Immune Cell Function Research Articles

Abstract IA014: Unraveling pancreatic tumor defenses: inside the stromal orchestra with the HOST-factor

Abstract Dive into how members of the Cukierman lab and their collaborators explore desmoplasia, the dense “shield” around tumors. Discover their groundbreaking 3D model that reveals the intricate “symphony” of fibroblasts and the interstitial extracellular matrix they produce. Learn how these elements impact cancer cells, as well as the function of immune and other tumor microenvironment cells. Central to the lab’s research is the HOST-Factor (Harmonic Output of Stromal Traits), a new tool to measure and eventually modify the microenvironment’s influence on tumors. Don’t miss this opportunity to see how the team is transforming our understanding of pancreatic cancer’s onset, progression, and treatment responses. Citation Format: Edna Cukierman. Unraveling pancreatic tumor defenses: inside the stromal orchestra with the HOST-factor [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Tumor-body Interactions: The Roles of Micro- and Macroenvironment in Cancer; 2024 Nov 17-20; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2024;84(22_Suppl):Abstract nr IA014.

Single-cell expression and immune infiltration analysis of polyamine metabolism in breast cancer.

Breast cancer is one of the most threatening women health diseases worldwide and its molecular heterogeneity offers a range of response to therapy. The role of polyamine metabolism is receiving increasing attention. Polyamine metabolism not only plays an important role in the occurrence and development of breast cancer, but also interacts with tumor immune microenvironment. In this work, we applied single-cell RNA-sequencing (scRNA-seq) and systems immunological approaches to interrogate immune cell infiltration gene-to-gene co-expressions in the bulk tumor transcriptomes of breast cancer. We acquired breast cancer sample data from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO), evaluated the infiltration status of 22 immune cell types using CIBERSORTx tool, respectively. By leveraging the Retrospective Breast sample of various technologies including gene expression and methylation, we identified 46 breast cancer proliferation-associated co-expression modules using weighted gene coexpression network analysis (WGCNA) approach along with machine learning models which in turn delineated single cell level expressions features that these selected module possessed. We observed substantial cellular heterogeneity in the breast cancer microenvironment, where lineage-specific gene expression patterns were highly associated with tumor progression. Moreover, we also identified the gene modules correlated with immune cell infiltration level that could function as regulators in response to tumors for immune therapy. Moreover, risk scores were correlated with immune cell function in different patient groups defined by high- and low-risk. The findings of this study shed a new light upon molecular classification prognostic assessment and personalized treatment in breast cancer.

LRRC8A drives NADPH oxidase-mediated mitochondrial dysfunction and inflammation in allergic rhinitis.

Allergic rhinitis (AR) is a complex disorder with variable pathogenesis. Increasing evidence suggests that the LRRC8A is involved in maintaining cellular stability, regulating immune cell activation and function, and playing significant roles in inflammation. However, the involvement of LRRC8A in AR inflammation and its underlying mechanisms remain unclear. LRRC8A expression in AR patients, confirmed by qRT-PCR and Western blotting, was analyzed to investigate its relationship with the clinical characteristics of AR patients. In vitro, IL-13 stimulated HNEpCs to establish a Th2 inflammation model, with subsequent LRRC8A knockout or overexpression. NOX1/NOX4 inhibitor (GKT137831) and chloride channel inhibitor (DCPIB) were utilized to investigate AR development mechanisms during LRRC8A overexpression. An OVA-induced AR model with nasal mucosa LRRC8A knockdown confirmed LRRC8A's regulatory role in AR inflammation. LRRC8A mRNA and protein levels were significantly elevated in AR patients, positively correlating with NADPH oxidase subunits and Th2 inflammatory markers. In vitro, IL-13 stimulation of HNEpCs resulted in upregulation of LRRC8A and increased expression of NOX1, NOX4, and p22phox, along with mitochondrial dysfunction and NF-κB pathway activation. The knockout of LRRC8A reversed these effects. In nasal mucosal epithelial cells, DCPIB and GKT137831 completely blocked mitochondrial dysfunction caused by the overexpression of LRRC8A, which led to up-regulation of NOX1, NOX4, and p22phox. In vivo, knocking down LRRC8A reduced eosinophil infiltration, downregulated the expression of NOX1, NOX4, p22phox IL-4, IL-5, and IL-13, and decreased NF-κB pathway activation. LRRC8A drives the upregulation of NOX1, NOX4, and p22phox, leading to ROS overproduction and mitochondrial dysfunction. It also activates NF-κB, ultimately leading to nasal mucosal epithelial inflammation. LRRC8A may be a potential target for the treatment of AR.

