bluuebunny/crossref_metadata_2025_split huggingface dataset:
Type 2 cytokines trigger eomesodermin-associated pathway conferring robust interferon-g expression in human NK cells
Authors: Ohayon David E , Donmez Omer , Parameswaran Sreeja , Kottyan Leah C. , Weirauch Matthew T. , Waggoner Stephen N 
Published: January 2023

Abstract
Asthma encompasses a spectrum of chronic respiratory symptoms, generally associated with aberrant expression of type 2 cytokines. As many as 10% of patients are classified as having severe asthma, characterized by poor control of disease symptoms and a paradoxical mixed milieu of both type 2 (IL-4 and IL-33) and type 1 (IFN-γ) cytokines. The source of IFN-g and mechanisms driving expression of this cytokine, which can exacerbate airway hyper-responsiveness, remain poorly defined. Here, we show that in human NK-cell cultures, combined IL-4 and IL-33 stimulation triggers high expression levels of IFN-g, even in the absence of STAT4 activation by prototypical type 1 stimuli like IL-12. At picomolar concentrations, IL-4 enhanced the expression of eomesodermin (Eomes), a critical transcription factor for IFN-γ expression. We performed anti-Eomes ChIP-seq in NK cells, generating a high-quality genome-wide map of Eomes binding with robust peak counts, strong overlap with T cell datasets, and strong enrichment for the Eomes DNA binding motif. These data support a model in which Eomes interacts with the IFNG locus to promote enhanced IFNG expression in NK cells. We also performed ATAC-seq and ChIP-seq following IL-4/IL-33 stimulation to reveal changes in chromatin accessibility and Eomes binding resulting from cytokine exposure. Collectively, our results reveal a novel pathway of IFN-γ induction in type 2 diseases that could contribute to exacerbated pulmonary dysfunction in severe asthma.
Mst1 regulates Foxo1 transcription to differentially control memory CD8 T cell differentiation and survival
Authors: Abdullah Leena , Hills L. Benjamin , Lust Hannah E , Huang Yina H 
Published: January 2023

Abstract
Foxo1 is an essential transcription factor required for the differentiation and survival of memory CD8 T cells. Foxo1 activity is heavily regulated by post translational modifications, yet it is unclear whether memory T cell differentiation is regulated in the same manner as survival. Two S/T kinases, Akt1 and Mst1 phosphorylate Foxo1. While Akt1 mediated phosphorylation is known to inhibit Foxo1 transcriptional activity, the effect of Mst1 phosphorylation remains poorly understood. To determine the impact of Mst1 regulation on Foxo1-dependent CD8 T cell differentiation and survival, we generated Foxo1 variants that mimic Mst1 phosphorylation (SD-Foxo1) or disrupt Mst1 phosphorylation (SA-Foxo1). Reconstitution of Foxo1-null T cells with SA- or SD-Foxo1 allowed us to evaluate their effects on early response genes in vitro and memory differentiation and survival in vivo following Listeria monocytogenes infection. We observed significantly higher expression of canonical Foxo1 target genes, including Il7r and Sell when CD8 T cells expressed SA-Foxo1. In contrast, CD8 T cells expressing SD-Foxo1 were defective in inducing canonical Foxo1 targets and in generating memory precursor effector cells post Listeria infection. However, SD-Foxo1 expression promoted survival of memory CD8 T cells as compared to the SA-Foxo1 in vitro. RNAseq analysis revealed that SD-Foxo1 induces an altered Foxo1 transcriptional program including the upregulation of Purinergic Receptor P2X7 (P2RX7), which was recently shown to be required for memory CD8 T cell maintenance and survival. Together, our data suggest that Mst1 regulates a distinct mode of Foxo1 transcription to balance Foxo1-dependent differentiation and survival in CD8 T cells.
Altered ligand-interaction contributes to functional insufficiency due to CTLA-4 gene mutation
Authors: Zhao Zhishan , Lu Linrong 
Published: January 2023

