bluuebunny/crossref_metadata_2025_split huggingface dataset:
The transcription factor EPAS1 links DOCK8 deficiency to atopic skin inflammation via IL-31 induction
Authors: Kunimura Kazufumi , Fukui Yoshinori 
Published: January 2023

Abstract

Introduction
Mutations of DOCK8 in humans cause a combined immunodeficiency characterized by atopic dermatitis. However, the molecular link between DOCK8 deficiency and atopic skin inflammation is unknown.

Materials and Methods
The skin disease development was compared between Dock8−/− and Dock8+/−mice expressing TCR transgene. After stimulation with the cognate antigen, CD4+T cells were used for cytokine production assay, microarray analysis and ChIP assay. IL-31 promoter activation, EMSA and immunoprecipitation were performed by standard techniques. Nuclear translocation of EPAS1 was examined in mouse embryonic fibroblasts generated from wild-type and Dock8−/−mice.

Results
We found that unlike Dock8+/−mice, Dock8−/−mice spontaneously developed severe atopic skin inflammation, when crossed with transgenic mice expressing TCR with a particular antigen specificity. Upon stimulation, CD4+T cells from Dock8−/−mice produced large amounts of IL-31, a major pruritogen associated with atopic dermatitis. This IL-31 induction critically depended on the transcription factor EPAS1, and its conditional deletion in CD4+ T cells abrogated skin disease development in Dock8−/−mice. Although EPAS1 is known to form a complex with aryl hydrocarbon receptor nuclear translocator (ARNT) and control hypoxic responses, EPAS1-mediated Il31 promoter activation was independent of ARNT, but in collaboration with SP1. In addition, we found that DOCK8 acted as an adaptor and negatively regulated nuclear translocation of EPAS1.

Conclusions
EPAS1 links DOCK8 deficiency to atopic skin inflammation via IL31 induction in CD4+T cells.
Oral tolerance to peanut allergy is mediated by CTLA-4-positive regulatory T cells
Authors: Krempski James W , Iijima Koji , Kobayshi Takao , Kita Hirohito 
Published: January 2023

Abstract
Peanut allergies are life-long diseases that cause severe anaphylactic responses to affected individuals. Oral ingestion of peanut products prevents infants from developing peanut allergy. However, little information is currently available regarding the immunologic mechanisms for this protection. Therefore, the goal of this project was to establish an oral tolerance model to peanut allergy in mice and to determine the immunologic mechanisms.
Naïve BALB/c mice that were exposed intranasally (i.n.) to peanut flour (PNf) developed peanut allergy as demonstrated by increased serum levels of IgE antibody as well as acute anaphylactic response when challenged with peanut extract. When mice were fed peanut butter (PNB) prior to i.n PNf exposure, they were protected from developing peanut allergy; these mice showed decreased serum levels of IgE antibody and lacked anaphylactic response. T follicular helper (Tfh) cells and germinal center (GC) B cells were decreased in lung draining lymph nodes of mice fed PNB. Furthermore, scRNSseq revealed 2 distinct CD4+ T cell subpopulations that are increased in those protected mice. CTLA-4, a checkpoint molecule, was highly expressed in one of these subpopulations. Systemic administration of a CTLA-4 blocking antibody to mice fed PNB increased the numbers of Tfh cells and GC B cells and increased serum levels of IgE antibody. Finally, anti-CTLA-4 reversed the clinical efficacy of oral PNB administration, resulting in manifestation of acute anaphylaxis when challenged with peanut extract.
Thus, oral administration of peanut product(s) prevents development of peanut allergy in mice. CTLA4+CD4+ T cells likely play a pivotal role in this process by regulating the development of Tfh cells.
An epigenetic link between the gut microbiome and immune responses in atopy
Authors: Cait Alissa , Hughes Michael R , Bilenky Misha , Cait Jessica , Pepin Deanna , Hirst Martin , Mohn William W. , McNagny Kelly 
Published: January 2023

