bluuebunny/crossref_metadata_2025_split huggingface dataset:
Monocyte-derived IL-1α enables host resistance to M. tuberculosis by activating stroma-derived TNF-α and stalling pathogen replication in vivo. (P1247)
Authors: Shayakhmetov Dmitry , Di Paolo Nelson , Shafiani Shahin , Day Tracey , Papayannopoulou Thalia , Russell David , Iwakura Yoichiro , Sherman David , Urdahl Kevin 
Published: January 2023

Abstract
Mycobacterium tuberculosis (M.tb) is one of the most prevalent and deadly human pathogens. The molecular mechanisms determining the outcomes of infection with M.tb remain incompletely understood. Here we show that IL-1α-mediated signaling from infected macrophages is absolutely required for effective pathogen control in a model of pulmonary M.tb infection in mice. We further show that M.tb replication and survival of infected cells in vivo is controlled through an IL-1α-driven signaling to stroma cells that secrete in response TNF-α and enable cell-intrinsic resistance to the pathogen by limiting its replication at a single cell level. The lack of IL-1α leads to profound non-resolving inflammation that contributes to pathology, rather than to pathogen control. Restoration of IL-1α expression in CD11c-positive lung leukocytes in IL-1alpha-deficient mice alleviates inflammation and improves survival of animals after M.tb infection. Our study implicates IL-1α-driven leukocyte-stroma cell crosstalk as a key step in triggering M.tb control mechanisms that are critical for host survival. These data reveal fundamental role of innate immunity in M.tb pathogenesis and define novel molecular targets for the development of drugs to control tuberculosis epidemics.
Biphasic STAT1 phosphorylation in response to double-stranded RNA (P1397)
Authors: Matsumiya Tomoh , Dempoya Junich , Xing Fei , Hayakari Ryo , Imaizumi Tadaatsu , Yoshida Hidemi , Satoh Kei 
Published: January 2023

Abstract
Viral nucleic acids are sensed by pattern recognition receptors, leads to produce of type I IFN to exert antiviral activities. Type I IFN binds to its cognate receptor, IFNAR, resulting in the activation of STAT1. Thus it has long been thought dsRNA-introduced STAT1 phosphorylation is through transactivation of type I IFN signaling. Foreign RNA entered into cell such as viral RNA is sensed by cytoplasmic sensors retinoic acid-inducible gene-I (RIG-I) and melanoma differentiation-associated gene-5 (MDA-5). In this study, we explored the molecular mechanism of how STAT1 phosphorylation is regulated by dsRNA through the cytosolic RNA sensors. A synthetic dsRNA polyinosinic-polycytidylic acid (polyI:C) induces STAT1 phosphorylation. We found the polyI:C-induced initial STAT1 phosphorylation is dependent on RIG-I pathway and MDA-5 is not involved in the STAT1 phosphorylation. Neither the pathway for RIG-I nor type I IFN is involved in the late phosphorylation of STAT1. polyI:C were able to stimulate STAT1 phosphorylation in type I IFN receptor-deficient U5A cells, suggesting this initial phosphorylation is predominantly type I IFN-dependent; however, studies using IFN receptor neutralizing antibody indicated the presence of IFN independent- and RIG-I-dependent pathway for STAT1 activation. Taken together, our results showed comprehensive regulation in which dsRNA induces STAT1 phosphorylation, indicating importance of STAT1 with such a tight regulation in innate immune system.
Exome sequencing identifies novel mutations in the Toll-like receptor 3 pathway contributing to herpes simplex encephalitis susceptibility (P1403)
Authors: Sancho Shimizu Vanessa , Mashbat Bayarchimeg , Itan Yuval , Lorenzo Lazaro , Zhang Shen-Ying , Puel Anne , Levin Michael , Casanova Jean Laurent 
Published: January 2023

