bluuebunny/crossref_metadata_2025_split huggingface dataset:
Role of NKT cell in the regulation of antigen presenting cell-function during RSV infection (175.5)
Authors: Durre Kainath , Wu Sherman , Qureshi Nagib , Beal Brooks , Qureshi Mahboob 
Published: January 2023

Abstract
Survivors of RSV bronchiolitis and pneumonia develop increased susceptibility to asthma. We showed that skewed polarization of dendritic cells (DC) towards plasmacytoid DC (pDC) in the pups in response to RSV is inhibited by exogenous administration of osteopontin (OPN) with an associated Th1 immune response. In the present study, we examined the expression of MHC-II, an indicator of antigen presenting function, on the antigen presenting cells (APC) in the RSV-infected lungs and its dependence on NKT cells. Wild type (WT) and NKT knock out (NKT-/-) pups were infected with RSV and were treated with or without OPN. Expression of MHCII on the lung APCs, including macrophages (MQ) and DCs (pDC; CD11blo/-CD11Clo/-CD45Rhi) and mDC; CD11blo/-CD11ChiCD45Rlo/-), was determined by flowcytometry (FACS). The effect of OPN on MHCII expression in the presence or absence of NKT cells was studied. FACS revealed that expression of MHCII was higher on the pDCs than mDCs in the RSV-infected WT lungs. In the absence of NKT cells, MHCII expression on pDCs was increased. OPN treatment augmented expression of MHCII on MQ and DCs, which was further enhanced in the absence of NKT cells. These data suggest that OPN- induced MHCII expression on the lung APCs is NKT dependent. Further experiments will explore the underlying mechanism of this phenomenon, which may help developing a therapeutic strategy to stop skewed polarization of DC in RSV infected lungs in preventing susceptibility to asthma.
A Bovine Whey Protein Extract Can Inhibit TH2 Cell Function and Show the Potential to Alleviate Asthma Symptoms in a Murine Asthma Model (175.6)
Authors: Huang Po-Han , Chen Jiunn-Horng , Chen Hui-Chen 
Published: January 2023

Abstract
Asthma patients have dramatically increased in the past decades and cost of care is more than 11.3 billion per year. The use of steroid is the major treatment to control symptoms; however the side effects are often devastating. Seeking new drugs or new strategies in reducing the dose of steroid taken has always been an important task. A whey protein extract (WPE) from bovine that is enriched in growth factor TGF-β has been demonstrated with potential for reducing symptoms associated with mild-to moderate TH1 mediated psoriasis in human. However whether WPE also has potential for inhibiting TH2 mediated disease is still unclear. In this paper, using a murine asthma model, we have identified that daily feeding the sensitized mice with WPE before challenge was able to reduce airway inflammation, serum OVA-specific IgE and airway hyperresponsiveness. In the presence WPE, an increased in regulatory T cell population in vitro and in vivo were observed. Moreover, the production of IL-4, IL-5 and IL-13 and the expression of TH2 master transcription factor GATA3 by stimulated TH2 cells were reduced when TH2 cells were cultured with WPE. Using TGF-β blocking antibody, we further identified that TGF-β is the main component in the WPE that exert the inhibitory effect. Thus, our data suggested that WPE has a potential to alleviate the symptoms of asthma by regulating TH2 cell functions. Therefore, taking WPE regularly might be potentially beneficial for asthma patient
Aberrant expression of MCC in TRAF3-deficient mouse B lymphoma and human multiple myeloma (176.12)
Authors: Edwards Shanique , Baron Jacqueline , Moore Carissa , Liu Yan , Hart Ronald , Xie Ping 
Published: January 2023