Abstract
CTLA-4 is one of the key inhibitory immune receptors and plays a critical role in maintaining immune tolerance. Both loss of CTLA-4 gene in mice and mutations in humans result in systemic autoimmune diseases with a similar phenotype. However, the precise mechanisms of CTLA-4 have not yet been entirely clarified. Structural and functional analysis of the reported autoimmune cases revealed that pathogenic CTLA-4 mutations occur frequently in ligand binding and dimerization regions. Through genetic mutation screening study, we have discovered a new CTLA-4 point mutation in a patient with recurrent autoimmune inflammation. We used steered molecular dynamics (SMD) simulation, single-molecule biophysical approaches, as well as functional assays to compare the function of this CTLA-4 mutant to the WT molecule. We demonstrated that, mechanical force induces conformational changes in CTLA-4 to enhance pre-existing contacts and activates new interactions at the CTLA-4-CD80 and CD86 binding interface. Although the mutant CTLA-4 can function to induce downstream signals, its ability in trans-endocytosis of CD80 and CD86 is impaired due to altered ligand interaction. The conclusions from this study will help us elucidate the immunoregulatory mechanisms of CTLA-4 and provide new strategies for more effective targeting of CTLA-4 in autoimmune diseases and tumors.
Intravenous tolerance induces T cell anergy/apoptosis via IFN-γ/IL-27/PD-L1 axis
Authors: Casella Giacomo , Rasouli Javad , Thome Rodolfo , Alvarez Jorge Ivan , Hunter Christopher A , Zhang Guang-Xian , Ciric Bogoljub , Rostami Abdolmohamad M 
Published: January 2023

Abstract
The induction of peripheral tolerance by intravenous injection (i.v.) of auto-Ags has shown to suppress experimental autoimmune encephalomyelitis (EAE), a mouse model of Multiple Sclerosis, by eliciting tolerogenic APCs, Tregs, and suppressing self-reactive T cells. The programmed cell death protein (PD)-1 and its ligands, PD-L1 and PD-L2, regulate the balance between T cell activation and immune tolerance. Although PD-L1 and PD-L2 are expressed on a variety of cell types, however, the mechanisms related to peripheral tolerance that induce these molecules are still unclear. Here we show that PD-L1, but not PD-L2, is critical for inducing peripheral tolerance in EAE, and that PD-L1-dependent tolerance relies on both IFN-γ and IL-27. I.v. administration of auto-Ag(s) attenuates the progression of EAE, by inducing PD-L1 expression in monocyte-derived DCs (moDCs) in the CNS, via IFN-γ/ IL-27-dependent mechanism. Indeed, when PD-L1 is blocked, autoantigen(s)/i.v treatment becomes ineffective. Following IFN-γ−/− CD4+ T cell transfer into Rag1−/− mice, i.v. tolerance treatment failed to suppress EAE. Moreover, loss of IFN-γR signaling in classical DCs type I (cDCs I) compromised IL-27 production and consequent PD-L1 expression by moDCs. We also show that IL-27 stimulates moDCs to over-express PD-L1, in a STAT-3-dependent way. Indeed, in CCR2−/−/WSX−/− (CD45.2) → CD45.1 radiation-induced bone marrow chimera mice, auto-Ag(s)/i.v. treatment failed to suppress EAE. Similarly, EAE mice that expressed mutant STAT-3 (muSTAT-3) in CCR2+ cells were also insensitive to i.v. tolerance induction. Our data reveal a mechanism whereby IFN-γ and IL-27 are the key factors in PD-L1 induction and subsequent peripheral tolerance restoration.
Cul4b promotes DNA damage repair during T cell proliferation
Authors: Dar Asif Amin , Dybas Joseph , Sawada Keisuke , Moser Emily K , Oliver Paula 
Published: January 2023

Abstract
Ability of T cells to become activated and clonally expand during pathogen invasion is pivotal for the induction of protective immunity. Understanding how T cell receptor (TCR) signaling, cell cycle, and survival are coordinated could allow development of therapeutics designed to regulate the numbers of antigen-specific T cells. Activating mutations in Cul4b and its orthologue Cul4a are known to drive cell cycle and cancer development. Loss-of-function mutations in Cul4b have been identified in X-linked mental retardation patients. However, how Cul4b controls the function of primary T cell remains unknown.
Using a novel proteomics screen, we identified Cul4b as highly active following TCR stimulation. Cul4b is expressed in naïve T cells but its levels and activity increased on TCR stimulation. We found that Cul4b was more abundant in T cells than Cul4a, and a significant proportion of Cul4b was associated with chromatin. To study the role of Cul4b in T cells we generated mice lacking Cul4b specifically in T cells. Loss of Cul4b impaired maintenance, proliferation and survival of activated T cells. Supporting this, Cul4b-deficient T cells were unable to expand and drive colitis. Cul4b deficient cells showed enrichment of cell cycle and DNA damage related pathways, with concomitant accumulation of pATM, P53, pCHK1, and γ-H2AX. In CD4 T cells, Cul4b preferentially associated with the substrate receptor DCAF1 to form an active CRL4B complex. Additionally, both Cul4b and DCAF1 were found to interact with proteins associated with DNA damage response and repair pathways. These findings demonstrate an essential role for Cul4b in promoting the rapid repair of damaged DNA to allow proliferation, survival and overall expansion of activated T cells.
Inhibins/TGFβRIII modulate T cell activation and Th1/Th17 effector differentiation
Authors: Soldevila Gloria , Ortega-Francisco Sandra A , Morales Alexandra , de Oca Selina Montes , Albarran Adrian , Hernandez-Campos Oscar , Olguin-Alor Roxana 
Published: January 2023

Abstract
Inhibins, ligands of the TGFβ superfamily, and their molecular pair, TGF-β type III receptor (TβRIII), have been shown to regulate the development of T cells within the thymus. Moreover, we recently reported that TβRIII acts as an activation marker after TCR stimulation However, the intrinsic role of Inhibins in T cell activation and differentiation is currently unknown. Here, we describe for the first time that T cells are able to produce Inhibin A after a polyclonal TCR stimulation which raises the possibility of this ligand playing a direct role in T cell responses. Interestingly, Inhα−/− naïve T cells showed lower expression of activation markers, including TβRIII, after TCR stimulation, compared with their wild type counterparts. Moreover, Inhα−/− naïve T cells showed a significant decrease in Th1 differentiation under polarizing conditions in vitro, that correlated with lower levels of activation. Furthermore, when we evaluated the differentiation of Inhα−/− naïve T cells towards Th17, a TGFβ-dependent lineage, we observed an increase in the percentage of IL-17+ T cells compared to wild type. Interestingly, this altered Th differentiation could be rescued by addition of exogenous Inhihin A, leading to a significant decrease in IL-17 production and a trend towards an increase in IFNγ production. These data suggest that Inhibins play an intrinsic role during T cell activation and may be key modulators of T effector cell differentiation during an immune response.
Homeostasis and transitional activation of regulatory T cells require c-Myc
Authors: Saravia Jordy , Zeng Hu , Dhungana Yogesh , Chapman Nicole M , Wang Yanyan , Raynor Jana L , Chi Hongbo 
Published: January 2023