Abstract
Herpes simplex encephalitis is a rare manifestation of herpes simplex virus-1 infection. Mutations in genes of the toll-like receptor 3-interferon pathway have been shown to predispose to childhood herpes simplex encephalitis, including UNC93B1, TLR3, TRIF, TRAF3 and TBK1. We investigated herpes simplex encephalitis patients with impaired toll-like receptor 3 signaling for whom the involvement of the known genetic etiologies have been excluded. Exome sequencing was used to identify other mutations underlying herpes simplex encephalitis, paying particular attention to the toll-like receptor 3-interferon pathway by employing a candidate gene based ‘connectome’ approach. One patient in particular carried a novel heterozygous missense mutation in a known gene in the nuclear factor-κB / toll-like receptor 3 pathway. The patient’s cells showed a decrease in interferon regulatory factor-3 dimerization and reduced nuclear translocation of nuclear factor-κB consistent with the lack of type I interferon and IL6 production following toll-like receptor 3 stimulation. The patients’ cells were also more susceptible upon viral infections. Further characterization of the mutation and its impact on type I interferon signaling in the context of herpes simplex virus-1 infection will provide a better understanding of the etiology of childhood herpes simplex encephalitis.
Mechanism of induction and genotype-phenotype correlation of IL28B and ISG expression in HCV-infected primary human hepatocytes and liver (P1383)
Authors: Thomas Emmanuel , Noureddin Mazen , Rotman Yaron , Liang T. Jake 
Published: January 2023

Abstract
Background: IL28B gene polymorphisms associated with hepatitis C virus (HCV) clearance suggests a role for type III interferons (IFNs. However, the intrinsic innate immune response following HCV infection remains poorly understood. Methods: Immunofluorescence staining of innate immune molecules (IRF3, ISG15) were performed on HCV infected PHHs. PHHs were also studied for correlation of IL28 genotype with type III IFN and ISG expression. In addition, RNA was extracted from 60 pre-treatment archived liver biopsies and hepatic expression of IFNs was measured by qPCR. Rs12979860 genotype was determined in PHHs and patients. Results: Primary human hepatocytes infected with HCV, but not contaminating non-parenchymal cells, demonstrate activated nuclear IRF3, supporting a direct anti-viral response to HCV pathogen associated molecular pattern (PAMP). In the patient cohort, there was a significant correlation between the hepatic expression of type III IFNs (IL28B & IL29, r=0.60, P &lt;0.0001). ISGs expression was positively correlated with Type III IFNs (e.g. for ISG115 r=0.55, p&lt;0.001). Conclusions: Our study demonstrates that HCV infection results in a rapid and robust intrinsic innate response in the liver. Although non-parenchymal cells may subsequently participate in this response, it is the infected hepatocyte that signals the initial danger signal. Finally, the hepatic expression of ISGs in HCV patients is mainly associated with type III IFNs.
Salt-dependent chemotaxis of macrophages (P5122)
Authors: Mueller Silke , Quast Thomas , Hucke Stephanie , Klotz Luisa , Schroeder Agnes , Jantsch Jonathan , Titze Jens , Gerzer Rupert , Hemmersbach Ruth , Kolanus Waldemar 
Published: January 2023

Abstract
Recent studies support the hypothesis that macrophages are not only essential for efficient immune responses, but are also regulators of local tissue electrolyte composition and hence arterial hypertension. Blockade of this macrophage-dependent regulatory axis resulted in skin electrolyte accumulation and blood pressure increase. Based on the observation that macrophages accumulate in skin tissue of rats fed under high salt diet conditions, the question arose whether macrophages actively migrate to sites of high sodium storage. We therefore investigated the migratory behavior of RAW264.7 macrophages, murine bone marrow-derived macrophages and murine peritoneal macrophages toward different NaCl gradients, showing that NaCl may act as a chemotactic stimulus per se. We also assessed the reorganization of the actin cytoskeleton, a potential NaCl-induced chemokine CCL2 production and the role of the osmoprotective transcription factor TonEBP in salt-dependent chemotaxis. Although the underlying mechanism remains unidentified, we propose that salt-dependent chemotaxis might be an important functional feature of macrophages within the context of excess salt clearance in vivo.
Pathogenic role for chemerin receptor CMKLR1 in experimental pulmonary fibrosis (P5138)
Authors: Monnier Justin , Lewen Suzanna , Carlson Jeffrey , Zabel Brian 
Published: January 2023