Abstract
We recently reported that specific deletion of a novel tumor suppressor gene, TRAF3, in B lymphocytes leads to B lymphoma development in mice. Interestingly, B lymphoma development in B-TRAF3-/- mice exhibits a long latency (about 9 months), indicating that additional oncogenic alterations are required for B lymphomagenesis. To delineate such oncogenic alterations in TRAF3-/- B lymphomas, we performed microarray analyses and identified mutated in colorectal cancer (MCC) as a gene consistently up-regulated in B lymphomas spontaneously developed in different individual B-TRAF3-/- mice. We verified the striking up-regulation of MCC expression in TRAF3-/- B lymphomas at both the mRNA and protein levels by quantitative real time PCR and Western blot analyses, respectively. We further found that the MCC transcript and protein were aberrantly elevated in 6 human patient-derived multiple myeloma cell lines with TRAF3 deletions or relevant mutations. In contrast, MCC expression was not detected in normal mouse splenic B cells or premalignant TRAF3-/- B cells. Furthermore, MCC expression was not induced in normal splenic B cells or premalignant TRAF3-/- B cells by a variety of B cell stimuli, including CD40, BCR, LPS, and CpG. Taken together, our findings indicate that aberrant MCC expression is associated with B cell tumorigenesis. Our ongoing study will further elucidate the roles and mechanisms of MCC in TRAF3 deficiency-initiated B cell malignant transformation.
MicroRNA-568 inhibit CD4+ T cell activation through targeting NFAT5 (176.2)
Authors: Wen Weihong , Li Wei , Yang An-Gang 
Published: January 2023

Abstract
MicroRNAs (miRNAs) are small noncoding RNAs that regulate gene expression posttranscriptionally and are also known to be involved in lymphocyte development and function. In our previous study, by using microRNA array, we tried to identify the miRNAs that may regulate T cell activation, and we have reported that miR-181c can regulate T cell activation through directly targeting IL-2 (Mol Immunol, 2011, 48: 592-599). Here we reported that during CD4+ T cell activation, the expression of miR-568 was decreased. Forced expression of miR-568 can significantly inhibit the activation of Jurkat cells and human peripheral CD4+ T cells after stimulation. NFAT5 was predicted to be a potential target of miR-568, and the expression of NFAT5 was increased during CD4+ T cell activation. NFAT5 3’UTR luciferase reporter assay showed that miR-568 can inhibit the expression of luciferase, but can’t inhibit the mutated NFAT5 3’UTR luciferase reporter expression. Upregulation of miR-568 can inhibit the expression of NFAT5 in CD4+ T cells, while miR-568 inhibitors can increase the NFAT5 level. Furthermore, we found that knockdown of NFAT5 can inhibit the activation of CD4+ T cells after stimulation. Thus, our results demonstrated that microRNA-568 can inhibit CD4 T cell activation, at least in part, through targeting NFAT5.
Endogenous ROS Regulates Vα14iNKT Cells Signaling during Agonistic Fas mAb-dependent Fulminant Liver Failure (176.3)
Authors: Ajuebor Maureen , Liu Jianfeng , Adegboyega Patrick , Aw Tak Yee , Downs Isaac 
Published: January 2023

Abstract
Current theories recognize uncontrolled systemic activation of the immune system as an early initiating event that leads to development of acute fulminant liver failure (FLF) in mice after treatment with agonistic Fas mAb. In the present study, we identify a novel and previously unrecognized pro-inflammatory and pro-apoptotic role for endogenous ROS in stimulating signaling in IFN-γ-expressing Vα14iNKT cells in a pSTAT-1/T-bet dependent manner to promote the development of FLF. Specifically, we show that treatment of mice with N-acetylcysteine (NAC), an ROS scavenger and glutathione (GSH) precursor, almost completely abolished IFN-γ signaling and nitrosative stress in Vα14iNKT cells. Conversely, fortification of the antioxidant, GSH, in the liver due to Vα14iNKT cells deficiency, induces anti-inflammatory responses to prevent/limit the development of FLF and hepatic apoptosis in Jα18−/− mice through suppression of IFN-γ signaling and effector functions. This study provides critical new insights into how ROS regulates IFN-γ signaling in intrahepatic Vα14iNKT cells to impact inflammatory and pathological responses.
CD47 protects naïve murine B cells from anti-CD19 mAb-mediated depletion (176.6)
Authors: Gallagher Sandra , Wang Yue , Yusuf Isharat , Herbst Ronald , Carter Laura 
Published: January 2023