Abstract
Atopy is the most common childhood disease in developed countries. Dysbiosis of the microbiome is now understood to be a driving force behind the development and severity of allergy/atopy. We previously showed that antibiotic treatment of newborn mice leads to a life-long perturbation of the gut microbiome marked by reduced bacterial production of the short chain fatty acid, butyrate. These mice exhibit a striking pro-inflammatory phenotype, marked by a heightened Th2 response, that was completely reversible with dietary supplementation of butyrate.
Butyrate is known to exert its effects on target cells via inhibition of histone deacetylases that have long term effects on gene expression. Consistent with a role for epigenetic skewing on the hematopoietic compartment of antibiotic treated mice, we found that bone marrow transplantation was sufficient to transfer the pro Th2 inflammatory phenotype into chimeric mice. Strikingly, we found unique regulatory states (H3K27ac) in purified hematopoietic stem and progenitor cells of these Th2 skewed mice. Single cell sequence analyses identified a distinct stem/progenitor cell transcriptomic signature in butyrate depleted mice that was reversed by butyrate supplementation.
We identified a metagenomic gene signature present in fecal microbiome samples of 3-month-old children who subsequently developed atopy. Consistent with our observations in mice, this signature included depletion of the bacterial genes required for breakdown of indigestible carbohydrates in breast milk and the loss of genes required for butyrate fermentation. This work provides novel evidence for a butyrate-driven epigenetic process that links the fetal microbiome to long term sculpting of the immune response.
Effector CD8 T Cell Infiltration into the Skin to Mediate Contact Hypersensitivity Responses Requires TLR4 Signaling on Precursors of Gr-1+CXCR2+Bone Marrow Cells
Authors: Kish Danielle , Fairchild Robert L 
Published: January 2023

Abstract
Contact hypersensitivity (CHS) is a CD8 T cell-mediated response to hapten skin sensitization and subsequent challenge. Challenge of dinitrofluorobenzene (DNFB) sensitized mice generates hapten-presenting endothelial cells (EC) that activate hapten-primed CD8 T cells to produce IFN-γ and IL-17. These cytokines stimulate the EC to produce CXCL1 that directs the recruitment and activation of Gr-1+CXCR2+cells required for hapten-reactive CD8 T cell infiltration into the skin parenchymal tissue. This study investigated the role of TLR4 receptor signaling during elicitation of CHS to DNFB. The production of CXCL1, ICAM, IFN-γ, CXCL9/10, and TNF-α and neutrophil infiltration evoked by hapten challenge of sensitized WT mice was markedly decreased following challenge of sensitized TLR4−/−mice. Hapten-primed CD8 T cells stimulated cultured hapten-labeled WT but not TLR4−/− EC to produce CXCL1. DNFB sensitization of WT and TLR4−/−mice induced similar numbers of hapten-reactive CD8 T cells producing IFN-g and IL-17 in the lymph nodes, but the CHS response to challenge in sensitized TLR4−/−mice was decreased &gt; 50% vs. WT mice. Challenge of DNFB sensitized WT, but not TLR4−/−, mice induced the bone marrow (bm)-derived Gr-1+CXCR2+cells needed to direct T cells into the challenge site. Transfer of hapten-primed WT CD8 T cells to naïve WT, but not TLR4−/−, mice induced CHS in response to hapten challenge. However, transfer of WT bm Gr-1+CXCR2+cells restored T cell infiltration and the CHS response to hapten challenge of sensitized TLR4−/−mice. Collectively, these results indicate that TLR4 signaling in bm Gr-1+CXCR2+precursor cells is required to evoke the innate immune response required for subsequent hapten-reactive T cell mediated CHS.
Metabolic shift induced by systemic activation of T cells in PD-1-deficient mice perturbs brain monoamines and emotional behavior
Authors: Miyajima Michio , Zhang Baihao , Guerrini Matteo , Sugiura Yuki , Fagarasan Sidonia 
Published: January 2023

Abstract

Introduction
While change of intracellular metabolism in T cell activation is well studied, whether T cell activation affects systemic metabolome outside cells is largely unknown. In present study, we examined systemic metabolome change in T cell activation and its effect on brain functions like emotional behaviors.

Results
Concentrations of amino acids in sera were decreased in PD-1-deficient mice in a T cell-dependent manner. On the other hands, concentrations of amino acids in lymph node were increased in lymph node of PD-1 deficient mice with increased number of total and activated T cells. Activated T cells increased expression of amino acid transporter and intracellular incorporations of tryptophan and tyrosine, two representative amino acids. Decreased concentrations of serum tryptophan and tyrosine lead to decreased serotonin and dopamine in brain of PD-1-deficient mice. PD-1-deficient mice showed enhanced anxiety-like behaviors and fear response.