Abstract
Pulmonary fibrosis (PF) is a debilitating interstitial lung disease with few treatment options. The pathogenesis of idiopathic PF likely involves recurring microinjuries to the alveolar epithelium, leukocyte infiltration and inflammation, and an aberrant pro-fibrotic wound-healing response. CMKLR1 is a chemoattractant receptor for chemerin that is expressed on NK cells and other immune cells implicated in PF. Our goal was to determine the role of CMKLR1 in the pathogenesis of bleomycin-induced pulmonary inflammation and fibrosis. During the inflammatory phase of the model, neutrophilic infiltration of the airways was significantly increased in CMKLR1-deficient mice compared to wild-type (WT). During the fibrotic phase, CMKLR1-deficient mice developed more severe pulmonary fibrosis than WT as measured by lung collagen content and histopathology. The levels of key pro-inflammatory and pro-fibrotic cytokines (TNFα, IFNγ, IL-10, IL-17, and TGFβ) were significantly elevated in interstitial lung tissue from bleomycin-treated CMKRL1 KO mice. There was also a significant reduction in the recruitment of NK cells into the airways in CMKLR1 KO mice during the fibrotic phase. We hypothesize that chemerin and CMKLR1 play a protective role in lung fibrosis by dampening the initial inflammatory response and by recruiting anti-fibrotic leukocytes. Augmentation of the CMKLR1/chemerin system may therefore provide a novel approach to engage anti-fibrotic leukocytes for PF therapy.
Orai1 function is essential for T cell homing to lymph nodes (P5102)
Authors: Greenberg Milton , Yu Ying , Leverrier Sabrina , Parker Ian , Cahalan Michael 
Published: January 2023

Abstract
In T lymphocytes, Ca2+ release-activated Ca2+ (CRAC) channels composed of Orai1 subunits trigger antigen-induced gene expression through the NFAT pathway. Lymphocyte homing into lymph nodes may also require CRAC channel function. We evaluated the requirements for human lymphocyte homing, using expression of a dominant-negative Orai1-E106A mutant to suppress Ca2+ signaling. To investigate homing and motility of human lymphocytes we transferred human T cells into immunocompromised mouse hosts following stable reconstitution. Human lymphocyte homing was assessed by flow cytometry, and cells were tracked within lymph nodes by two-photon microscopy. Our results demonstrate that human T lymphocytes home into and migrate within the lymph nodes of immunocompromised NOD.SCID.B2 mice, similar to murine lymphocytes. Human T cells migrated in a random walk at velocities of 12.8 ± 0.4 µm/min. Expression of Orai1-E106A inhibited CRAC channel function in human T cells and prevented homing from high endothelial venules into murine lymph nodes. Ca2+ signals induced by CCL21 were also inhibited in T cells expressing Orai1-E106A. With CRAC channels inhibited, the high-affinity form of LFA-1 failed to become active, and T cells failed to migrate across endothelial cells in a transwell model. These results establish a requirement for CRAC channel-mediated Ca2+ influx for T cell homing to lymph nodes mediated by high-affinity integrin activation and chemokine-induced transendothelial migration.
The role of pTα/pre-TCR in susceptibility to autoimmunity (P1464)
Authors: Mayans Sofia , Lambolez Florence , Roh Sujin , Larange Alexandre , Becart Stephane , Cheroutre Hilde 
Published: January 2023

Abstract
Autoimmune diseases result from a breakdown in self-tolerance, with a major contribution of pathogenic self-reactive T cells. Individuals with a particular autoimmune disease are often at risk of developing additional autoimmunity directed towards other target tissues. These observations suggest that there might be a mechanism leading to a general defect in self-tolerance, resulting in increased susceptibility to autoimmune disease. Tolerance towards self is initially established in the thymus during the process of thymic selection. Developing thymocytes are first immature CD4 and CD8 double negative thymocytes. Cells with a productive TCRβ gene rearrangement will express a pre-TCR/CD3 complex on the cell surface by combining a TCRβ chain with the pTα chain. Signaling through the pre-TCR, β-selection, plays a crucial role in the generation αβT cells, by enabling further maturation to the CD4 and CD8 double positive stage. The crucial role of pTα at β-selection together with the genetic localization of the ptcra gene and the fact that variations in pTα will affect all developing T cells, suggests that pTα could be a common factor leading to a general defect in self-tolerance. We have discovered differences in the isoform expression pattern and amino acid sequence of pTa between NOD and B6 mice. These findings are consistent with the hypothesis that alterations in the pre-TCR might affect selection, giving a modified TCR repertoire and increased susceptibility to autoimmunity.
Matricellular protein CYR61 expands thymic stroma (P1423)
Authors: Emre Yalin , Irla Magali , Dunand-Sauthier Isabelle , Ballet Romain , Meguenani Mehdi , Jemelin Stephane , Vesin Christian , Reith Walter , Imhof Beat 
Published: January 2023

