bluuebunny/crossref_metadata_2025_split huggingface dataset:
Bile acid conditioned Dendritic cells through FXR and specialize T cell function in the ileum
Authors: Huang Xiangsheng , Sundrud Mark S , Eltzschig Holger , Moore David 
Published: August 2023

Abstract
The accumulation of locally-reabsorbed bile acids (BAs) is suggested to contribute to the development of terminal ileitis. Our previous data showed nuclear receptor Constitutive Androstane Receptor (CAR) can directs T cell adaptation to BAs in the ileum by promoting the IL-10 producing Tr1 cells to prevent ileitis. Still, the mechanisms by which BA activate CAR in ileal T cells is not known. As CAR is not recognized as a BA sensor, its activation in ileal T cells may involves indirect pathways, such as dendritic cells (DCs). Farnesoid X receptor (FXR), a direct primary BA sensor, is highly expressed in both human and mouse DCs. Therefore, we hypothesized that BA-sensing by mucosal DCs through FXR may condition mucosal T cells in the ileum to upregulate CAR and to enforce anti-inflammatory T cell functions. Our result indicated WT DCs exposed to direct FXR agonist, chenodeoxycholic acid (CDCA), displayed increased production of IL-23a and decreased IL-6. While, CD4+ T cells cocultured with CDCA-treated DCs displayed increased CAR/Nr1i3, and its targets, cMyc and MDR1. Importantly, these observations were diminished in DCs from FXR−/− mice. In addition, when FXR is depleted in DC (CD11cCreFXRfl/fl, FXRΔDC), the DC migration in the intestine is deficient, with low expressions of CCL19, CCR9 and less CD11c+CD11b−CD103+MHCII+ migratory DC population in the mesenteric lymph nodes. Meanwhile, the FXRΔDC mice failed to promote CAR/Nr1i3 as well as IL10 in T cells. Furthermore, FXR−/−RAG2−/− mice developed severe ileitis after engrafted with WT naïve T cell. These results suggest that FXR specializes intestinal DC and T cell function in the ileum. Collectively, these studies will shed new light on the understanding and treatment of ileitis in patients.
Fibroblasts participated in mucosal pathology in the oral disease periodontitis
Authors: Ikeuchi Tomoko , Rodriguez Belmaliz Cardona , Chen Zuojia , Wild Teresa Greenwell , Wu Chuan , Moutsopoulos Niki M 
Published: August 2023

Abstract
The oral cavity is a unique stricture; it combines mucosal and bone tissue microenvironments with their respective immunological responses. In fact, oral mucosal inflammation leads to bone destruction in the prevalent human disease, periodontitis. In periodontitis, immune cells, in particular Th17 and neutrophil mediated responses have been linked to pathogenesis, however it is not yet understood how the stromal tissue microenvironment may participate in disease pathology. To date, studies in humans reveal inflammatory signatures in oral mucosal stromal cells of periodontitis, linked to neutrophil recruitment. To understand fibroblast responses and function in periodontitis, we performed scRNA-seq in mouse oral mucosa during a time course in the experimental periodontitis model. We characterize an early responding fibroblast subpopulation with a distinct inflammatory signature, characterized by induction of the IL33- ST2 cytokine axis. We confirm induction of soluble ST2 in oral mucosal fibroblasts during periodontitis and uncover an immune-regulatory role for ST2 within the oral microenvironment. Our work highlights the nature of oral mucosal immune-responsiveness and provides insights into a common human disease.
Supported by NIH intramural funding
Deep myeloid cell profiling provides new insights into modulators of CAR T cell expansion in patients with pediatric solid tumors
Authors: Kaczanowska Sabina , Murty Tara , Alimadadi Ahmad , Contreras Cristina F , Hedrick Catherine C , Ramakrishna Sneha , Kaplan Rosandra 
Published: August 2023

