used. In summary, with IL-33, we define for the first time, to our knowledge, a macrophage-derived regulator of placental growth during early pregnancy.
CagA-Dependent Downregulation of B7-H2 Expression on Gastric Mucosa and Inhibition of Th17 Responses during Helicobacter pylori Infection
Authors: Lina Taslima T. , Pinchuk Irina V. , House Jennifer , Yamaoka Yoshio , Graham David Y. , Beswick Ellen J. , Reyes Victor E. 
Published: August 2013

Abstract
Gastric epithelial cells (GECs) are the primary target for Helicobacter pylori infection and may act as APCs regulating local T cell responses. We previously reported that H. pylori infection of GECs induces the expression of the T cell coinhibitory molecule B7-H1 on GECs. This process contributes to the hyporesponsiveness of CD4+ effector T cells and accumulation of regulatory T cells. In the present study, we investigated the impact of H. pylori cytotoxin-associated gene A (CagA) on the modulation of the expression of the T cell costimulator B7-H2 by GECs. B7-H2 is involved in promoting Th17 type responses. H. pylori infection downregulates B7-H2 expression by GECs in a CagA-dependent manner. IFN-γ, which is increased in the H. pylori–infected gastric mucosa, synergizes with H. pylori in downregulating B7-H2 expression by GECs. CagA-mediated modulation of B7-H2 on GECs involves p70 S6 kinase phosphorylation. The CagA-dependent B7-H2 downregulation in GECs correlates with a decrease in Th17 type responses in vitro and in vivo. Furthermore, CagA-dependent modulation of Th17 responses was inversely correlated with the H. pylori colonization levels in vivo. Our data suggest that CagA contributes to the ability of H. pylori to evade Th17-mediated clearance by modulating expression of B7-H2 and, thus, to the establishment of the H. pylori chronic infection.
Mycobacteria-Infected Dendritic Cells Attract Neutrophils That Produce IL-10 and Specifically Shut Down Th17 CD4 T Cells through Their IL-10 Receptor
Authors: Doz Emilie , Lombard Robin , Carreras Florence , Buzoni-Gatel Dominique , Winter Nathalie 
Published: August 2013

Abstract
Neutrophils participate in the control of mycobacterial infection both by directly eliminating bacilli and by interacting with macrophages and dendritic cells (DCs). Despite host defenses, slow-growing mycobacteria can persist in the host for decades, mostly inside macrophages and DCs, and eventually destroy tissues after exacerbated inflammation. IL-17A–driven neutrophil recruitment may participate in this process. We report that mouse bone marrow–derived DCs infected with live Mycobacterium bovis Bacillus Calmette-Guérin (BCG) produced large amounts of CXCL1 and CXCL2, and attracted neutrophils. After physical contact with DCs infected with live BCG, the neutrophils produced large quantities of the immunosuppressive cytokine IL-10 via the MyD88 and spleen tyrosine kinase pathways. The CD11b integrin was involved in this neutrophil–DC interaction and allowed IL-10 production. TCR OVA transgenic mice immunized with a BCG strain producing OVA mounted an OVA-specific Th17 and Th1 CD4 response. Interestingly, IL-10–producing neutrophils specifically shut down IL-17A production by Th17 CD4 cells, but not IFN-γ production by Th1 cells. This was due to Th17 CD4 cell–restricted expression of the receptor for IL-10. After neutrophil depletion, total mouse lung cells produced less IL-10 but more IL-17A; IFN-γ production was not affected. Therefore, we suggest that during mycobacterial infection, regulatory neutrophils are instructed by infected reservoir DCs to produce IL-10 that specifically targets IL-10Rα–expressing Th17 CD4 T cells. This could be important to control the otherwise exuberant Th17 response.
HLA-G5 Induces IL-4 Secretion Critical for Successful Pregnancy through Differential Expression of ILT2 Receptor on Decidual CD4+ T Cells and Macrophages
Authors: Lombardelli Letizia , Aguerre-Girr Maryse , Logiodice Federica , Kullolli Ornela , Casart Ysabel , Polgar Beata , Berrebi Alain , Romagnani Sergio , Maggi Enrico , Le Bouteiller Philippe , Piccinni Marie-Pierre 
Published: August 2013

