Resolving molecular mechanisms of autoimmune disease in primary CD4 T cells
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA560653 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR9992740.fastq.gz | Fastqsanger.gz | |||
| SRR9992750.fastq.gz | Fastqsanger.gz | |||
| SRR9992760.fastq.gz | Fastqsanger.gz | |||
| SRR9992741.fastq.gz | Fastqsanger.gz | |||
| SRR9992751.fastq.gz | Fastqsanger.gz |
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Project description:The mechanisms behind survival of autoimmune CD4 T cells during chronic stimulation are unclear. Examining early time-points during T cell priming showed that activation of autoimmune CD4 T cells in the absence of infectious signals allowed maintenance of TCF1 expression, albeit at reduced levels. Tcf7 locus was epigenetically modified in circulating autoimmune CD4 T cells, suggesting a pre-programmed de novo methylation of the locus in early stages of autoimmune CD4 T cell differentiation which mirrored the epigenetic profile of recently recruited CD4 CD62L+ T cells in the tissue. Collectively, the data presented here show that the unique environment during autoimmune CD4 T cell priming allows T cells to finetune TCF1 expression to maintain long-term survival and function.
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Project description:The mechanisms behind survival of autoimmune CD4 T cells during chronic stimulation are unclear. Examining early time-points during T cell priming showed that activation of autoimmune CD4 T cells in the absence of infectious signals allowed maintenance of TCF1 expression, albeit at reduced levels. Tcf7 locus was epigenetically modified in circulating autoimmune CD4 T cells, suggesting a pre-programmed de novo methylation of the locus in early stages of autoimmune CD4 T cell differentiation which mirrored the epigenetic profile of recently recruited CD4 CD62L+ T cells in the tissue. Collectively, the data presented here show that the unique environment during autoimmune CD4 T cell priming allows T cells to finetune TCF1 expression to maintain long-term survival and function.
2024-10-12 | GSE273633 | GEO
Project description:Inappropriate activation or inadequate regulation of CD4+ and CD8+ T cells may contribute to the initiation and progression of multiple autoimmune and inflammatory diseases. Studies on disease-associated genetic polymorphisms have highlighted the importance of biological context for many regulatory variants, which is particularly relevant in understanding the genetic regulation of the immune system and its cellular phenotypes. Here we show cell type-specific regulation of transcript levels of genes associated with several autoimmune diseases in CD4+ and CD8+ T cells including a trans-acting regulatory locus at chr12q13.2 containing the rs1131017 SNP in the RPS26 gene. Most remarkably, we identify a common missense variant in IL27, associated with type 1 diabetes that results in decreased functional activity of the protein and reduced expression levels of downstream IRF1 and STAT1 in CD4+ T cells only. Altogether, our results indicate that eQTL mapping in purified T cells provides novel functional insights into polymorphisms and pathways associated with autoimmune diseases.
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Project description:Background & Aims: In most autoimmune disorders, crosstalk of B cells and CD4 T cells results in the accumulation of autoantibodies targeting specific self-antigen like the Soluble Liver Antigen (SLA or SepSecs) in autoimmune hepatitis (AIH). But the associated autoreactive CD4 T cells have not been characterized yet. Here we isolated and deeply characterized SLA-specific CD4 T cells in AIH patients. Methods: We used brief ex vivo re-stimulation with overlapping SLA-derived peptides to isolate and phenotype circulating SLA-specific CD4 T cells, and integrative single-cell RNA-seq (scRNA-seq) to characterize their transcriptome and T cell receptor (TCR) repertoire. Identified auto-reactive TCRs were reconstituted cloned and expressed in T cell hybridoma to identify dominant SLA-derived CD4 T cell epitopes. SLA-specific CD4 T cells were tracked in peripheral blood through TCR sequencing, to identify their phenotypic niche. We further characterized disease-associated peripheral blood T cells by high content flow cytometry in an additional cohort of n=42 AIH patients and n=17 non-alcoholic steatohepatitis (NASH) controls. Results: Frequency of autoreactive SLA-specific CD4 T cells was associated with anti-SLA autoantibodies and had a memory CD45RA-CD27+PD-1+CXCR5-CCR6- phenotype. ScRNA-seq revealed their pro-inflammatory/B-Helper profile (IL21, IFNG, TIGIT, CTLA4, NR3C1, CD109, KLRB1 and CLEC2D). SLA81-100 and SLA177-204 contain dominant T cell epitopes. Autoreactive TCR clonotypes were restricted to the memory PD-1+CXCR5- CD4 T cells which was significantly increased in the blood of AIH patients and supported B cell differentiation through IL-21. Finally, we identified a specific phenotype (CD45RA-PD-1+CD38+CXCR5-CD127-CD27+) of T cells linked to disease activity and IgG response during AIH. Conclusions: This work provides for the first time a deep characterization of rare circulating autoreactive CD4 T cells and the identification of their peripheral reservoir in AIH. We also propose a generic phenotype of pathogenic T cells related to AIH disease activity which will be essential to track, delineate and potentially target those pathogenic cells.
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Project description:The mechanisms behind survival of autoimmune CD4 T cells during chronic stimulation are unclear. Examining early time-points during T cell priming showed that activation of autoimmune CD4 T cells in the absence of infectious signals allowed maintenance of TCF1 expression, albeit at reduced levels. Tcf7 locus was epigenetically modified in circulating autoimmune CD4 T cells, suggesting a pre-programmed de novo methylation of the locus in early stages of autoimmune CD4 T cell differentiation which mirrored the epigenetic profile of recently recruited CD4 CD62L+ T cells in the tissue. