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Proceedings of the National Academy of... Jun 2024Regulatory T cells (Tregs) are central in controlling immune responses, and dysregulation of their function can lead to autoimmune disorders or cancer. Despite extensive...
Regulatory T cells (Tregs) are central in controlling immune responses, and dysregulation of their function can lead to autoimmune disorders or cancer. Despite extensive studies on Tregs, the basis of epigenetic regulation of human Treg development and function is incompletely understood. Long intergenic noncoding RNAs (lincRNA)s are important for shaping and maintaining the epigenetic landscape in different cell types. In this study, we identified a gene on the chromosome 6p25.3 locus, encoding a lincRNA, that was up-regulated during early differentiation of human Tregs. The lincRNA regulated the expression of interleukin-2 receptor alpha (IL2RA), and we named it the lincRNA regulator of IL2RA (LIRIL2R). Through transcriptomics, epigenomics, and proteomics analysis of LIRIL2R-deficient Tregs, coupled with global profiling of LIRIL2R binding sites using chromatin isolation by RNA purification, followed by sequencing, we identified IL2RA as a target of LIRIL2R. This nuclear lincRNA binds upstream of the locus and regulates its epigenetic landscape and transcription. CRISPR-mediated deletion of the LIRIL2R-bound region at the locus resulted in reduced IL2RA expression. Notably, LIRIL2R deficiency led to reduced expression of Treg-signature genes (e.g., , , and ), upregulation of genes associated with effector T cells (e.g., and ), and loss of Treg-mediated suppression.
Topics: Humans; RNA, Long Noncoding; T-Lymphocytes, Regulatory; Forkhead Transcription Factors; Interleukin-2 Receptor alpha Subunit; Epigenesis, Genetic; Gene Expression Regulation; Cell Differentiation
PubMed: 38805281
DOI: 10.1073/pnas.2315363121 -
Scientific Reports May 2024T cells are one of the main cell types shaping the immune microenvironment in chronic obstructive pulmonary disease (COPD). They persist andplay cytotoxic roles. The...
T cells are one of the main cell types shaping the immune microenvironment in chronic obstructive pulmonary disease (COPD). They persist andplay cytotoxic roles. The purpose of this study aimed to explore the potential related-genes of T cells in lung tissue of COPD. Chip data GSE38974 and single_celldata GSE196638 were downloaded from the GEO database. Difference analyses and WGCNA of GSE38974 were performed to identify DEGs and the modules most associated with the COPD phenotype. Various cell subsets were obtained by GSE196638, and DEGs of T cells were further identified. GO, GSEA and KEGG enrichment analyses were conducted to explore the biological functions and regulatory signaling pathways of the DEGs and DEGs of T cells. The intersection of the DEGs, module genes and DEGs of T cells was assessed to acquire related-genes of T cells. The mRNA and protein expression levels of related-genes ofT cells were verified in lung tissue of mouse with emphysema model. Based on GSE38974 difference analysis, 3811 DEGs were obtained. The results of WGCNA showed that the red module had the highest correlation coefficient with the COPD phenotype. GSE196638 analysis identified 124 DEGs of T cells. The GO, GSEAand KEGG enrichment analyses mainly identified genes involved in I-kappaB kinase/NF-kappaB signaling, receptor signaling pathway via STAT, regulationof CD4-positive cells, regulation of T-helper cell differentiation, chemokine signaling pathway, Toll-likereceptor signaling pathway, CD8-positive cells, alpha-beta T cell differentiation, MAPK signaling pathway and Th17 cell differentiation. The DEGs, genes of the red module and DEGs of T cells were overlapped to acquire FOXO1 and DDX17. The results of RT-qPCR and Western Blot indicate that the mRNA and protein expression levels of FOXO1 and DDX17 in lung tissue of emphysema mice were significantly higher compared with those in air-exposed mice. FOXO1 as well as DDX17 may be related-genesof T cells in lung tissue of patient with COPD, and their participation in the biological processes of different signaling pathways may inspire further COPD research.
Topics: Pulmonary Disease, Chronic Obstructive; Computational Biology; Animals; Mice; Lung; T-Lymphocytes; Humans; Gene Expression Profiling; Signal Transduction; Disease Models, Animal; Gene Regulatory Networks; Databases, Genetic
PubMed: 38802460
DOI: 10.1038/s41598-024-62758-w -
Molecular Cytogenetics May 2024T-cell acute lymphoblastic leukemia (T-ALL) represents a rare and clinically and genetically heterogeneous disease that constitutes 10-15% of newly diagnosed pediatric...
BACKGROUND
T-cell acute lymphoblastic leukemia (T-ALL) represents a rare and clinically and genetically heterogeneous disease that constitutes 10-15% of newly diagnosed pediatric ALL cases. Despite improved outcomes of these children, the survival rate after relapse is extremely poor. Moreover, the survivors must also endure the acute and long-term effects of intensive therapy. Although recent studies have identified a number of recurrent genomic aberrations in pediatric T-ALL, none of the changes is known to have prognostic significance. The aim of our study was to analyze the cytogenomic changes and their various combinations in bone marrow cells of children with T-ALL and to correlate our findings with the clinical features of the subjects and their treatment responses.
RESULTS
We performed a retrospective and prospective comprehensive cytogenomic analysis of consecutive cohort of 66 children (46 boys and 20 girls) with T-ALL treated according to BFM-based protocols and centrally investigated cytogenetics and immunophenotypes. Using combinations of cytogenomic methods (conventional cytogenetics, FISH, mFISH/mBAND, arrayCGH/SNP and MLPA), we identified chromosomal aberrations in vast majority of patients (91%). The most frequent findings involved the deletion of CDKN2A/CDKN2B genes (71%), T-cell receptor (TCR) loci translocations (27%), and TLX3 gene rearrangements (23%). All chromosomal changes occurred in various combinations and were rarely found as a single abnormality. Children with aberrations of TCR loci had a significantly better event free (p = 0.0034) and overall survival (p = 0.0074), all these patients are living in the first complete remission. None of the abnormalities was an independent predictor of an increased risk of relapse.
CONCLUSIONS
We identified a subgroup of patients with TCR aberrations (both TRA/TRD and TRB), who had an excellent prognosis in our cohort with 5-year EFS and OS of 100%, regardless of the presence of other abnormality or the translocation partner. Our data suggest that escalation of treatment intensity, which may be considered in subsets of T-ALL is not needed for nonHR (non-high risk) patients with TCR aberrations.
PubMed: 38783324
DOI: 10.1186/s13039-024-00682-4 -
KLRG1-expressing CD8+ T cells are exhausted and polyfunctional in patients with chronic hepatitis B.PloS One 2024Killer cell lectin-like receptor G1 (KLRG1) has traditionally been regarded as an inhibitory receptor of T cell exhaustion in chronic infection and inflammation....
Killer cell lectin-like receptor G1 (KLRG1) has traditionally been regarded as an inhibitory receptor of T cell exhaustion in chronic infection and inflammation. However, its exact role in hepatitis B virus (HBV) infection remains elusive. CD8+ T cells from 190 patients with chronic hepatitis B were analyzed ex vivo for checkpoint and apoptosis markers, transcription factors, cytokines and subtypes in 190 patients with chronic hepatitis B. KLRG1+ and KLRG1- CD8+ T cells were sorted for transcriptome analysis. The impact of the KLRG1-E-cadherin pathway on the suppression of HBV replication mediated by virus-specific T cells was validated in vitro. As expected, HBV-specific CD8+ T cells expressed higher levels of KLRG1 and showed an exhausted molecular phenotype and function. However, despite being enriched for the inhibitory molecules, thymocyte selection-associated high mobility group box protein (TOX), eomesodermin (EOMES), and Helios, CD8+ T cells expressing KLRG1 produced significant levels of tumour necrosis factor (TNF)-α, interferon (IFN)-γ, perforin, and granzyme B, demonstrating not exhausted but active function. Consistent with the in vitro phenotypic assay results, RNA sequencing (RNA-seq) data showed that signature effector T cell and exhausted T cell genes were enriched in KLRG1+ CD8+ T cells. Furthermore, in vitro testing confirmed that KLRG1-E-cadherin binding inhibits the antiviral efficacy of HBV-specific CD8+ T cells. Based on these findings, we concluded that KLRG1+ CD8+ T cells are not only a terminally exhausted subgroup but also exhibit functional diversity, despite inhibitory signs in HBV infection.