Abstract
T-cell development is dependent on microenvironments generated by stromal cells such as thymic epithelial cells (TEC). TEC population, which is phenotypically and functionally heterogeneous, controls the migration, proliferation and selection of differentiating thymocytes. CYR61 (cysteine-rich protein 61) is a matricellular protein reported to promote proliferation and migration of cancer cells. Here we investigated the impact of CYR61 treatment on T-cell development. We found that matricellular protein CYR61 was strongly expressed in TEC and favored TEC/thymocyte interaction by binding to LFA1 and ICAM1. Treatment of thymic lobes with recombinant CYR61 expanded the thymic stromal compartment. Thymocyte-independent TEC proliferation occurred through CYR61 binding to integrin alpha6/beta1 and the activation of Akt signaling pathway. Engraftment of thymic lobes mildly overexpressing CYR61 into athymic nude mice drastically boosted thymic output through the expansion of TEC. Actually, CYR61-expanded stroma offered more space for the recruitment of circulating hematopoietic progenitors and for the development of T-cells. Our results reveal CYR61 as a potent target for the development of thymic stroma and T-cells.
Comparison of neonatal and adult T cells’ responses to TCR, CD43 and TLR5 signals (P1427)
Authors: Santana M. Angelica , Galindo-Albarrán Ariel , Rodríguez-Jorge Otoniel , Labastida-Conde Rosario , Ramírez-Pliego Oscar 
Published: January 2023

Abstract
Characterisation of neonatal T cell response is largely incomplete, despite infants under 6 months old are highly susceptible to infections. It has been reported that neonatal cells require strong signals for differentiation into the pro-inflammatory Th1 phenotype, which is needed to fight viral and intracellular bacteria infections. We decided to evaluate the response of human neonatal and adult naïve T cells to two accessory molecules that have been reported to induce a Th1 profile. CD43 is a transmembrane Type One mucin-like molecule that has been proposed as one of the first molecules to make contact with APCs, regulating cell adhesion and function. We found that toll like receptor 5 (TLR5), which recognizes the flagellin monomer, is highly expressed in T-lymphocytes. It was reported that human neonatal CD8 T cells respond to flagellin with a strong expression of IFNγ. We compared the response of ex-vivo human neonatal CD4 and CD8 T cells to TCR and either CD43 or TLR5 signals alone or in combination. We evaluated the expression of cytokines of the major differentiation profiles (Th1, Th2, Th17 and Treg) and found that neonatal cells produce lower levels of all cytokines, with the exception of TGFβ, and have a higher requirement for TCR signals as compared to the adult cells.
Bifidobacterium longum subsp. longum KACC 91563 from Korean neonates alleviate the food allergy by decrease of mast cells in the gut. (P3172)
Authors: Kim Jung-Hwan , Jeun Eun Ji , Ham Jun-Sang , Jang Min Seung , Hong Chun Pyo , Lee Eun-Jung , Yang Bo Gie , Jang Myoung Ho 
Published: January 2023

Abstract
Gut microbiota which establish the habitat in our gut, have formidable effects on human body via complex mechanisms, including metabolism, development, behavior, immune defense and diseases. Probioitcs are live microorganism that confers a benefit on the host when administrated adequate amount. Food allergy is a potentially serious disease caused by abnormal immune response to food or food additives and hospital visits for food allergy have been dramatically increased in the last several decades. Here we investigated the effects of new probiotics that isolated from the feces of healthy Korean infants on food allergy. Among them, we found that new subspecies of Bifidobacterium Longum suppress the diarrhea in allergen-induced food allergy mouse model. When we administrated B. longum subsp. longum KACC 91563, the accumulation of mast cells was significantly decreased in small intestinal lamina propria and mast cell proteases were down regulated in serum. However Th1, Th2, Th17 and regulatory T cells were not involved in the alleviation of allergen-induced food allergy in small intestinal lamina propria. These findings suggest that oral administration of newly isolated B. longum, ameliorates the severity of allergen-induced food allergy by decrease of mast cells.
Regenerating islet-derived III-gamma regulates pulmonary Th17 immunity by altering the gut microbiome (P3164)
Authors: McAleer Jeremy , Nguyen Nikki , Chen Kong , Ricks David , Binnie Matthew , Sheppard Dean , Ouyang Wenjun , Kolls Jay 
Published: January 2023