Abstract
Chimeric antigen receptor (CAR) T cells have shown remarkable results in hematological malignancies but limited efficacy in the setting of solid tumors. As myeloid-mediated immune suppression is known to play an important role in dampening antitumor activity, we hypothesized that myeloid cells impact CAR T cell expansion in patients with solid tumors. A phase I trial (NCT02107963) was performed to determine the feasibility and safety of administering 3rd generation GD2-CAR (GD2-CAR.OX40.28.z.ICD9) T cells in children and young adults with neuroblastoma and osteosarcoma. 76.9% of patients had stable disease by day 28, eventually all patients had disease progression. We stratified patients based on good versus poor CAR T cell expansion and evaluated peripheral immune profiles pre- and post-treatment by qPCR, ELISA, CyTOF, ATAC-seq, and RNA-seq. While A higher proportion of monocytes in pre-treatment apheresis was associated with poor CAR T cell expansion and CXCR3 expression on monocytes was the most robust marker of good CAR T cell expansion in this cohort. Longitudinal analysis demonstrated that CXCR3+ monocytes were low following treatment in both good and poor CAR T cell expanders, demonstrating a transition in myeloid populations in response to GD2-CAR T cell treatment. Together, these data suggest that GD2-CAR T cell administration is associated with changes in the myeloid cell compartment. This study provides evidence of novel myeloid-based pre-treatment biomarkers of CAR T cell expansion and rationale for the combination of CAR T cells with myeloid-modulating therapies as a strategy to improve outcomes for patients with solid tumors.
Clinical trial supported in part by: Intramural Research Program, National Cancer Institute, NIH Clinical Center, National Institutes of Health. Scientific and financial support for the CIMAC-CIDC Network are provided through the National Cancer Institute (NCI) Cooperative Agreements: U24CA224331 (to the Dana-Farber Cancer Institute CIMAC), U24CA224309 (to the Stanford University CIMAC), and U24CA224316 (to the CIDC at Dana-Farber Cancer Institute). Scientific and financial support for the Partnership for Accelerating Cancer Therapies (PACT) public-private partnership (PPP).
The landscape of glioma-infiltrated immune cells after immune checkpoint blockade treatment
Authors: Kang In , Park Janghyun 
Published: August 2023

Abstract
Despite the immune checkpoint blockade (ICB) having succeeded in multiple cancer therapies, high-grade gliomas such as glioblastoma multiforme (GBM) have a very low response rate to ICB, and GBM patients still do not benefit from ICB. To overcome this limitation, understanding the unique immunologic characteristics of brain tumors is needed. Here, we used single-cell RNA sequencing to analyze the macroscopic immune landscape of the tumor microenvironment (TME) under the treatment of ICB in a murine GBM model. CD8+ T cells showed both invigoration and exhaustion states, representing that CD8+ T cells show a mixed phenotype in the brain tumor. Furthermore, we found an increase in the number of anti-inflammatory macrophages in the TME after the ICB treatment, which is dependent on the increased CCL5 expression. Therefore, we hypothesized that the recruitment of anti-inflammatory macrophages mediated by CCL5 is associated with the exhaustion state of CD8 T cells and subsequent unresponsiveness of GBM against ICB. Finally, we compared our observations in the murine GBM model with publicly available data obtained from recurrent GBM patients. Our study provides critical information for the immune landscape of glioma after the ICB treatment and potentiates the development of novel immunotherapies to overcome the proposed limitations of ICB treatment.
Insights into the regulation of brain metastasis by natural killer cells using single-cell RNA sequencing and imaging mass cytometry
Authors: McMullen Timothy P , Longworth Aaron , Ma Dennis , Adam Isam , Evans Katrina T , Lawson Devon A 
Published: August 2023

Abstract
Metastatic brain tumors are incurable, rapidly fatal, and five times more common than primary glial or meningeal tumors of the central nervous system (CNS). Natural Killer (NK) cells are cytotoxic lymphocytes with strong in vivo anti-tumor activity, a native ability to cross the blood-brain barrier (BBB), and a demonstrated role in the regulation of metastasis in peripheral organs. NK cells perform critical roles in anti-tumor immunosurveillance via the expression of germline-encoded activation and inhibition receptors on the cell membrane. These receptors recognize ligands on both normal and transformed cells, and ultimately determine whether an NK cell will be stimulated to kill a neoplastic cell or inhibited from killing a healthy cell. Notably, NK cells are under investigation in clinical trials as both drug targets and adoptive cell therapies. We are working to characterize NK cell-mediated regulation of brain metastasis, which appears to be dysfunctional relative to the robust NK cell anti-metastatic activity observed in peripheral tissues. We seek to elucidate a molecular mechanism for this NK cell dysfunction using in vivo models of brain metastasis in conjunction with flow cytometry, single-cell RNA sequencing (scRNA-seq), and imaging mass cytometry (IMC). An improved understanding of the functional status and transcriptional programs of NK cells in brain metastasis will inform the development of neuroprotective anti-metastatic therapies aimed at modulating and potentiating the anti-tumor action of both native and adoptively-transferred NK cells.
Supported by grants from the National Cancer Institute (R01CA237376-01A1), the UCI Stem Cell Research Center, and the UCI Medical Scientist Training Program
High-dimensional profiling of circulating dendritic cells and monocytes in atopic dermatitis patients by mass cytometry
Authors: Jeong Soyoung , Bang Yoon Ji , Lee Brian H , Lee Dong Gun , Lee Yu Jin , Kim Hyun Jee , Kang Hoon , Park Chung-Gyu , Lee Dong Hun , Kim Jung Eun , Kim Hyun Je 
Published: August 2023