Topics: Humans; CD8-Positive T-Lymphocytes; Lectins, C-Type; Receptors, Immunologic; Hepatitis B, Chronic; Female; Male; Hepatitis B virus; Adult; Middle Aged; Virus Replication; Cadherins; Perforin
PubMed: 38776335
DOI: 10.1371/journal.pone.0303945 -
Breeding Science Dec 2023The development of resistant rice ( L.) varieties is a key strategy for the eco-friendly control of brown planthopper (BPH: Stål). However, BPH outbreaks occur...
The development of resistant rice ( L.) varieties is a key strategy for the eco-friendly control of brown planthopper (BPH: Stål). However, BPH outbreaks occur frequently owing to the evolution of virulent strains in the field and the rapid breakdown of monogenic resistance to BPH. Therefore, to enhance BPH resistance and gauge the effectiveness of gene pyramiding against strongly virulent BPH, we developed pyramided lines (PYLs) in the genetic background of 'IR64' carrying BPH resistance genes. We developed six IR64-PYLs ( + , + , + , + , + , and + ) through marker-assisted selection. To assess the resistance of the IR64-PYLs, we conducted antibiosis test, honeydew test, and modified seedbox screening test (MSST) using strongly virulent BPH populations. The level of BPH resistance increased in all six IR64-PYLs compared to both 'IR64' and the corresponding NILs in MSST. Among them, IR64- + and IR64- + exhibited the highest resistance to BPH. However, the resistance level of most IR64-PYLs was not significantly higher than that of the corresponding NILs in antibiosis test. Thus, these PYLs could serve as a valuable resource for breeding programs aimed at improving resistance to virulent strains of BPH and enhancing their durability.
PubMed: 38737919
DOI: 10.1270/jsbbs.23028 -
Cell Reports. Medicine May 2024Stimulator of IFN genes (STING) is a promising target for adjuvants utilized in in situ cancer vaccination approaches. However, key barriers remain for clinical...
Stimulator of IFN genes (STING) is a promising target for adjuvants utilized in in situ cancer vaccination approaches. However, key barriers remain for clinical translation, including low cellular uptake and accessibility, STING variability necessitating personalized STING agonists, and interferon (IFN)-independent signals that can promote tumor growth. Here, we identify C100, a highly deacetylated chitin-derived polymer (HDCP), as an attractive alternative to conventional STING agonists. C100 promotes potent anti-tumor immune responses, outperforming less deacetylated HDCPs, with therapeutic efficacy dependent on STING and IFN alpha/beta receptor (IFNAR) signaling and CD8 T cell mediators. Additionally, C100 injection synergizes with systemic checkpoint blockade targeting PD-1. Mechanistically, C100 triggers mitochondrial stress and DNA damage to exclusively activate the IFN arm of the cGAS-STING signaling pathway and elicit sustained IFNAR signaling. Altogether, these results reveal an effective STING- and IFNAR-dependent adjuvant for in situ cancer vaccines with a defined mechanism and distinct properties that overcome common limitations of existing STING therapeutics.
Topics: Animals; Membrane Proteins; CD8-Positive T-Lymphocytes; Receptor, Interferon alpha-beta; Chitin; Mice; Adjuvants, Immunologic; Signal Transduction; Mice, Inbred C57BL; Humans; Cancer Vaccines; Cell Line, Tumor; Female; Nucleotidyltransferases; Programmed Cell Death 1 Receptor; Neoplasms
PubMed: 38729159
DOI: 10.1016/j.xcrm.2024.101560 -
Laboratory Investigation; a Journal of... May 2024The glycans form a unique complex on the surface of cancer cells and play a pivotal role in tumor progression, impacting proliferation, invasion, and metastasis....
