Impact of the Multiple Sclerosis associated genetic variant CD226 Gly307Ser on human CD8 T cell functions
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ABSTRACT:
PROVIDER: PRJNA1105955 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR28834000_1.fastq.gz | Fastqsanger.gz | |||
| SRR28834000_2.fastq.gz | Fastqsanger.gz | |||
| SRR28834001_1.fastq.gz | Fastqsanger.gz | |||
| SRR28834001_2.fastq.gz | Fastqsanger.gz | |||
| SRR28834002_1.fastq.gz | Fastqsanger.gz |
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Project description:Background and Objectives: The rs763361 non-synonymous (Gly307Ser) variant in the CD226 gene has been identified as a risk factor for several immune-mediated diseases, including multiple sclerosis (MS). Compelling evidence suggests that this allele may be one of the genetic driving forces contributing to suceptibility to MS by decreasing the immune-regulatory capacity of Treg cells and increasing the pro-inflammatory potential of CD4 T cells. However, the impact of this CD gene variant on CD8 T cell functions, a population that also plays a key role in MS, remain T to be determined. Methods: In order to study whether the CD226 risk variant affects human CD8 T cells functions, we used CD8 T cells isolated from PBMC of 16-age matched healthy donors homozygous for either the protective or risk allele of CD226. We characterized these CD8 T cells upon TCR stimulation using high-parametric flow cytometry, bulk RNAseq, and through characterization of canonical signaling pathways and cytokine production. Results: Upon TCR engagment, the phenotype of ex vivo CD8 T cells bearing the protective (CD226-307Gly) or the risk (CD226-307Ser) allele of CD226 was largely overlapping. However, transcriptomic signature of CD8 T cells from the donor carrying the risk allele presented an enrichment in TCR, JAK/STAT and INFg signaling.
2024-09-13 | GSE266132 | GEO
Project description:Systemic sclerosis (SSc) is an autoimmune disease characterized by vascular damage, and fibrosis of the skin and internal organs. Because activated and oligoclonally expanded CD8+ T cells can be detected in peripheral blood and lung of SSc patients, effector memory CD8+ T cells may play a critical role for organ involvement in SSc; however, the pathogenic functions of effector memory CD8+ T cells remain incompletely understood. Here we performed DNA microarray analysis of the sort-purified effector memory CD8+ T cells from SSc patients and healthy controls, and showed that the expression of genes related to immune response and cell adhesion, including CD226 (also known as DNAX accessory molecule-1, DNAM-1), was significantly altered. Moreover, detailed analysis of CD226 revealed that CD226highCD8+ T cells were increased in SSc patients (mean, 50.7%) compared with healthy controls (32.9%) and were appreciably associated with the severity of skin sclerosis and interstitial lung disease. Further, CD226highCD8+ T cells from SSc patients produced abundant IL-13 and were positively correlated with the cytotoxic capacity of CD8+ T cells against HUVECs. Finally, the neutralization of CD226 impaired IL-13 production and cytolysis against HUVECs. These findings indicate that upregulated CD226 expression on CD8+ T cells reflects disease severity and are involved in SSc pathogenesis via the production of profibrotic IL-13 and endothelial cell injury, and that CD226 may be a useful target in the treatment of SSc. We first purified effector memory CD8+ T cells (CD3+CD8+CD45RO+CD62L+ cells) from peripheral blood by cell sorting and subsequently performed cDNA microarray analysis of the sort-purified effector memory CD8+ T cells from 9 SSc patients and 5 healthy controls.
2014-12-06 | E-GEOD-63903 | biostudies-arrayexpress
Project description:Systemic sclerosis (SSc) is an autoimmune disease characterized by vascular damage, and fibrosis of the skin and internal organs. Because activated and oligoclonally expanded CD8+ T cells can be detected in peripheral blood and lung of SSc patients, effector memory CD8+ T cells may play a critical role for organ involvement in SSc; however, the pathogenic functions of effector memory CD8+ T cells remain incompletely understood. Here we performed DNA microarray analysis of the sort-purified effector memory CD8+ T cells from SSc patients and healthy controls, and showed that the expression of genes related to immune response and cell adhesion, including CD226 (also known as DNAX accessory molecule-1, DNAM-1), was significantly altered. Moreover, detailed analysis of CD226 revealed that CD226highCD8+ T cells were increased in SSc patients (mean, 50.7%) compared with healthy controls (32.9%) and were appreciably associated with the severity of skin sclerosis and interstitial lung disease. Further, CD226highCD8+ T cells from SSc patients produced abundant IL-13 and were positively correlated with the cytotoxic capacity of CD8+ T cells against HUVECs. Finally, the neutralization of CD226 impaired IL-13 production and cytolysis against HUVECs. These findings indicate that upregulated CD226 expression on CD8+ T cells reflects disease severity and are involved in SSc pathogenesis via the production of profibrotic IL-13 and endothelial cell injury, and that CD226 may be a useful target in the treatment of SSc.