Abstract
Atopic dermatitis (AD) is a chronic inflammatory skin disorder, with a multifactorial pathophysiology, including barrier dysfunction, dysbiosis and immune dysregulation. Although AD has been characterized by a T helper type 2 cell response, the role of the myeloid populations in the pathogenesis of AD still remains unclear. Here, we used mass cytometry, a high-dimensional analysis tool, primarily focusing on these cell populations to identify differences in the immune phenotypes of circulating dendritic cells and monocytes in AD. Peripheral blood mononuclear cells (PBMCs) from 48 Korean AD patients and 48 age-, sex-matched healthy controls were profiled. We report significant differences in the frequency and phenotypic markers of dendritic cells and monocytes. The frequency of CD141+ CLEC9A+ cDC1 was significantly decreased in AD, and its frequency negatively correlated with disease severity and serum IgE levels. This suggests that cDC1 may have preferentially migrated to the lesional skin to control the inflammation, especially in severe AD. CLEC9A expression was significantly reduced, while FceRIa expression was significantly increased in cDC1. The expression of FceRIa was also elevated in cDC2, pDC, and Axl+ DC. In cDC2, HLA-DR expression was decreased, and CD163 expression was increased. These results indicate changes in the immunophenotypes of circulating dendritic cells in AD compared with healthy controls. Although further investigation is needed, our results suggest a potential role of dendritic cells in modulating AD pathophysiology.
Regulation of eosinophils by the transcription factor Ikaros
Authors: Schjerven Hilde , Vestbøstad Johanne , Howell William 
Published: August 2023

Abstract
Immune cell development is a tightly controlled process that enables a homeostatic level of innate and adaptive immune cells of the myeloid and lymphoid lineages, respectively. Imbalance in immune cells can lead to diseases due to immune defects or over-activation. such as immunodeficiency, allergies or autoimmunity. Ikaros is a transcription factor known to be critically important for lymphoid development, with recurrent mutations in different human diseases, but less is known about the role of Ikaros in myeloid development. Ikaros is encoded by the Ikzf1 gene, and contains four DNA-binding zinc fingers (ZnF) and two ZnFs mediating protein dimerization. The four DNA-binding ZnFs (ZnF1 through ZnF4) are encoded by three exons, with the two central ZnF2 and ZnF3 encoded by exon 5 being required for binding to the core DNA recognition site. The two flanking ZnFs 1 and 4 are encoded by exon 4 and exon 6, and can modulate DNA binding by contacting the flanking DNA. Interestingly, Ikaros is highly alternatively spliced, creating multiple isoforms with different combinations of the DNA-binding ZnFs. We study the role of Ikaros in immune cell development using Ikzf1-mutant mouse models, and analysis of mice with deletions of exon 4 or exon 6 (encoding ZnF1 and ZnF4, respectively) has revealed differential phenotypes in the two mutant mouse models. Here, we describe a new role of Ikaros in regulation of eosinophils. We have found that Ikaros is required for limiting eosinophil production in bone marrow (BM), as both mutants show increased levels of BM eosinophils. Interestingly, the levels of peripheral tissue eosinophils differ between the two mutants, suggesting a second role of Ikaros in regulating migration, tissue recruitment or retention.
Metformin treatment of CD8 T cells decreases pro-inflammatory cytokine production and shifts their metabolic state toward oxidative metabolism
Authors: Molloy Caitlyn Therese , Alwarawrah Yazan , MacIver Nancie 
Published: August 2023