Abstract
Studies with human CD19 transgenic mice demonstrate that the primary mechanism of anti-CD19 mAb mediated B cell depletion is antibody-dependent cellular phagocytosis (ADCP) mediated by macrophages. We hypothesize that the balance between positive and negative regulators of phagocytosis is an important mechanism regulating the efficiency of B cell depletion in vivo. One potential pathway involved in this regulation is CD47, which is ubiquitously expressed on cells, binding to CD172a on macrophages to generate a negative signal and prevent phagocytosis of self. Here, we investigated the role of CD47-CD172a in anti-CD19 mAb-mediated B cell depletion. All B cells in the blood, spleen and bone marrow express CD47 to some extent; the highest level of CD47 was detected on plasma cells, which are typically resistant to depletion. Further, CD47 KO B cells are more susceptible to in vitro depletion than WT B cells. And, anti-CD47 F(ab)2 mAb blockade of CD47-CD172a enhances ADCP of WT cells. Accordingly, in vivo treatment with anti-CD19 mAb demonstrated enhanced depletion in CD47-/- mice compared to WT mice even when a more potent, afucosylated anti-CD19 mAb is utilized. In conclusion, CD47 binding to CD172a counteracts anti-CD19 mAb-mediated phagocytosis of B cells. Future studies are warranted to investigate the regulatory role of CD47 in B cell depletion in clinical settings.
Mouse CD229 ligation costimulates T cell activation (176.7)
Authors: Wang Jinghua , Wu Guoping , Hao Ruyi 
Published: January 2023

Abstract
CD229 (SLAMF3) is a receptor protein primarily found on mature T cells, B cells, myeloid cells, macrophages, and thymocytes. The exact functions of this receptor remain uncertain. Data from CD229 knockout mice showed that CD229 is uniquely involved in enhancing T cell activation. However, coligation of CD229 and TCR with anti-CD229 (mAb) and anti-CD3 antibodies has been demonstrated to inhibit T cell activation. To study the functions of CD229, we expressed a soluble polyHistidine tagged protein containing the mouse CD229 extracellular domain (aa48-454) and investigated its function in purified mouse CD3+ cells in vitro. Concurrent ligation of CD229 and TCR with immobilized CD229-His protein and anti-CD3 antibody significantly enhanced cell proliferation and IFN-γ secretion in murine CD3+ splenocytes in a dose-dependent manner. Furthermore, pre-treatment of CD3+ splenocytes with polyclonal anti-CD229 antibody completely abolished co-stimulative actions of CD229-His. This suggests that CD229-His co-stimulates T cells through CD229 receptors on T cell surface. Moreover, ligation of CD229 with CD229-His in CD3+ cells led to ERK1/2 phosphorylation in response to anti-CD3 stimulation. Taken together, these results suggest that CD229 acts as a hemophilic costimulatory molecule and is able to up-regulate T-cell activation.
Effects of KOB03, a polyherbal medicine in mast cell-mediated allergic response in ovalbumin-induced allergic rhinitis in vivo model and RBL-2H3 mast cells. (177.14)
Authors: Jung Jinki , Jung Hyo Won , Kang Seok Yong , Kim Songhee , Park Yong-Ki 
Published: January 2023