Abstract
Regulatory T (Treg) cell activation and expansion during neonatal life and in response to inflammation are critical for immunosuppression, yet the mechanisms governing these events are incompletely understood. We report that the oncogene and transcriptional regulator c-Myc (Myc) controls immune homeostasis through regulation of Treg cell accumulation and functional activation. Myc activity is enriched in Treg cells generated during neonatal life and responding to inflammation. Myc-deficient Treg cells show cell-intrinsic defects in overall accumulation and ability to transition to an activated state during early life or acute inflammation. Consequently, loss of Myc in Treg cells results in a rapid, early-onset autoimmune disorder accompanied by uncontrolled effector CD4+ and CD8+ T cell responses. We also provide evidence that Myc regulates mitochondrial oxidative metabolism but is dispensable for fatty acid oxidation (FAO). Indeed, Treg cell-specific deletion of Cox10, which is required for oxidative phosphorylation, but not Cpt1a, the rate-limiting enzyme for FAO, results in impaired Treg cell function and maturation. Thus, Myc coordinates Treg cell accumulation, transitional activation and metabolic programming to orchestrate immune homeostasis.
LSECtin interacts with BTN3A1 to inhibit T cell activation
Authors: Wang Jinghua , Manick Brain , Renelt Mark , Gerassenkov Tatsiana , Bi Ming , Kalabokis Vassilios , Person Anthony , Wu Guoping 
Published: January 2023

Abstract
LSECtin is a type II transmembrane protein which belongs to the C-type lectin receptor superfamily. Previous studies revealed that LSECtin is expressed on melanoma cells, acts as a co-inhibitor of human T cell immunity and may hamper anti-tumor T cell immune responses. However, the mechanisms by which LSECtin suppresses T cell immunity remain unknown. In this study, we demonstrate that the LSECtin protein inhibits human T cell activation through the butyrophilin family receptor BTN3A1. LSECtin markedly suppressed human T cell proliferation in the presence of T cell receptor signaling. Furthermore, LSECtin significantly reduced IFN-γ, IL-2, IL-17 and TNF-a cytokine and IL-8/CXCL8, MIG/CXCL9, IP-10/CXCL10, and TARC/CCL17 chemokine production by anti-CD3 activated human T cells. Moreover, a functional ELISA binding assay revealed that LSECtin bound to BTN3A1. Anti-BTN3A1 neutralizing antibody attenuated the binding of LSECtin to BTN3A1. BTN3A1 is expressed on both resting and activated human T cells, and pretreatment of immobilized LSECtin with the BTN3A1 protein or an anti-BTN3A1 antibody partially attenuated the ability of LSECtin to inhibit IL-2 secretion from anti-CD3-activated T cells, suggesting that BTN3A1 acts as a receptor for LSECtin to deliver a negative signal to T cells. Thus, we show that LSECtin/BTN3A1 represents a novel negative regulatory pathway on T cells and may serve as a unique target for developing new immunotherapy strategies for the treatment of immune-related diseases, including cancers.
Treatment with natural AhR ligand leads to amelioration of LPS-induced acute lung injury by decreasing microRNA 29b-2-5p expression targeting increased IL-22 production
Authors: Holloman Bryan L , Nagarkatti Prakash S , Nagarkatti Mitzi 
Published: January 2023