Conclusions
Enhanced incorporation of amino acids in activated T cells leads to serum decrease in amino acids, which leads to serotonin and dopamine decrease in brain and enhanced anxiety-like behavior and fear response in PD-1-deficient mice.
CD71+erythroid cells promote Tregs and via ectonucleotides CD39 and CD73 modulate T cell responses
Authors: Elahi Shokrollah , Shahbaz Shima , Koleva Petya 
Published: January 2023

Abstract
CD71+erythroid cells are abundant in newborns with immunomodulatory properties. Recently, we showed a subset of neonatal CD71+erythroid cells express significant levels of V-domain Ig Suppressor of T Cell Activation (VISTA) and via TGF-β play a pivotal role in promotion of naïve CD4+T cells into regulatory T cells (PLOS Biology Dec. 2018). Here, we have demonstrated another novel immunomodulatory mechanism for CD71+erythroid cells. A subset of CD71+erythroid cells express significant levels of ectonucleotides CD39 and CD73, which culminating in the formation of adenosine. Extracellular adenosine has a marked dampening effects on the immune cells, suppressing effector T cells and assisting regulatory T cells. In addition, we found that CD71+erythroid cells express adenosine receptor (A2A) and constitutively produce TGF-β. Interestingly, exogenous or endogenous TGF-β upregulates expression of CD73 on CD71+erythroid cells. Collectively, these studies provide a novel insight into the crosstalk between CD71+ erythroid cells and regulatory T cells. Our results highlight the important biological role of CD71+erythroid cells in immune homeostasis.
Immune subsets in the murine pituitary gland and potential impacts on the HPG axis
Authors: Nicholas Dequina , Lawson Mark A. 
Published: January 2023

Abstract
Tissue-resident immune cells are known to regulate local homeostasis, including but not limited to inflammation and tissue repair. Recent research has implicated the importance of the immune system in reproduction. However, little data exists delineating the role of the immune system in the hypothalamic-pituitary-gonadal (HPG) axis, an important regulator of reproduction. The goal of this study was to apply conventional immunological techniques to assess the tissue-resident population of immune cells in the pituitary. We hypothesized that, like most tissues, a resident population of immune cells exists to promote homeostasis and may be dysregulated in disease. To test this, we prepared single cell suspensions of pituitary tissue from ~8–10 wk old wildtype male C57BL/6 mice and stained for CD45+ leukocytes and GnRHR+ gonadotropes. We found that 5–10% of the pituitary comprises CD45+ leukocytes. We designed an 11-color flow cytometry panel to immunophenotype subsets in the CD45+ population. Surprisingly, B cell and T cell populations, including CD4+ and CD8+ T cells, are underrepresented in the pituitary relative to mouse peripheral blood, spleen, and lymph nodes. B cells were ~9% of CD45+ cells while CD3+ T cells were ~ 15% of CD45+ cells. Conversely, approximately 40% of CD45+ cells in the pituitary are CD11b+ (likely macrophages) which constitute ~3% of all cells in the pituitary. The substantial presence of CD11b+ cells in the pituitary implicates a role for macrophages in pituitary homeostasis and function. Future work will focus on the role of pituitary tissue resident macrophages in the HPG axis.
A loss-of-function single nucleotide polymorphism in cytochrome b5 reductase 3 amplifies the response of bone marrow-derived macrophages to high salt
Authors: Jerome Jacob A , DeVallance Evan R , Pagano Patrick J , Straub Adam C 
Published: January 2023

Abstract

Introduction
High dietary salt intake is a risk factor for hypertension and autoimmune diseases. Recent studies show high salt intake can result in high-concentration interstitial salt accumulation. In macrophages, similar concentrations induce pro-inflammatory gene expression and amplify activation by LPS. African Americans, a notably salt-sensitive population, have an exclusively high frequency (~23%) for a missense single nucleotide polymorphism (SNP) in cytochrome b5 reductase 3 (CYB5R3), an enzyme important for oxidative stress resistance. We have shown this SNP, T117S, decreases enzymatic activity. Given macrophages’ sizable productive capacity for reactive oxygen species (ROS), we hypothesize T117S expression amplifies salt-mediated pro-inflammatory gene expression and ROS production.

Results
Culture of bone marrow-derived macrophages (BMDMs) from WT or T117S-expressing mice in high salt medium (+51mM NaCl) increased expression of pro-inflammatory genes iNOS, IL-6, and IL-1β. However, the increase was significantly greater in T117S BMDMs. High salt also increased hydrogen peroxide (H2O2) production in both groups, but more so in T117S BMDMs. Of note, pretreatment with inhibitors targeting p38, a MAP kinase involved in the inflammatory response, or NOX2, the major macrophage superoxide source, ablated salt-mediated H2O2 production in both groups.

Conclusions
We show presence of loss-of-function variant T117S CYB5R3 in macrophages enhances salt-mediated pro-inflammatory gene expression and ROS production in a p38 and NOX2-dependent manner. This suggests CYB5R3 may be involved in the response to high salt and raises the possibility that T117S carriers may have an exacerbated response to high salt intake.
Identification of TRM subsets with distinct cellular states and memory potential
Authors: Omilusik Kyla , Milner J Justin , Kurd Nadia , Toma Clara , Chang John T. , Goldrath Ananda W 
Published: January 2023

Abstract
The memory CD8+ T cell population consists of distinct subsets that collaborate to provide robust immunological protection. Within the circulation, two broad classes exist – the shorter-lived effector and effector memory (TEM) cells with heightened effector function for immediate protection and the longer-lived central memory (TCM) cells with stem-like qualities and increased proliferation potential. Tissue-resident memory (TRM) cells are the prominent cell type permanently residing in non-lymphoid tissues acting as sentinels against reinfection. Despite the critical importance of the TRM subset, the extent of their phenotypic and functional heterogeneity remains unknown. Using single-cell gene expression analyses, we assessed small intestine intraepithelial TRM cells over the course of acute infection. Distinct subsets were identified and distinguished by reciprocal expression of effector- and memory-associated transcriptional regulators, Blimp1 and Id3, respectively. While the Blimp1hi subset was prominent at early time points, the Id3hi population persisted and was more abundant over time. Importantly, examination of the subset-specific transcriptional profiles revealed considerable enrichment for the effector/effector-memory gene signature within the Blimp1hiTRM subset and the central-memory gene signature within the Id3hi TRM population. Furthermore, Id3hi TRM cells exhibited more stem-like characteristics including increased capacity to proliferate following rechallenge. Taken together, this study reveals that similar to circulating memory, the TRM population is heterogeneous, comprising cells with contrasting differentiation states and memory potential.
NUR77 HAS A CELL INTRINSIC ROLE IN NATURAL KILLER T CELL DEVELOPMENT AND FUNCTION
Authors: Kumar Amrendra , Suryadevara Naveenchandra , Hill Timothy M , Gordy Laura E , Bezbradica Jelena S , Wu Lan , Acharya Pankaj , Hiebert Scott W , Van Kaer Luc , Joyce Sebastian 
Published: January 2023

Abstract
Natural killer T (NKT) cells are innate-like lymphocytes that respond to self and foreign glycolipids under inflammatory conditions. NKT cells have constitutively high levels of Nur77, an orphan nuclear receptor family transcription factor that is induced very early during their ontogeny. Nur77 function in NKT cells has not been explored, however. Nur77 is known to transcriptionally control negative selection of conventional T cells, development of regulatory T cells and differentiation of effector CD8+ T cells. Thus, we hypothesized that Nur77 controls a lineage-specific gene expression program essential for the proper development of functional NKT cells. We found that, akin to conventional T cells, NKT cells poorly developed in transgenic mice that overexpressed wild type Nur77 (wtNur77tg) in T lineage only. Introgression of the rearranged Va14i a-chain gene into wtNur77tg mice (wtNur77tg; Va14tg mice) rescued NKT cell development but was arrested at the precursor stage 0. NKT cells in wtNur77tg; Va14tg mice expressed lower levels of PLZF when compared to NKT cells in non-transgenic mice. So also, NKT cells in wtNur77tg; Va14tg mice do not respond to glycolipid agonists. These findings are consistent with differences in the transcripomes of stage 0 NKT cells isolated from Va14tg versus wtNur77tg; Va14tg mice. Collectively, our data suggest that Nur77 induction initiates a gene expression program in developing NKT cells that are critical for developmental progression and function of NKT cells.
Supporting scientific knowledge communication and translation efforts by engaging appropriately with the Pacific audience
Authors: Sika-Paotonu Dianne , Laing Bridie , Anitelea Toni , Uiese Tina , Puni Ron , Vaipuna Tevita , Fa’atoese Adam 
Published: January 2023