Abstract
KOB03 is a polyherbal medicine originating from Korean Traditional Medicine, which has been clinically applied for the treatment of allergic diseases. Here, we investigated the inhibitory effects of KOB03 on mast cell-mediated allergic responses on ovalbumin-induced allergic rhinitis in guinea pigs and RBL-2H3 mast cells. To determine the effect of KOB03 on mast cell-mediated allergic reactions, we investigated the parameter changes on ovalbumin (OVA)-induced allergic rhinitis in guinea pigs, and the release of allergic inflammatory mediators such as histamine, IgE and inflammatory cytokines in DNP-IgE-stimulated RBL-2H3 mast cells. The oral administration of KOB03 at doses of 200 and 500 mg/kg in OVA-sensitized/challenged guinea pig significantly decreased the serum levels of OVA-specific IgE, histamineand TNF-alpha KOB03 also inhibited the histopathological changes of nasal mucosa with the infilteration of eosinophils and inflammatory cells. Furthermore, KOB03 significantly inhibited DNP-IgE-induced release of histamine in RBL-2H3 cells via suppressing the ERK1/2 phosphorylation. These data suggest that KOB03 has an anti-allergic activity by modulating mast cell-mediated allergic responses.
Purified Natural Ara h 6: An Important Marker for IgE Responses to Peanut (177.15)
Authors: Koid Audrey , Hamilton Robert , van Ree Ronald , Versteeg Serge , Dreskin Stephen , Chapman Martin , Wuenschmann Sabina 
Published: January 2023

Abstract
Ara h 6 has a reported seroprevalence similar to Ara h 2, a major peanut allergen. Both allergens have a similar molecular weight (14.5kD - Ara h 6; 17-18kD - Ara h 2) and share 55% identity in their amino acid sequences. Thus, it has been difficult to obtain natural Ara h 6 (nAra h 6) free of Ara h 2. Our study compares the IgE antibody reactivity of highly purified nAra h 6 to a natural Ara h 6 reference reagent (nAra h 6-R), recombinant Ara h 6 (rAra h 6) and natural Ara h 2 (nAra h 2). SDS-PAGE of the highly purified allergen revealed a single 14.5kD band and the identity of Ara h 6 was confirmed by tandem mass spectrometry (LC/MS-MS). The purified nAra h 6 contained &lt;0.005% traces of nAra h 2 as assessed by ELISA. Natural Ara h 6 had a lower biological activity in basophil histamine release assays than nAra h 2. Chimeric ELISA showed that 70 and 75% of peanut allergic patients (n=57) had specific-IgE to nAra h 2 and nAra h 6 respectively. Natural Ara h 6-R and rAra h 6 displayed similar IgE antibody reactivity when compared to the nAra h 6. In conclusion, Ara h 6 is a major peanut allergen, with comparable immunoreactivity to Ara h 2. The highly purified Ara h 6, free of Ara h 2, will be useful for diagnostic IgE antibody assays, and for molecular and cellular studies to further investigate the immunological mechanisms of peanut allergy.
The nascent truncation of FcϵRIβ confers calmodulin binding which is essential for microtubule formation and degranulation in human mast cells (177.17)
Authors: Cruse Glenn , Beaven Michael , Bradding Peter , Gilfillan Alasdair , Metcalfe Dean 
Published: January 2023

Abstract
The gene locus containing the MS4A2 gene (encoding FcϵRIβ) has strong linkage to allergy susceptibility. MS4A2 was considered as a candidate gene, but studies on the functional consequence of mutations in FcϵRIβ have been disappointing. We have identified a truncation of FcϵRIβ (t-FcϵRIβ) in humans. In this study we sought to identify the function of this variant. We determined that t-FcϵRIβ forms a complex with Fyn kinase and Gab2 in the cytosol and that the truncation of FcϵRIβ exposes a calmodulin (CaM) binding domain. Using co-IPs we show that in the presence of Ca2+, CaM binds to the t-FcϵRIβ complex, allowing phosphorylation of Fyn and Gab2, which are involved in microtubule formation. Confocal microscopy revealed translocation of the t-FcϵRIβ complex to a tubulin-rich region after cell activation. Deconvolution and 3D modeling of the imaging data demonstrated that the translocated complex surrounds the centrosome, forming an intricate network with microtubules. Utilizing lentiviral shRNA to silence the FcϵRIβ variants, we identified that knockdown of t-FcϵRIβ attenuated microtubule formation, degranulation and cytokine production in response to thapsigargin. Ca2+ influx and PGD2 production were unaffected. These data suggest that t-FcϵRIβ propagates Ca2+ signals by binding CaM and initiating microtubule formation which is essential for mast cell degranulation and cytokine release. Thus, targeting t-FcϵRIβ may offer a novel approach to treatment of allergic diseases.
Thymol inhibits passive cutaneous anaphylaxis in mice through induction of apoptotic cell death in mast cells (177.3)
Authors: Wechsler Joshua , Hsu Chia-lin , Bryce Paul 
Published: January 2023