Metabolic Regulation of Inflammation: Exploring the Potential Benefits of Itaconate in Autoimmune Disorders.

Itaconic acid and its metabolites have demonstrated significant therapeutic potential in various immune diseases. Originating from the tricarboxylic acid cycle in immune cells, itaconic acid can modulate immune responses, diminish inflammation, and combat oxidative stress. Recent research has uncovered multiple mechanisms through which itaconic acid exerts its effects, including the inhibition of inflammatory cytokine production, activation of anti-inflammatory pathways, and modulation of immune cell function by regulating cellular metabolism. Cellular actions are influenced by the modulation of metabolic pathways, such as inhibiting succinate dehydrogenase (SDH) activity or glycolysis, activation of nuclear-factor-E2-related factor 2 (Nrf2), boosting cellular defences against oxidative stress, and suppression of immune cell inflammation through the NF-κB pathway. This comprehensive review discusses the initiation, progression, and mechanisms of action of itaconic acid and its metabolites, highlighting their modulatory effects on various immune cell types. Additionally, it examines their involvement in immune disease like rheumatoid arthritis, multiple sclerosis, type 1 diabetes mellitus, and autoimmune hepatitis, offering greater understanding for creating new therapies for these ailments.

Metabolic Reprogramming of Immune Cells in the Tumor Microenvironment

Metabolic reprogramming of immune cells within the tumor microenvironment (TME) plays a pivotal role in shaping tumor progression and responses to therapy. The intricate interplay between tumor cells and immune cells within this ecosystem influences their metabolic landscapes, thereby modulating the immune evasion tactics employed by tumors and the efficacy of immunotherapeutic interventions. This review delves into the metabolic reprogramming that occurs in tumor cells and a spectrum of immune cells, including T cells, macrophages, dendritic cells, and myeloid-derived suppressor cells (MDSCs), within the TME. The metabolic shifts in these cell types span alterations in glucose, lipid, and amino acid metabolism. Such metabolic reconfigurations can profoundly influence immune cell function and the mechanisms by which tumors evade immune surveillance. Gaining a comprehensive understanding of the metabolic reprogramming of immune cells in the TME is essential for devising novel cancer therapeutic strategies. By targeting the metabolic states of immune cells, it is possible to augment their anti-tumor activities, presenting new opportunities for immunotherapeutic approaches. These strategies hold promise for enhancing treatment outcomes and circumventing the emergence of drug resistance.

Natural products: promising therapeutics for targeting regulatory immune cells in the tumor microenvironment

Regulatory immune cells regulate immune responses through various mechanisms, affecting the occurrence, development, and therapeutic effects of tumors. In this article, we reviewed the important roles of regulatory immune cells, such as regulatory T cells (Tregs), regulatory B cells (Bregs), myeloid-derived suppressor cells (MDSCs), regulatory dendritic cells (DCregs), and tumor-associated macrophages (TAMs), in the tumor microenvironment (TME). The immunomodulatory effects of natural products, such as polysaccharides, polyphenols, glycosides, alkaloids, terpenoids, quinones, and other compounds, which affect the functions of regulatory immune cells through molecular signaling pathways, thereby enhancing the potential of the antitumor immune response, are discussed. These findings provide new ideas and possibilities for the application of natural products in tumor treatment, which can help enhance the effectiveness of tumor treatment and improve patient prognosis.