2014-12-06 | GSE63903 | GEO
Project description:Type 2 innate lymphoid cells (ILC2s) play a pivotal role in type 2 asthma. CD226 is a costimulatory molecule involved in various inflammatory diseases. Here, we aimed to investigate CD226 expression and function within human and mouse ILC2s, and to assess the impact of targeting CD226 on ILC2-mediated airway hyperreactivity (AHR). Our findings demonstrated an inducible expression of CD226 in activated ILC2s, enhancing their cytokine secretion and effector functions. Blocking CD226 ameliorates ILC2-dependent AHR in IL-33 and Alternaria Alternata-induced models. Interestingly, CD226 is expressed and inducible in human ILC2s, and its blocking reduces cytokine production. Finally, we showed that peripheral ILC2s in asthmatic patients exhibited elevated CD226 expression compared to healthy controls.Our findings underscore the potential of CD226 as a novel therapeutic target in ILC2s, presenting a promising avenue for ameliorating AHR and allergic asthma.
2024-04-16 | GSE264060 | GEO
Project description:We recently found that loss of the activating receptor CD226 (DNAM-1) was a critical mechanism affecting CD8+ T cell responsiveness to TCR stimulation. To better understand the molecular differences between CD226- and CD226+ CD8+ T cells, we decided to perform a global transcriptional analysis of purified naive (Tn, CD62L+CD45RA+), central memory (Tcm, CD62L+CD45RA-) and terminal effector memory (Temra, CD62L-CD45RA+) CD226+ and CD226- CD8+ T cells using next generation RNA sequencing.
2020-10-30 | GSE135291 | GEO
Project description:We recently found that loss of the activating receptor CD226 (DNAM-1) was a critical mechanism affecting CD8+ T cell responsiveness to TCR stimulation. To better understand the molecular differences between CD226- and CD226+ CD8+ T cells, we decided to perform a global transcriptional analysis of purified CD226+ and CD226- CD8+ effector memory T cells before and after TCR activation using next generation RNA sequencing. We report here the total RNA sequencing of healthy donor resting CD226- and CD226+ CD8+ Tem cells (n=6/group) or activated (ACT, n=4/group) by α-CD2/CD3/CD28 for 24 hrs.
2020-10-30 | GSE133397 | GEO
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Project description:Elevated genetic risk for multiple sclerosis originated in Steppe Pastoralist populations
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Project description:Immunotherapeutics that modulate T cell activation represent a crucial component for inhibiting the autoimmune pathogenesis of type 1 diabetes (T1D) and improving the efficacy of β-cell replacement therapy. Here, we present a novel strategy for reducing diabetes incidence in the NOD mouse using monoclonal antibodies (mAbs) to block the T cell costimulatory receptor, CD226. Notably, female NOD mice treated with 600 µg of ⍺-CD226 mAbs between 7-8 weeks of age showed decreased disease incidence at 30 weeks and reduced insulitis severity compared to mice treated with an isotype control. Ex vivo analysis performed five weeks post-treatment revealed ⍺-CD226 mAbs persist in vivo, reducing the availability of CD226 on CD8+ T cells and Tregs. Flow cytometric analysis demonstrates that ⍺-CD226 mAbs inhibit the proliferation of both CD4+ and CD8+ T cells in vitro. Similarly, ex vivo samples had reduced CD4+ and CD8+ effector memory T cell proliferation following ⍺-CD226 mAb treatment. Splenocytes treated with ⍺-CD226 mAbs exhibited a more immunoregulatory cytokine profile with decreased IFN-γ and increased IL-10 production. This phenotype was further corroborated by 51Cr-release assays demonstrating reduced cell-mediated lympholysis (CML) of murine β-cells by ⍺-CD226 mAb-treated autoreactive cytotoxic lymphocytes. Ex vivo phenotyping of FOXP3+Helios+ Tregs revealed increased CD25 expression following ⍺-CD226 mAb treatment, with Tregs displaying augmented suppressive capacity of CD4+ responders during in vitro suppression assays. These data suggest that ⍺-CD226 mAbs both reduce T cell cytotoxicity and improve Treg function, with important therapeutic implications for the prevention or suspension of T1D.
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