Abstract
Successful pregnancy in humans has been associated with production of IL-4 by T cells at the feto–maternal interface. Soluble HLA-G5 produced by trophoblasts potentially controls the decidual T cell cytokine profile. We studied the effect of HLA-G5 on the cytokine profile of purified human macrophages and Ag-specific T cells in vitro. We demonstrated that HLA-G5 increased production of IL-12 by purified peripheral blood macrophages. Although IL-12 production by macrophages is known to induce IFN-γ production by CD4+ T cells, HLA-G5 increased production of IL-4 but not IFN-γ by CD4+ T cells after Ag presentation by macrophages. We found that this apparent paradox was due to the differential expression of the ILT2 HLA-G5 receptor on activated T cells and macrophages. This receptor was upregulated in the former and downregulated in the latter after Ag presentation and activation of both cell types. This observation was confirmed in situ, where decidual macrophages and T cells are continuously exposed to HLA-G5 produced locally and activated by trophoblast alloantigens. Freshly isolated decidua basalis macrophages expressed lower levels of ILT2 than peripheral blood macrophages from the same pregnant women. They did not spontaneously produce IL-12, whereas freshly isolated decidual CD4+ T cells expressed high levels of activation markers (CD25, HLA-DR, and CD69) as well as ILT2 and spontaneously produced IL-4 but not IFN-γ. Therefore, HLA-G5 could be responsible, at least in part, via its interaction with ILT2, for decidual T cell IL-4 production, known to be crucial for successful pregnancy.
Exacerbation of Allergen-Induced Eczema in TLR4- and TRIF-Deficient Mice
Authors: Brandt Eric B. , Gibson Aaron M. , Bass Stacey , Rydyznski Carolyn , Khurana Hershey Gurjit K. 
Published: August 2013

Abstract
Despite its presence on resident skin cells, the role of TLR4 in skin diseases remains poorly understood. This is highly significant because the skin biome is rich with potential TLR4 agonists. We aimed to establish the contribution of TLR4 to atopic dermatitis and determine the mechanism by which TLR4 acts in an experimental model of atopic dermatitis. MyD88, TLR4, or Toll–IL-1R domain-containing adapter-inducing IFN-β (TRIF)–deficient and wild-type mice were epicutaneously exposed to Aspergillus fumigatus allergen over 3 wk. Impaired skin barrier function was assessed by measuring transepidermal water loss (TEWL). Skin levels of innate and adaptive genes were quantified. In an experimental model of atopic dermatitis, TEWL, allergic sensitization, and epidermal thickness were increased following cutaneous allergen exposure, and these were further enhanced in the absence of TLR4. Increased allergen-induced skin levels of innate (S100A8/A9, IL-1β, TNF-α, and CXCL2) and Th17 genes (IL-17A and IL-17F) were observed in TLR4-deficient mice compared with wild-type mice. The absence of MyD88 alleviated disease (decreased TEWL, skin thickness, proinflammatory cytokines), whereas TRIF deficiency exacerbated disease. In conclusion, signaling through the TLR4 and TRIF pathways limits skin barrier dysfunction, cutaneous allergic sensitization, and proinflammatory cytokine production.
Cutting Edge: Mycobacterium tuberculosis but Not Nonvirulent Mycobacteria Inhibits IFN-β and AIM2 Inflammasome–Dependent IL-1β Production via Its ESX-1 Secretion System
Authors: Shah Swati , Bohsali Amro , Ahlbrand Sarah E. , Srinivasan Lalitha , Rathinam Vijay A. K. , Vogel Stefanie N. , Fitzgerald Katherine A. , Sutterwala Fayyaz S. , Briken Volker 
Published: August 2013

Abstract
Mycobacterium tuberculosis extracellular DNA gains access to the host cell cytosol via the ESX-1 secretion system. It is puzzling that this extracellular DNA of M. tuberculosis does not induce activation of the AIM2 inflammasome because AIM2 recognizes cytosolic DNA. In this study, we show that nonvirulent mycobacteria such as Mycobacterium smegmatis induce AIM2 inflammasome activation, which is dependent on their strong induction of IFN-β production. In contrast, M. tuberculosis, but not an ESX-1–deficient mutant, inhibits the AIM2 inflammasome activation induced by either M. smegmatis or transfected dsDNA. The inhibition does not involve changes in host cell AIM2 mRNA or protein levels but led to decreased activation of caspase-1. We furthermore demonstrate that M. tuberculosis inhibits IFN-β production and signaling, which was partially responsible for the inhibition of AIM2 activation. In conclusion, we report a novel immune evasion mechanism of M. tuberculosis that involves the ESX-1–dependent, direct or indirect, suppression of the host cell AIM2 inflammasome activation during infection.