Abstract
Acute lung injury and acute respiratory distress syndrome (ALI/ARDS) are severe pulmonary inflammatory diseases that cause destruction and remolding of the lung epithelial barrier, which may lead to restriction of pulmonary functionality and/or death. Indole-3-carbinol (I3C), a naturally occurring Ahr ligand has been shown to ameliorate multiple inflammatory disorders. Our studies are aimed at determining whether treatment with the I3C affects reparative reepithelialization and restores lung functioning through an immune-mediated mechanism. Towards this, 5mg/kg of LPS was intranasally injected in C57BL/6 mice to induce ALI. Three hours following LPS administration, the mice were treated with 40mg/kg I3C. After 48 hours, we examined lung functions using Buxco plethysmography and noticed LPS + I3C treated-mice have similar functionality as naïve mice in multiple parameters including ratio of time peak expiratory flow (Rpef), rejection index (Rinx), and tidal volume (TV) basal pulmonary functions whereas LPS+vehicle treated mice showed alterations. Histopathological analysis revealed fibrotic tissue in lung sections of LPS + Vehicle administered mice, but not in LPS + I3C treated mice. In addition, I3C increased the expression of Th22 (CD3+CD4+IL22+) cells, which are key mediators of epithelial cell layer protection, antimicrobial peptide production, and reepithelialization improvement. I3C increased IL-22 expression in bronchoalveolar lavage fluid, and decreased the expression in miR-29b-2-5p transcript that directly regulates IL-22 expression. In conclusion, our studies suggest that Ahr ligand I3C alleviates lung injury by maintaining lung epithelium integrity which may be mediated by IL-22 secreting T cells.
Induction of autophagy or mitophagy improves the cardiovascular lesions of Kawasaki Disease in a murine model of vasculitis
Authors: Marek-Iannucci Stefanie , Gomez Angela C , Moreira Debbie , Lane Malcolm , Porritt Rebecca , Lee Youngho , Shimada Kenichi , Crother Timothy R , Rivas Magali Noval , Arditi Moshe 
Published: January 2023

Abstract
Kawasaki Disease (KD), an acute febrile illness and systemic vasculitis of unknown etiology, is the leading cause of acquired heart disease among children. NLRP3 activation and IL-1 signaling are required for the development of coronary arteritis and abdominal aorta aneurysms (AAA) in the KD vasculitis murine model. NLRP3 is also activated by mitochondrial (mt) DNA released from impaired mitophagy-autophagy processes. How autophagy and mitophagy participate in KD cardiovascular lesions remain unknown. We investigated the role of autophagy/mitophagy by using the well-accepted Lactobacillus casei cell wall extract (LCWE) murine model of KD vasculitis. LCWE injection in WT mice results in coronary arteritis, aortitis, myocarditis as well as AAA. p62 and Parkin, were expressed significantly higher in whole lysate and mt fractions of cardiovascular tissues from LCWE-injected mice compared to control, suggesting an impaired autophagic flux and lack of degradation and cell clearance. Parkin−/− mice developed significantly higher LCWE-mediated cardiovascular lesions and AAA, compared to control mice. Conversely, autophagy induction in WT mice by intermittent fasting or by treatment with a Glucagon-like peptide-1 receptor agonist, led to a significant decrease in LCWE-mediated cardiovascular lesions and AAA. This data suggests that induction of autophagy leads to decreased cardiovascular lesions, whereas impaired mitophagy results in exacerbation of LCWE-induced cardiovascular lesions in this murine model of KD vasculitis. These findings enhance our understanding of the pathogenesis of the cardiovascular lesions in KD vasculitis and may provide novel therapeutic targets to prevent or treat these complications.
Regulatory Role of STAT3-PLSCR2 Axis in Antiviral and Inflammatory Response
Authors: Lee Chien-Kuo , Tsai Ming-Hsun 
Published: January 2023

Abstract
Cytokines are key factors for initiating inflammatory response and among them IFN-I is one of the most versatile because of its dual roles in antiviral and inflammatory activities. While STAT1 and STAT2 are critical for triggering antiviral response, the signaling events downstream of IFN-I receptor contributing to inflammation have yet to be defined. Here we demonstrate that STAT3 and one of its interacting partners PLSCR2 negatively regulate IFN-I-mediated antiviral and inflammatory response. Enhanced expression of IFN-I-stimulated genes (ISGs) is found in cells either absence of STAT3 or PLSCR2, leading to increased resistance to viral infection in vitro and in vivo. Moreover, STAT3 can cooperate with PLSCR2 to suppress IFN-I response. Interestingly, GSEA analysis for IFN-I-stimulated cells lacking PLSCR2 versus WT control displays an inflammatory signature with increased expression of inflammatory cytokines and chemokines, their receptors and TLRs. Stimulation of TLR ligands, including LPS, R848 or CpG, also results in enhanced expression of IFN-I and inflammatory cytokines and chemokines in PLSCR2KO cells as opposed to WT control. PLSCR2KO mice are also more susceptible to LPS-induced endotoxic shock in vivo with increased serum TFN. Similarly, PLSCR2KO mice also display increased acute lung injury in response to intratracheal administration of LPS with increased infiltration of macrophages and neutrophils and production of inflammatory cytokines and chemokines. Enhanced TLR response is also found in STAT3KO BM-derived macrophages. Therefore, these results demonstrate that STAT3 coordinates with PLSCR2 to regulate antiviral and inflammatory response and define a novel axis in modulating IFN-I-mediated response.
Damage-induced pyroptotic cell death facilitates regeneration of the thymus
Authors: Kinsella Sinéad , Evandy Cindy A , Hopwo Kayla S , Cooper Kirsten , Iovino Lorenzo , Smith Colton W , Jain Reema , deRoos Paul , Dudakov Jarrod A 
Published: January 2023