Abstract
Obesity is a systemic metabolic disorder that affects over 40% of the U.S. adult population. Among many other serious health consequences, obesity leads to increased morbidity and mortality from select infections and impaired immunological memory responses to these infections. CD8 T cells mediate the clearance of pathogens and establish immunological memory. Many studies have established that T cell metabolism and function are linked, and that changes in T cell metabolism can alter T cell responses; however, it is currently unknown how obesity impacts CD8 T cell metabolism and their ability to respond to pathogens. Furthermore, it is also unknown if drugs used to reverse the metabolic effects of obesity can alter CD8 T cell metabolism and impact CD8 T cell response to infection. To test this, we first isolated splenic CD8 T cells from lean or diet-induced obese (DIO) mice, activated them in the presence or absence of the drug metformin, and measured T cell function and metabolism using flow cytometry and extracellular flux analysis. CD8 T cells activated in the presence of metformin showed significantly decreased production of IFN-γ and Granzyme B and decreased oxidative metabolism. To note, we saw a similar decrease in oxidative metabolism in splenic CD8 T cells isolated from DIO mice that were treated with metformin systemically for six weeks. These results demonstrate that metformin treatment either in vitro or in vivo affects CD8 T cell metabolism and function. To determine if metformin treatment improves immunological memory in the context of infectious diseases, future studies will include immunological analyses of CD8 T cells from lungs of influenza virus-infected lean and DIO mice that have been treated with out without metformin.
Supported by grants from NIH (R01-DK106090)
Sargassum horneri suppresses PM-induced oxidative DNA damage in alveolar macrophage (AM) of allergic asthma: Relevance to PM-mediated M1/M2 AM polarization
Authors: Jin Kim Hyo , Yang Jiwon , Herath Kalahe Hewage Iresha Nadeeka Madushani , Jeon You-Jin , Kim Hyun Jung , Jee Youngheun 
Published: August 2023

Abstract
Particulate matter (PM) exposure causes oxidative damage to the lung by attaching to the alveolar macrophages (AM) and alveolar epithelial cells (AEC). Sargassum horneri can be a promising source to mitigate PM-induced oxidative damage. This study investigated the role of Sargassum horneri ethanol extract (SHE) against PM-induced oxidative DNA damages in allergic asthma mice. We discovered that PM triggered prolonged oxidative stress leading to lipid peroxidation in AEC and AM. PM-induced oxidative stress in AM caused the increase of CD80+ AM (M1 phenotype) and CD206+ AM (M2 phenotype) populations, especially, the number of M2-polarized AM, producing skewed AM polarization. Furthermore, we observed high expression of 8-OHdG, an oxidative DNA damage marker, in AM, the accumulation of which caused apoptotic cell death. However, SHE treatment, however, attenuated PM-induced lipid peroxidation and recovered balance of antioxidant enzymes in AEC and AM of allergic asthma mice. It resulted in the decrease of AM polarization mitigating the oxidative stress. More importantly, SHE salvaged AM from apoptotic cell death by attenuating oxidative DNA damage. Therefore, we demonstrated that SHE ameliorates oxidative DNA damage of M1- and M2-polarized AM in PM-induced allergic asthma mice in this study.
This research was funded by the Ministry of Education (2019R1A6A1A10072987) and the Ministry of Oceans and Fisheries, Republic of Korea (Project NO. 20172085).
Pulmonary ILC2-derived serotonin mediates RSV-evoked airway hyperreactivity in mice
Authors: Luo Chia-Hui , Chang Ya-Jen 
Published: August 2023

Abstract
Respiratory syncytial virus (RSV) infection is epidemiologically linked to asthma. During RSV infection, lung epithelial cell-released IL-33 is elevated and promotes group 2 innate lymphoid cells (ILC2s) activation, leading to type 2 cytokines production and asthma development. Serotonin is a neurotransmitter involved in numerous biological functions in the central nervous system as well as peripheral tissues. Previous studies have found elevated serotonin levels in plasma and bronchoalveolar lavage fluid (BALF) from asthma patients, implying that serotonin may involve in the pathogenesis of asthma. Therefore, we aimed to elucidate the role of ILC2-released serotonin in the regulation of RSV-induced airway hyperreactivity (AHR). To investigate whether ILC2 would secrete serotonin upon activation, pulmonary ILC2s were sorted from C57BL/6 mice and then treated with IL-33 in vitro, and we found an increase in the production of serotonin from IL-33-activated ILC2s. Furthermore, elevated BALF serotonin levels were also found in RSV-infected mice. Moreover, we clarified that ILC2 as a major source of serotonin during RSV infection. Next, to determine the role of serotonin in RSV-evoked AHR, we found that the treatment of Clozapine (serotonin receptor inhibitor) significantly attenuated AHR and decreased IL-13 expression. Meanwhile, we demonstrated that the administration of exogenous serotonin exacerbated RSV-caused AHR. Furthermore, serotonin enhanced IL-5 and IL-13 production from IL-33-activated ILC2 in vitro. Taken together, our results indicated that pulmonary ILC2-derived serotonin contributes to RSV-evoked AHR and exacerbates type 2 cytokines through a positive regulation of ILC2 function.
Identifying the expression and function of Blimp-1 in ILC2s in allergic asthma
Authors: Zheng Yibo , Zhang Jinyi , He Kun , Poholek Amanda C 
Published: August 2023