Abstract 4137296: Single-cell Atlas of Human Epicardial Adipose Tissue Reveals Aging IL4R + Naive B cell Contributing To Atrial Fibrillation

Background: Numerous recent evidence suggested a role of epicardial adipose tissue (EAT), the visceral fat depot of the heart, in the development of Atrial Fibrillation (AF). However, the cellular and molecular mechanisms underlying the association remain elusive. Methods: We performed single-nucleus RNA sequencing on eleven EAT samples collected from 2 groups of subjects: patients with nonvalvular AF undergoing coronary bypass surgery for severe CAD (n=7), and a control group of patients without concomitant AF (n=4). Comparative analyses were performed between the groups, including cellular compositional analysis, cell type–resolved transcriptomic changes, and functional analysis. Results: Unsupervised clustering of 92734 nuclei identified 11 clusters, encompassing all known cell types in the adipose tissue. Pseudobulk differential expression analysis between the AF and control groups revealed pronounced differences in a select subset of genes located on the X and Y chromosomes, including XIST and TSIX. Subsequent pathway analysis identified that the most significantly impacted pathways were those associated with immune cell functions. Meanwhile, differences in cellular composition and transcriptomic profiles, particularly concerning B cells, were observed between normal and AF conditions, highlighting distinct immune cell dynamics. Comparison of pathways across different B cell states revealed the enrichment of distinct pathways within each state, including those involved in cellular senescence, antigen processing and presentation, and programmed cell death signatures. Notably, aging IL4R + naive B cell and inflammatory ITGB1 + memory B cell were identified as important regulators potentially involved in functional changes of EAT and AF pathogenesis. Conclusions: We built a complete single-nucleus transcriptomic atlas of human EAT in normal and AF conditions. Our study lays the foundation for developing novel therapeutic strategies for treating AF by targeting and modifying B cell functions within EAT.

BIOM-29. UNMASKING COPPER DEPENDENCE IN GLIOMA: 19-GENE SIGNATURE FOR PATIENT STRATIFICATION AND TARGETED THERAPY

Abstract Adult-type diffuse gliomas exhibit poor prognosis with limited treatment options. Although copper-targeted therapies have been previously explored in these tumors, they have yet to show significant benefits. To understand the role of copper in glioma biology we performed an in silico data analysis on the TCGA glioma cohorts to identify copper-homeostasis related genes (CHRG) with prognostic significance. This was done to enable patient stratification into appropriate treatment arms for future clinical trials involving copper targeted therapies. Furthermore, in vitro experimentation was performed to validate the functional outcomes observed from the in silico results. 19 CHRGs were identified to have prognostic association from the TCGA glioma cohorts. This gene signature regulates a broad range of cellular processes, including metal homeostasis, metabolism, extracellular matrix organization, and immune cell function. The CHRG signature enabled the development of a predictive model that allowed stratification of patients between high and low risk groups. In vitro spheroid growth assays in both U87 cell lines with or without IDH mutation elicited sustained growth inhibition after 6 days post treatment. Furthermore, copper chelation therapy modified the energy potential of these glioma cells in vitro leading to growth inhibition. This study established a predictive model using 19 CHRGs that enable patient stratification between high and low risk glioma patients. Furthermore, our in vitro experiments show the suitability of targeting intracellular copper to inhibit tumor growth. Further research is needed to understand the underlying mechanisms and explore optimal treatment combinations for improved outcomes. We aim to extend this approach to pediatric gliomas for improved risk assessment and personalized medicine.

Mesenchymal stem cell application in pulmonary disease treatment with emphasis on their interaction with lung-resident immune cells

Due to the vital importance of the lungs, lung-related diseases and their control are very important. Severe inflammatory responses mediated by immune cells were among the leading causes of lung tissue pathology and damage during the COVID-19 pandemic. In addition, uncontrolled immune cell responses can lead to lung tissue damage in other infectious and non-infectious diseases. It is essential to control immune responses in a way that leads to homeostasis. Immunosuppressive drugs only suppress inflammatory responses and do not affect the homeostasis of reactions. The therapeutic application of mesenchymal stem cells (MSCs), in addition to restoring immune homeostasis, can promote the regeneration of lung tissue through the production of growth factors and differentiation into lung-related cells. However, the communication between MSCs and immune cells after treatment of pulmonary diseases is essential, and investigating this can help develop a clinical perspective. Different studies in the clinical phase showed that MSCs can reverse fibrosis, increase regeneration, promote airway remodeling, and reduce damage to lung tissue. The proliferation and differentiation potential of MSCs is one of the mechanisms of their therapeutic effects. Furthermore, they can secrete exosomes that affect the function of lung cells and immune cells and change their function. Another important mechanism is that MSCs reduce harmful inflammatory responses through communication with innate and adaptive immune cells, which leads to a shift of the immune system toward regulatory and hemostatic responses.

Association analysis of gut microbiota with LDL-C metabolism and microbial pathogenicity in colorectal cancer patients

BackgroundColorectal cancer (CRC) is the most common gastrointestinal malignancy worldwide, with obesity-induced lipid metabolism disorders playing a crucial role in its progression. A complex connection exists between gut microbiota and the development of intestinal tumors through the microbiota metabolite pathway. Metabolic disorders frequently alter the gut microbiome, impairing immune and cellular functions and hastening cancer progression.MethodsThis study thoroughly examined the gut microbiota through 16S rRNA sequencing of fecal samples from 181 CRC patients, integrating preoperative Low-density lipoprotein cholesterol (LDL-C) levels and RNA sequencing data. The study includes a comparison of microbial diversity, differential microbiological analysis, exploration of the associations between microbiota, tumor microenvironment immune cells, and immune genes, enrichment analysis of potential biological functions of microbe-related host genes, and the prediction of LDL-C status through microorganisms.ResultsThe analysis revealed that differences in α and β diversity indices of intestinal microbiota in CRC patients were not statistically significant across different LDL-C metabolic states. Patients exhibited varying LDL-C metabolic conditions, leading to a bifurcation of their gut microbiota into two distinct clusters. Patients with LDL-C metabolic irregularities had higher concentrations of twelve gut microbiota, which were linked to various immune cells and immune-related genes, influencing tumor immunity. Under normal LDL-C metabolic conditions, the protective microorganism Anaerostipes_caccae was significantly negatively correlated with the GO Biological Process pathway involved in the negative regulation of the unfolded protein response in the endoplasmic reticulum. Both XGBoost and MLP models, developed using differential gut microbiota, could forecast LDL-C levels in CRC patients biologically.ConclusionsThe intestinal microbiota in CRC patients influences the LDL-C metabolic status. With elevated LDL-C levels, gut microbiota can regulate the function of immune cells and gene expression within the tumor microenvironment, affecting cancer-related pathways and promoting CRC progression. LDL-C and its associated gut microbiota could provide non-invasive markers for clinical evaluation and treatment of CRC patients.

Epigenetic Regulation of Immune Cells in Health and Disease: A Comprehensive Review

Epigenetic regulation plays a crucial role in the development, differentiation, and function of immune cells. Mechanisms such as DNA methylation, histone modifications, chromatin remodeling, and non-coding RNA interactions dynamically shape gene expression, enabling immune cells to adapt to environmental stimuli and mediate appropriate immune responses. Aberrant epigenetic regulation is implicated in a range of diseases, including autoimmune disorders, cancer, and chronic inflammatory conditions. In autoimmune diseases, such as systemic lupus erythematosus and rheumatoid arthritis, altered DNA methylation and histone modifications contribute to immune dysregulation and tissue damage. In cancer, immune cells in the tumor microenvironment often exhibit epigenetic changes that facilitate immune evasion. Emerging therapeutic strategies targeting epigenetic pathways, including DNA methyltransferase inhibitors, histone deacetylase inhibitors, and CRISPR-based epigenome editing, offer promising approaches for treating immune-mediated diseases. This review provides a comprehensive overview of the epigenetic mechanisms governing immune cell behavior, their dysregulation in disease, and the potential of epigenetic therapies to restore immune homeostasis and improve patient outcomes. Keywords: Epigenetics, immune cells, DNA methylation, histone modifications, non-coding RNAs, autoimmune diseases, immunotherapy

The Risk Genes SIRP5, CMC1, and ASAH1 as Potential Targets for the Diagnosis, Immunotherapy, and Treatment of Colon Adenocarcinoma by Single-Cell and Bulk RNA Sequencing Analysis.

Globally, one of the main causes of cancer-related mortality is Colon Adenocarcinoma (COAD). In this study, a new special Immune Cell Functions (ICF) risk model was constructed using single-cell and bulk RNA sequencing data to develop a new understanding and clinical applications for COAD. The immune function gene sets were downloaded from a literature reference, and the COAD single-cell dataset GSE146771 was downloaded from the Tumour Immune Single Cell Hub database. Using Lasso analysis, a multiple gene signature was made from the enrichment scores of immune function gene sets that were enriched in different ways. Robust validation of the signature was then performed in multiple independent cohorts. After that, we built the model using a 10-fold cross-test and evaluated its independence for clinical usage using a nomogram. We also investigated the connection between signature and immune function, genetic variation, immunotherapy, and the cancer immunological microenvironment. Lastly, we used qPCR and immunohistochemistry to examine the expression of the unreported model genes. To find the regulatory functions of unreported model genes, an EdU assay was employed. First, 20 differentially enriched immune function gene sets were identified. Ten genes can be used as a risk profile to assess the prognosis of colon cancer, according to Lasso regression analysis. Signature performance was stable in both the training cohort and two independent GEO external cohorts, and risk scores were confirmed as independent prognostic factors. At the same time, our risk model continued to be highly predictive across various clinical clusters and clinical characteristics, such as immune checkpoints, tumour genome mutations, and chemotherapeutic drug resistance. Patients in the low-risk group have exhibited a higher chance of benefiting from immunotherapy, according to immunotherapy response research. qPCR and immunohistochemistry analysis have revealed SIRP5 expression as high in COAD tissues, while CMC1 and ASAH1 expression has been found to be low. According to the findings of the functional experiment, SIRP5, CMC1, and ASAH1 may control the ability of CRC cells to proliferate. In this study, using scRNA-seq and bulk RNA-seq data, we created a risk model to predict the prognosis and effectiveness of immunotherapy in patients with COAD. In addition, we have discovered three model genes (SIRP5, CMC1, and ASAH1) that have not been reported before. These genes have the potential to be novel therapeutic targets in Colorectal Cancer (CRC). These findings suggest that this model could be used to evaluate the prognostic risk and identify potential targets for COAD patient treatment.

Hyperactivation of the PI3K Pathway in Inborn Errors of Immunity: current understanding and therapeutic perspectives

Abstract Phosphoinositide-3-kinase (PI3K) pathway function is crucial to normal development, differentiation and function of immune cells including B, T and NK cells. Following the description of two cohorts of patients with a primary immunodeficiency with gain-of-function variants in the PIK3CD gene a decade ago, the disease entity activated PI3K delta syndrome (APDS) was named. Since then, many more patients with PIK3CD variants have been described, and loss-of-functions variants in PIK3R1 and PTEN have also been linked to APDS. Importantly, the availability of small molecules that inhibit the PI3K pathway have enabled targeted treatment of APDS patients. In this review, we define (1) the PI3K pathway and its role in inborn errors of immunity; (2) the clinical and immunological presentation of APDS1 (PIK3CD GOF), APDS2 (PIK3R1 LOF) and related disorders; (3) Diagnostic approaches to identify and functionally validate the genetic causes of disease; (4) therapeutic interventions to target PI3K hyperactivation; and finally (5) current challenges and future perspectives that require attention for the optimal treatment of patients with APDS and APDS-L diseases.

YTHDF2 upregulation and subcellular localization dictate CD8 T cell polyfunctionality in anti-tumor immunity.

RNA methylation is an important regulatory process to determine immune cell function but how it affects the anti-tumor activity of CD8 T cells is not fully understood. Here we show that the N6-methyladenosine (m6A) RNA reader YTHDF2 is highly expressed in early effector or effector-like CD8 T cells. We find that YTHDF2 facilitates nascent RNA synthesis, and m6A recognition is fundamental for this distinctively nuclear function of the protein, which also reinforces its autoregulation at the RNA level. Loss of YTHDF2 in T cells exacerbates tumor progression and confers unresponsiveness to PD-1 blockade in mice and in humans. In addition to initiating RNA decay that is necessary for mitochondrial fitness, YTHDF2 orchestrates chromatin changes that promote T cell polyfunctionality. YTHDF2 interacts with IKZF1/3, which is important for sustained transcription of their target genes. Accordingly, immunotherapy-induced efficacy could be largely restored in YTHDF2-deficient T cells through combinational use of IKZF1/3 inhibitor lenalidomide in a mouse model. Thus, YTHDF2 coordinates epi-transcriptional and transcriptional networks to potentiate T cell immunity, which could inform therapeutic intervention.

Obesity uncovers presence of inflammatory lung macrophage subsets with adipose tissue transcriptomic signature in influenza virus infection.

Obesity is a risk factor for increased lung damage and disease severity during influenza virus infection. White adipose tissue (WAT) inflammation is a key driver of disease pathogenesis in obesity. Whether and how obesity modifies lung and WAT immune cell character and function in obesity to amplify influenza disease severity remains unknown. We show that obesity establishes a proinflammatory transcriptome in lung immune cells that is further augmented upon influenza virus infection. Unexpectedly, we also show that influenza virus infection induces expression of inflammatory genes in visceral WAT and modifies WAT immune cell milieu in obesity. Notably, a decrease in WAT macrophage (ATM) populations inversely correlates to increase in infiltrating lung macrophage numbers in obese influenza virus-infected mice. Comparison of both lung and WAT immune cell transcriptional landscapes uncovers a presence of a macrophage subset in the lungs whose transcriptomic signatures matched those of an inflammatory ATM subset preferentially found in obese mice. Adoptive transfer of ATMs from obese mice into lean influenza-virus infected mice promotes host immune cell infiltration to the lungs. Together, our novel findings provide evidence of immune cell transcriptome and character changes in the lungs and WAT of influenza virus infected obese, but not lean, mice and suggest that visceral ATMs may contribute to the overall inflammatory milieu in this setting.

Sex-Based Differences in Thyroid Plasma B Cell Infiltration: Implications for Autoimmune Disease Susceptibility.

Thyroid autoimmune diseases, such as Hashimoto's thyroiditis and Graves' disease, are significantly more prevalent in women than in men, suggesting underlying biological differences in immune system function and regulation between sexes. Plasma B cells are crucial in autoimmunity due to their role in producing antibodies targeting self-antigens, but their presence in the thyroids of women without clinical autoimmune diseases remains largely unexplored. This study investigates the infiltration of plasma B cells in female thyroids specifically excluding those with any clinical signs of autoimmune diseases. Using bulk RNA-seq analysis, we identified significant sex differences in gene expression profiles, particularly in genes associated with plasma B cells. Single-cell RNA-seq and spatial transcriptomic analyses further revealed that the CXCL13-CXCR5 signaling axis plays a pivotal role in recruiting and organizing plasma B cells within the thyroid tissue. These findings suggest that the inherent presence of plasma B cells in the female thyroid, driven by CXCL13, may contribute to the higher risk of developing autoimmune thyroid diseases in women. Our study provides new insights into the immune landscape of the thyroid and underscores the importance of understanding sex-specific differences in immune cell distribution and function.

Function of immune cells and effector molecules of the innate immune system in the establishment and maintenance of pregnancy in mammals - A review.

In mammalian species, pregnancy is a complex process that involves the maternal recognition of pregnancy, implantation, decidualization, placentation, and parturition. The innate immune system is composed of cellular components, such as natural killer cells, neutrophils, monocytes, and macrophages, and effector molecules, such as cytokines, interferons, antimicrobial peptides, and complement components. The innate immune system plays a critical role as the first line of defense against infection or inflammation to maintain homeostasis and activate the adaptive immunity. During pregnancy, innate immune cells and effector molecules act on the regulation of innate immunity for host defense and processes such as embryo development, implantation, and placentation at the maternal-conceptus interface. In this review, we describe the components of the innate immune system and their functions at the maternal-conceptus interface to establish and maintain pregnancy in animal species that form hemochorial- or epitheliochorial-type placentas, including humans, rodents, ruminants, and pigs.

Tanshinone I inhibits the functions of T lymphocytes and exerts therapeutic effects on delayed-type hypersensitivity reaction via blocking STATs signaling pathways

Delayed-type hypersensitivity (DTH) reactions are a kind of chronic inflammatory diseases initiated by antigens and antigen-specific T cells. Currently, the therapy of DTH reactions is limited by the poor curative effects and serious adverse reactions of existing agents. In this study, we investigated the regulatory effects of tanshinone Ⅰ, a natural compound isolated from Salvia miltiorrhiza, on the functions of multiple immune cells and its therapeutic effects on DNFB-induced DTH reaction, and then explored its immunosuppressive mechanisms. The results showed that tanshinone Ⅰ at 5 to 20 μM moderately inhibited the activation of macrophages and dendritic cells, but did not weaken the activation of neutrophils. Tanshinone Ⅰ at 1 to 4 μM intensively suppressed the activation, proliferation, and differentiation of CD4+ and CD8+ T cells, and slightly affected the functions of B cells. Tanshinone Ⅰ administration markedly alleviated the edema, inflammatory response, and the infiltrations of CD4+ T cells, CD8+ T cells, and CD11b+ cells in ear tissues of mice which were induced DTH reactions by DNFB. Transcriptome analysis revealed that tanshinone Ⅰ strongly inhibited CD4+ T cells to express genes involving in cell proliferation, metabolism, activation, and differentiation. Furthermore, immunoblotting analysis showed that tanshinone Ⅰ selectively inhibited the phosphorylation of STAT3 and STAT5 in CD4+ T cells stimulated by anti-CD3e and anti-CD28 antibodies or IL-2. Collectively, tanshinone Ⅰ can strongly inhibit the functions of T lymphocytes, exert therapeutic effects on DTH reaction by blocking STATs signaling pathways, and has potential to be developed into therapeutic drug for DTH reactions.

Transcriptome Profiles Characteristics of the Peripheral Immune in Patients with Severe Fever with Thrombocytopenia Syndrome.

Severe fever with thrombocytopenia syndrome (SFTS) is an acute viral infection disease with a high mortality, but there are no specific effective drugs or vaccines available for use. To develop effective treatment methods, more basic researches are urgently needed to elucidate the response mechanisms of patients. Here, we conducted the transcriptomic analysis of peripheral immunity in 14 SFTS patients, ranging from moderate infection to severe and fatal disease. The results showed orderly cytokine signaling pathway modulation in moderate patients, cellular immunosuppression in severe patients, and significant dysregulation of the inflammatory response and coagulation dysfunction characteristic of deceased patients. In addition, WGCNA further showed a significant positive correlation between fatal outcomes and B cell and immunoglobulin mediated immune function modules, as well as a significant negative correlation with coagulation function modules. Overall, our research findings systematically observed potential immune mechanisms underlying clinical symptom heterogeneity and noteworthily revealed multiple signaling pathways leading to coagulation dysfunction in fatal outcomes, not just related to decreased platelet count, which can further elucidate the interaction between viruses and hosts and contribute to clinical treatment.

Genetic link between gut microbiota, immune cells, and rheumatoid arthritis: Mechanism of action of CD28 proteins

The gut microbiota serves a crucial function in modulating the immune responses of the host, as well as in managing inflammation within the body. In this particular study, the researchers sought to delve deeper into the specific mechanisms through which CD28 interacts with the gut microbiota and influences the functionality of immune cells. The study collected intestinal microbial samples from RA patients and healthy controls, analyzed microbial composition by high-throughput sequencing, and detected CD28 expression in T cells in combination with cellular immunology methods. At the same time, the effects of CD28 deletion on intestinal microbiota changes and inflammatory responses were evaluated using animal models. The findings from this study revealed a notable distinction in the gut microbiota profiles of individuals diagnosed with rheumatoid arthritis (RA) when compared to those of healthy control subjects. Specifically, the abundance of certain microbial species was observed to have a negative correlation with the expression levels of CD28, highlighting a complex interaction between the gut microbiome and the immune regulatory mechanisms involved in RA. Furthermore, experiments conducted on mice lacking CD28 demonstrated considerable alterations in their gut microbiota composition. These Cd28-deficient mice exhibited elevated levels of inflammatory markers, indicating an interplay between CD28 and the regulation of both the microbiota and the immune response.