Abstract
Endogenous thymus regeneration is a critical process that enables the restoration of immune competence after damage caused by infection, age and common cancer therapies; however, the molecular mechanisms regulating this process are poorly understood. Previously, we identified that depletion of CD4+CD8+ thymocytes (DPs) after injury precedes the induction of regenerative factors such as BMP4 from endothelial cells (ECs), and IL23 from dendritic cells (DCs), and that the presence of homeostatic apoptotic DPs can suppress BMP4 and IL23. Together with our findings that the metabolic needs of key thymus populations alter drastically following injury due to damage-induced metabolic remodeling, we hypothesize that further to the loss of DP-specific suppression after damage, metabolic dysfunction in DPs triggers mitochondrial-induced pyroptotic cell death, which can directly promote the production of regenerative factors. Here we demonstrate a disruption in glycolytic flux, increased mitochondrial biogenesis, an induction of ROS, and increased cleavage of caspase 1 in murine DPs after damage; key processes that can induce inflammasome activation, pyroptosis and the release of cellular DAMPs such as ATP and HMGB1. Interestingly, these metabolic perturbations were not observed in the regeneration-inducing ECs and DCs, suggesting metabolic stability may facilitate their radio-resistance. Secreted HMGB1 levels are increased in the thymus after damage, and extracellular stimulation of ECs in vitro with ATP increased Bmp4 expression. These studies describe a novel regulatory mechanism of metabolic-mediated tissue regeneration, and have the potential to lead to a superior therapeutic strategy to boost thymic function.
Effect of mesenchymal stem cell in adriamycin-induced renal nephropathy
Authors: Park Eun Jae , Kim Hyung Suk , Kang Yu Jeong , Lee Hye Jin , Jun Hye Won , Lee Hong Kyung , Hong Jin Tae , Kim Youngsoo , Han Sang-Bae 
Published: January 2023

Abstract
Mesenchymal stem cells (MSCs) are multi-potent progenitor cells able to differentiate into osteoblasts, chondrocytes, and adipocytes. MSCs secrete various soluble factors that are advantageous for tissue repair, anti-apoptosis, anti-fibrosis, and immunomodulation. Recently, MSCs improve the renal inflammation in adriamycin (ADR)-, adenine-, and cisplatin-induced animal model, but the mechanisms underlying their efficacy are unclear. In this study, we examined effect of MSCs in ADR-induced renal nephropathy. MSCs prolonged survival, restored body weight, and decreased serum creatinine and proteinuria levels in ADR-induced animal model. MSCs also inhibited renal fibrosis and podocyte damage by decreasing the expression of fibronectin, α-smooth muscle actin, and collagen 1α1. MSCs inhibited renal inflammation by decreasing the expression of CCL4, CCL7, CCL19, IFN-α/β, TNF-α, TGF-β and chitinase 3-like 1. Taken together, our data suggest that MSCs improve renal injury by decreasing inflammatory factor in ADR-induced nephropathy.