The glycans form a unique complex on the surface of cancer cells and play a pivotal role in tumor progression, impacting proliferation, invasion, and metastasis. TRA-1-60 is a glycan that was identified as a critical marker for the establishment of fully reprogrammed inducible pluripotent stem cells. Its expression has been detected in multiple cancer tissues, including embryonal carcinoma, prostate cancer, and pancreatic cancer, but the biological and pathological characterization of TRA-1-60-expressing tumor cells remains unclear within various types of malignancies. Here, we report the biological characteristics of TRA-1-60-expressing gastric cancer cells, especially those with its cell surface expression, and the therapeutic significance of targeting TRA-1-60. The cells with cell membrane expression of TRA-1-60 were mainly observed in the invasive area of patient gastric cancer tissues and correlated with advanced stages of the disease based on histopathological and clinicopathological analyses. In vitro analysis using a scirrhous gastric adenocarcinoma line, HSC-58, which highly expresses TRA-1-60 on its plasma membrane, revealed increased stress-resistant mechanisms, supported by the upregulation of glutathione synthetase and NCF-1 (p47phox) via lipid-ROS regulatory pathways, as detected by RNA-seq analysis followed by oxidative stress gene profiling. Our in vivo therapeutic study using the TRA-1-60-targeting antibody-drug conjugate, namely, Bstrongomab-conjugated monomethyl auristatin E, showed robust efficacy in a mouse model of peritoneal carcinomatosis induced by intraperitoneal xenograft of HSC-58, by markedly reducing massive tumor ascites. Thus, targeting the specific cell surface glycan, TRA-1-60, shows a significant therapeutic impact in advanced-stage gastric cancers.
PubMed: 38718982
DOI: 10.1016/j.labinv.2024.102073 -
AIDS Research and Therapy May 2024Human genetic contribution to HIV progression remains inadequately explained. The type 1 interferon (IFN) pathway is important for host control of HIV and variation in...
The association between single-nucleotide polymorphisms within type 1 interferon pathway genes and human immunodeficiency virus type 1 viral load in antiretroviral-naïve participants.
BACKGROUND
Human genetic contribution to HIV progression remains inadequately explained. The type 1 interferon (IFN) pathway is important for host control of HIV and variation in type 1 IFN genes may contribute to disease progression. This study assessed the impact of variations at the gene and pathway level of type 1 IFN on HIV-1 viral load (VL).
METHODS
Two cohorts of antiretroviral (ART) naïve participants living with HIV (PLWH) with either early (START) or advanced infection (FIRST) were analysed separately. Type 1 IFN genes (n = 17) and receptor subunits (IFNAR1, IFNAR2) were examined for both cumulated type 1 IFN pathway analysis and individual gene analysis. SKAT-O was applied to detect associations between the genotype and HIV-1 study entry viral load (log10 transformed) as a proxy for set point VL; P-values were corrected using Bonferroni (P < 0.0025).
RESULTS
The analyses among those with early infection included 2429 individuals from five continents. The median study entry HIV VL was 14,623 (IQR 3460-45100) copies/mL. Across 673 SNPs within 19 type 1 IFN genes, no significant association with study entry VL was detected. Conversely, examining individual genes in START showed a borderline significant association between IFNW1, and study entry VL (P = 0.0025). This significance remained after separate adjustments for age, CD4 T-cell count, CD4/CD8 T-cell ratio and recent infection. When controlling for population structure using linear mixed effects models (LME), in addition to principal components used in the main model, this was no longer significant (p = 0.0244). In subgroup analyses stratified by geographical region, the association between IFNW1 and study entry VL was only observed among African participants, although, the association was not significant when controlling for population structure using LME. Of the 17 SNPs within the IFNW1 region, only rs79876898 (A > G) was associated with study entry VL (p = 0.0020, beta = 0.32; G associated with higher study entry VL than A) in single SNP association analyses. The findings were not reproduced in FIRST participants.
CONCLUSION
Across 19 type 1 IFN genes, only IFNW1 was associated with HIV-1 study entry VL in a cohort of ART-naïve individuals in early stages of their infection, however, this was no longer significant in sensitivity analyses that controlled for population structures using LME.
Topics: Humans; HIV Infections; HIV-1; Polymorphism, Single Nucleotide; Viral Load; Interferon Type I; Male; Female; Adult; Genotype; Middle Aged; Receptor, Interferon alpha-beta; Cohort Studies; Disease Progression; CD4 Lymphocyte Count
PubMed: 38698440
DOI: 10.1186/s12981-024-00610-x -
Current Biology : CB Apr 2024Host reproduction can be manipulated by bacterial symbionts in various ways. Parthenogenesis induction is the most effective type of reproduction manipulation by...