Abstract
Allergic asthma is driven by type 2 inflammation from Th2 cell and Type 2 innate lymphoid cells (ILC2s). We recently demonstrated a critical role for Blimp-1, a transcriptional repressor, in Th2 cells to promote allergic asthma. However, the expression and function of Blimp-1 in ILC2s remains undefined. Using genetically modified mouse strains that report Blimp-1 expression via YFP, we surveyed Blimp-1 expression in allergic asthma and other type 2 immune models across various tissues. We found that Blimp-1 is induced in ILC2s in the lung in response to the typical alarmins IL-33 and IL-25, as well as house dust mite (HDM). However, ILC2 activation did not upregulate Blimp-1 in the skin or gut in response to peanut allergen, suggesting a tissue-specific requirement for Blimp-1 in ILC2s. IL-33, as known to be a potent activator of ILC2s, was not required for Blimp-1 expression upon HDM stimulation. Interestingly, IL-10, a potent driver of Blimp-1 in Th2 cells, induced Blimp-1 expression in ILC2s, suggesting IL-10 but not IL-33 may be important for a Blimp-1+ ILC2 state. Intriguingly, Blimp-1 expression did not correlate with cytokine production, potentially representing a unique functional state of ILC2 cells that are high for Blimp-1. To evaluate Blimp-1 function, we deleted Blimp-1 in ILC populations using IL-7Ra Cre crossed to Blimp-1 floxed mice and generated mixed bone marrow chimeras with IL-7Ra Cre control donors. Blimp-1 knockout ILC2s in response to HDM exhibited an alteration in markers of ILC2 activation including ST2, KLRG1 and GATA3, suggesting Blimp-1 plays a role in promoting ILC2 differentiation. Collectively, our study has identified a lung-specific state of ILC2s expressing Blimp-1 that are found in a model of allergic asthma.
Autocrine pro-inflammatory IL-10 initiates lung-specific Th2 responses to inhaled allergen to induce allergic asthma
Authors: He Kun , Xu Zhongli , MacDonald William A , Ray Anuradha , Chen Wei , Lambrecht Bart N , Poholek Amanda 
Published: August 2023

Abstract
Allergic asthma remains a significant health burden for both children and adults. CD4+ Th2 cells are critical drivers of disease, yet the mechanisms that support initiation of the Th2 cell response to environmental allergens are not well understood. We demonstrated a distinct requirement for the transcriptional repressor Blimp-1 to promote Th2 cells in the lung to inhaled but not systemically or subcutaneously delivered allergens. Using temporal, spatial and single cell transcriptomic tracking of house dust mite (HDM) specific T cell responses, we demonstrate that inhalation of HDM drove early Blimp-1 expression necessary for GATA3 upregulation and subsequent Th2 differentiation in the lung that coincides with IL2Rα expression. Blimp-1 expression remains confined to HDM-specific Treg and Th2 cells that traffic to the lung but importantly is dispensable for Th2 cell maintenance. We found that inhaled allergens induce a pattern of STAT activation with transient pSTAT5 concomitant with sustained pSTAT3 within GATA3+ allergen-specific T cells, which is critical for the induction of Blimp-1 during the earliest phase of T cell priming in the lymph node. IL2Rα cooperates with IL10Rα signaling acting directly on allergen specific T cells to drive Th2 cell differentiation. Furthermore, IL-10 derived from allergen specific T cells was sufficient to induce Th2 cells suggesting an autocrine or paracrine loop of IL-10 supports Blimp-1 to regulate GATA3 upregulation at the T-B border and subsequent Th2 differentiation. These data shed light on the steps initiating Th2 responses to inhaled allergens and identify an unexpected pro-inflammatory requirement for IL-10 and Blimp-1 driving inflammatory T cell responses to environmental antigens.