Abstract
It is recognised that Indigenous Māori and Pacific Peoples are affected disproportionately by Acute Rheumatic Fever (ARF) and Rheumatic Heart Disease (RHD). Rates of ARF and RHD in New Zealand and the Pacific Region are of concern. Appropriate community engagement and knowledge translation efforts that support dissemination of research work and findings of relevance to Pacific populations, are of importance for effective dialogue. Efforts to communicate scientific research work and engage appropriately with Pacific communities and audiences have been limited, and require cultural considerations to ensure communication and interactions are culturally appropriate, clear and meaningful. The purpose of this work was to facilitate discussion between researchers and Pacific communities, regarding ARF and RHD Penicillin related research works of direct relevance and importance to Pacific communities in the Wellington area. Led by a Pacific Biomedical Scientist and supported by University Pacific staff and Medical students, a Pacific Fono (gathering) outreach event in the Hutt Valley was held on the 24th July, 2018. Scientific information and research work with immunological components related to ARF and RHD were presented, followed by a question answer session. Members of the Pacific community that attended represented different Pacific population groups with written and verbal feedback indicating the event had been informative and was enjoyed by those in attendance. This scientific knowledge translation and science communication event demonstrated appropriate engagement had been achieved to support dialogue between researchers and the Pacific community, regarding ARF and RHD Penicillin related research efforts.
Cinemimmunology-the use of cinema to learn immunology
Authors: Siddiqui Sana , Olk Sandra , Collier Rashad , Fazal Nadeem 
Published: January 2023

Abstract
Film can be a powerful educational tool known as cinemeducation. We at College of Pharmacy applied this universal learning method to the first year pharmacy class of basic immunology. Two workshops were introduced to the course and the student’s assessment pre- and post-workshop were analyzed. We used two Hollywood blockbuster movies, i.e., The Incredibles 1 and 2 to enhance first year pharmacy students to grasp concepts of basic immunology. The students watched movies. The main plot was that the immune system is like a family with dad, mom, girls, boys and babies. Giving due credit to Brad Bird, the writer and director of The Incredibles. In his words (changed within brackets)-quoted as follows: The characters of “The dad is always expected in the family to be strong, so we made him (T cell) strong. The moms are always pulled in a million different directions, so we made her stretch like taffy (B cell). Teenagers, particularly teenage girls, are insecure and defensive, so we made her turn invisible and turn on shields (Antibody). And ten-year-old boys are hyperactive energy balls. Babies are unrealized potential. So, we made babies as cytokines.” Our results showed a significantly enhanced conceptual learning and long-term retention of immunological concepts. Even students with severe learning difficulties and disabilities who struggle with any kind of academic curriculum can often relate to film. It was also an example of associated learning using common movies with high yield of performance within a short period of time. We recommend the use of such strategies in immunology education. Commonly accepted education method is known as cinemeducation for imparting medical education and when we used it to teach immunology, we called it cinemimmunology.
Contextualisation of Immunology based teaching for undergraduate Medical science students that supports knowledge application
Authors: Sika-Paotonu Dianne , Yang Anne , Vaipuna Kalilea , Buckley Eilish , Bartlett Hannah , Kalyanasundaram Shiva , Faatoese Adam 
Published: January 2023

Abstract
Provision of appropriate clinically relevant Immunology examples to support understanding of the related mechanistic and cellular Immunology teaching content within undergraduate Medical sciences education is important for knowledge application. This work in part involved the incorporation of Immunologically based clinical research examples for undergraduate Medical science students, that were relevant to current health issues associated with Māori and Pacific population groups living in New Zealand (NZ) and the Pacific Region. Immunologically based Cancer and Acute Rheumatic Fever (ARF) related teaching examples were presented in class to 4th year undergraduate Medical science students. Untreated Group A Streptococcal (GAS) infection of the throat (and skin) can trigger ARF which is an autoimmune condition that can lead to development of permanent heart damage known as Rheumatic Heart Disease (RHD) if left untreated. Māori, Pacific and Indigenous Aboriginal population groups are affected disproportionately by ARF and RHD. As the Cancer burden for Pacific population groups in NZ and the Pacific Region remains of public health concern, Immunologically based Cancer research work was also presented. In-depth interest and understanding of the presented material was demonstrated in class and indicated in student feedback. A subset of students became subsequently engaged in Summer Scholarship research placements focused on varying Cancer related aspects. Based on student responses and subsequent research efforts, the contextualisation of the Immunology information was successfully achieved and raised awareness of the heath priorities for Māori and Pacific population groups living in NZ and the Pacific Region.