Host reproduction can be manipulated by bacterial symbionts in various ways. Parthenogenesis induction is the most effective type of reproduction manipulation by symbionts for their transmission. Insect sex is determined by regulation of doublesex (dsx) splicing through transformer2 (tra2) and transformer (tra) interaction. Although parthenogenesis induction by symbionts has been studied since the 1970s, its underlying molecular mechanism is unknown. Here we identify a Wolbachia parthenogenesis-induction feminization factor gene (piff) that targets sex-determining genes and causes female-producing parthenogenesis in the haplodiploid parasitoid Encarsia formosa. We found that Wolbachia elimination repressed expression of female-specific dsx and enhanced expression of male-specific dsx, which led to the production of wasp haploid male offspring. Furthermore, we found that E. formosa tra is truncated and non-functional, and Wolbachia has a functional tra homolog, termed piff, with an insect origin. Wolbachia PIFF can colocalize and interact with wasp TRA2. Moreover, Wolbachia piff has coordinated expression with tra2 and dsx of E. formosa. Our results demonstrate the bacterial symbiont Wolbachia has acquired an insect gene to manipulate the host sex determination cascade and induce parthenogenesis in wasps. This study reveals insect-to-bacteria horizontal gene transfer drives the evolution of animal sex determination systems, elucidating a striking mechanism of insect-microbe symbiosis.
PubMed: 38692276
DOI: 10.1016/j.cub.2024.04.035 -
Investigative Ophthalmology & Visual... Apr 2024Fungal endophthalmitis is characterized by chronic inflammation leading to the partial or complete vision loss. Herein, we analyzed the transcriptomic landscape of...
PURPOSE
Fungal endophthalmitis is characterized by chronic inflammation leading to the partial or complete vision loss. Herein, we analyzed the transcriptomic landscape of Aspergillus flavus (A. flavus) endophthalmitis in C57BL/6 mice to understand the host-pathogen interactions.
METHODS
Endophthalmitis was induced by intravitreal injection of A. flavus spores in C57BL/6 mice and monitored for disease progression up to 72 hours. The enucleated eyeballs were subjected to histopathological analysis and mRNA sequencing using the Illumina Nextseq 2000. Pathway enrichment analysis was performed to further annotate the functions of differentially expressed genes (DEGs) and validation of cytokines was performed in vitreous of patients with fungal endophthalmitis using multiplex ELISA.
RESULTS
Transcriptomic landscape of A. flavus endophthalmitis revealed upregulated T-cell receptor signaling, PI3K-AKT, MAPK, NF-κB, JAK-STAT, and NOD like receptor signaling pathways. We observed significant increase in the T-cells during infection especially at 72 hours infection along with elevated expression levels of IL-6, IL-10, IL-12, IL-18, IL-19, IL-23, CCR3, and CCR7. Furthermore, host-immune response associated genes, such as T-cell interacting activating receptor, TNF receptor-associated factor 1, TLR1, TLR9, and bradykinin receptor beta 1, were enriched. Histopathological assessment validated the significant increase in inflammatory cells, especially T-cells at 72 hours post-infection along with increased disruption in the retinal architecture. Additionally, IL-6, IL-8, IL-17, TNF-α, and IL-1β were also significantly elevated, whereas IL-10 was downregulated in vitreous of patients with Aspergillus endophthalmitis.
CONCLUSIONS
Regulating T-cell influx could be a potential strategy to modulate the excessive inflammation in the retina and potentially aid in better vision recovery in fungal endophthalmitis.
Topics: Animals; Aspergillus flavus; Mice; Mice, Inbred C57BL; Disease Models, Animal; Eye Infections, Fungal; Endophthalmitis; Aspergillosis; Adaptive Immunity; Immunity, Innate; Gene Expression Profiling; Cytokines; Transcriptome; Enzyme-Linked Immunosorbent Assay; Vitreous Body
PubMed: 38687493
DOI: 10.1167/iovs.65.4.44