Abstract
Commensal microbes are critical for the development of intestinal lymphoid tissues, but little is known about how they shape systemic immunity. Lung infection with Aspergillus fumigatus induces a potent IL-17 response from T cells. Vancomycin drinking water diminished lung il17a expression during infection, demonstrating a role for gram-positive commensals in amplifying pulmonary immunity. Since RegIIIγ is an intestinal anti-microbial factor that targets gram-positive bacteria, we hypothesized that it would decrease lung Th17 cytokine expression, similar to the effects of oral vancomycin. To test this, RegIIIγ-/- mice and C57BL/6 (WT) mice were infected with A. fumigatus, and lung cytokines were analyzed two days later. RegIIIγ-/- mice had elevated expression of il17a, il17f and il22, and this was positively correlated with intestinal colonization by segmented filamentous bacteria. Further, reconstitution of il22-/- mice with recombinant RegIIIγ by oral gavage decreased steady-state IL-17+ γδ T cells in the lung. To test if RegIIIγ regulates lung Th17 priming by interacting with intestinal microbiota, mice were treated with vancomycin water and then immunized with OVA plus cholera toxin. Notably, antibiotic treatment reduced lung Th17 numbers in RegIIIγ-/- mice to the level observed in WT mice. These data demonstrate that modulating the expression of an intestinal anti-bacterial lectin can have profound effects on pulmonary immunity by altering the gut microbiome.
The variation of CD4+ memory T cells in the development of asthma in mice (P6233)
Authors: Li Yanchun , Hua Shucheng , He Xiaoyan , Li Yun , Sun Ye 
Published: January 2023

Abstract
Objective To understand the role of CD4+ memory T cells in pathogenesis of asthma in mice Method Female BALB/c mice were sensitized and challenged with OVA for continuous 7 days. After one month, another challenge was given for one day. We detected the ratio changes of CD4+ memory T cells in CD4+ T cells during the treatment course, the membrane surface markers of CD3+, CD4+, CD44High, CD62L- were examined by using a flow cytometry. We further compared the different challenge time durations effect on CD4+ memory T cell numbers. Results In control mice, the ratios of CD4+ memory T cells in lung and spleen were 11.32% and 20.48%, respectively; After challenge, the ratio of CD4+ memory T cells increased gradually and reached the peak value ( 53% in lung and 45% in spleen) at one week after the last challenge. After one month these ratios returned to the levels of before the challenge. However, these memory T cells raised up rapidly on the next day during the second challenge, especially in the lung and kept relatively stable levels (about 35% in lung and 30% in spleen) within one week. We observed that the different challenge time durations had similar effect on the ratio of CD4+ memory T cells in lung, but it differ in spleen the peak value of CD4+ memory T cells at 30min challenge was 10% lower than that with 1 hour challenge and dropped earlier. Conclusion The CD4+ memory T cells play important roles in asthma pathogenesis, the detailed mechanisms warrant further exploration.
Allergenicity of the major birch pollen allergen Bet v 1 might arise from molecular mimicry of homologous bacterial proteins (P6210)
Authors: Smole Ursula , Ackerbauer Daniela , Lengger Nina , Radauer Christian , Wallner Michael , Svoboda Martin , Wills-Karp Marsha , Mechtcheriakova Diana , Breiteneder Heimo 
Published: January 2023

Abstract
Certain families of allergens contain domains that bear structural and functional similarity to homologs from pathogens enabling them to sabotage host immunity by hijacking crucial innate immune pathways. We focused on members of the Bet v 1-like superfamily that share a remarkably conserved architecture, the so called Bet v 1-fold, with the aim to identify structural mimicry as one possible cause of allergenicity. Here we show that Bet v 1, the major birch pollen (BP) allergen, has functional homology with a bacterial homolog, namely TTHA0849 from Thermus thermophilus. TTHA0849 and Bet v 1 competed for the same uptake mechanism by monocyte-derived DCs (MoDCs) of BP allergic and normal donors as visualized by fluorescence microscopy. Using a pre-designed antibacterial response PCR array, we could reveal striking similarities in gene expression patterns induced by Bet v 1 in MoDCs of both donor groups to those induced by TTHA0849. Importantly, Bet v 1 and its bacterial homolog also triggered the transcription of the Th2 signature cytokines IL-4 and IL-13, as well as EGR-3, a marker of early cell activation, in MoDCs from BP allergic but not normal donors. These findings propose that conserved structural features are present on both Bet v 1 and TTHA0849 targeting the same pathways common to allergic and normal individuals. Altered signal processing and translation in predisposed allergic individuals might be a mechanism underlying the phenomenon of allergic sensitization.