Abstract
Mast cells play a critical role in atopic dermatitis through the release of preformed and de novo synthesized pro-inflammatory mediators. In 1878, HR Crocker described the use of topical thymol in the treatment of advanced eczema. We hypothesized that the efficacy of thymol in eczema is due to a direct effect on mast cells. The effect of topical thymol was assessed on allergic murine ear swelling in the mast cell-dependent passive cutaneous anaphylaxis (PCA) model as well as on ear swelling directly and mast cells in vitro. Thymol dose-dependently inhibited PCA when administered topically prior to antigen challenge. Thymol induced a dose-dependent immediate ear swelling in mice, however lacked late phase swelling seen in PCA. This effect was associated with increased mast cell degranulation histologically and was inhibited in histamine deficient mice. Thymol induced mast cell degranulation and mRNA transcription in vitro, but prevented protein secretion. This was due to decreased mast cell viability from apoptosis. Mast cell activation from thymol occurred via sustained calcium flux. Thymol-induced calcium flux was not inhibited in TRPV3 KO mast cells, but was inhibited by HC-030031, a selective TRPA1 antagonist, and 2-APB, an IP3 receptor antagonist. However, HC-030031 and 2-APB were unable to prevent thymol-induced cell death. We are currently investigating the mechanism by which thymol leads to activation-induced cell death in mast cells.
Prostaglandin E2 affects T cell responses through modulation of CD46 expression. (178.8)
Authors: Astier Anne , Kickler Karoline , Ni Choileain Siobhan , Stephen Jillian , Hafler David , Jabbour Henry 
Published: January 2023

Abstract
The complement regulator CD46 controls T cell activation and differentiation. CD46-mediated differentiation pathway is defective in several chronic inflammatory diseases, underlying the importance of CD46 in controlling T cell function and the need to understand its regulatory mechanisms. Using an RNAi-based screening approach in primary T cells, we have identified that two members of the G-protein coupled receptor (GPCR) kinase family were involved in regulating CD46 expression at the T cell surface. We have investigated the role of prostaglandin E2 (PGE2), which binds to GPCRs, in the regulation of CD46 expression and function. Conflicting roles of PGE2 in T cell functions have been reported, and the reasons for these apparent discrepancies are not well understood. We show that: i) addition of PGE2 strongly downregulates CD46 expression in activated T cells, ii) PGE2 differentially affects T cell activation, cytokine production and phenotype depending on the activation signals received by the T cells, iii) this was correlated with a distinct pattern of the EP2-EP4 PGE2 receptors induced, with EP4 being preferentially expressed upon CD46, and iv) addition of an EP4 antagonist could reverse the effects observed on cytokine production upon CD46 costimulation. These data demonstrate a novel role of the PGE2-EP4-GRK axis in CD46 functions, which might partly explain the diverse roles of PGE2 in T cell functions.
Induced regulatory T cell-derived interleukin 10 is sufficient for the cure of experimental colitis (179.19)
Authors: Schmitt Erica , Haribhai Dipica , Williams Jason , Jia Shuang , Aggarwal Praful , Yan Ke , Broeckel Ulrich , Simpson Pippa , Salzman Nita , Hessner Martin , Williams Calvin 
Published: January 2023

Abstract
Induced Treg (iTreg) cells are essential for tolerance. Although in vitro derived iTreg cells can be used therapeutically in preclinical models of autoimmune disease, their stability in vivo and their mechanisms of suppression have not been examined. Here, we used a treatment model of lymphopenia-associated colitis to examine the role of IL-10 in iTreg cell function. Monotherapy with IL-10-deficient iTreg cells slowed the onset of colitis and decreased colon infiltration, but did not resolve disease. Mice treated with WT iTreg cells in combination with IL-10-deficient natural Treg (nTreg) cells survived and gained weight, even though iTreg cells were numerically disadvantaged and comprised just ~20% of all Treg cells in treated mice. Notably, ~85% of the transferred iTreg cells lost Foxp3 expression (ex-iTreg) but retained a portion of the iTreg transcriptome which failed to limit their pathogenic potential. The TCR repertoires of iTreg and ex-iTreg cells exhibited almost no overlap, indicating that maintenance of the iTreg pool is based on antigen specificity. These data demonstrate a potent and critical role for iTreg cell produced IL-10 that can supplant the IL-10 produced by nTreg cells and compensate for the inherent instability of the iTreg population.
CD8+CD122+ regulatory T cells contain clonally expanded cells with identical CDR3 sequences of T cell receptor β chain (179.9)
Authors: Suzuki Haruhiko 
Published: January 2023

Abstract
We identified CD8+CD122+ regulatory T cells (CD8+CD122+ Tregs) and reported their importance in maintaining immune homeostasis. The absence of CD8+CD122+ Tregs has been shown to lead to severe systemic autoimmunity in several mouse models including inflammatory bowel diseases (IBD) and experimental autoimmune encephalomyelitis (EAE). Interleukin-10 (IL-10) is an important effector molecule for CD8+CD122+ Tregs to suppress conventional T cells. The T-cell receptors (TCRs) expressed on CD8+CD122+ Tregs recognize the target cells to be regulated. To build a step to identify the target antigen(s) recognized by TCRs of CD8+CD122+ Tregs, we compared the TCR diversity of CD8+CD122+ Tregs with that of conventional naïve and memory T cells in mice. We analyzed the use of TCR-Vβ in IL-10-producing population of CD8+CD122+ Tregs marked by high-level expression of CD49d, and found the significantly increased use of Vβ13 in these cells. Immunoscope analysis of the CDR3 region of the TCR β-chain revealed remarkable skewing in a pair of Vβ regions, suggesting the existence of clonally expanded cells in CD8+CD122+ Tregs. Clonal expansion in Vβ13+ cells was confirmed by determining the DNA sequences of the CDR3s. The characteristic TCR found in this study would become a clue of further study to identify the target antigen recognized by CD8+CD122+ Tregs.
Role of HMGB1 in TLR3-mediated inflammation (180.10)
Authors: Son Mina , Kim Eun-sook , Shin Jeon-Soo 
Published: January 2023

Abstract
Nuclear high mobility group box 1 (HMGB1), a DNA binding protein, belongs to the superfamily of HMG proteins and mediates structural and functional changes to chromatin. HMGB1 can be released either passively by necrotic cells or actively by stimulated cells. The extracellular role of HMGB1 as a cytokine has been intensively studied and shown to be important as a danger-associated molecular pattern protein. HMGB1 co-operates with other pro-inflammatory molecules to induce inflammation. HMGB1 forms complexes with various Toll-like receptor (TLR) ligands of LPS and CpG, enhancing their cytokine-inducing function. In this study, we demonstrated that HMGB1 binds to TLR3 both directly and indirectly in cooperation with poly(I:C), using immunoprecipitation and surface plasmon resonance assays. Exogenous HMGB1 treatment to HEK293/TLR3 cells was co-localized in intracytoplasmic endosomes containing TLR3 followed by NF-κB activation. In conclusion, HMGB1 is a novel ligand of TLR3 and is involved in TLR3-mediated inflammation.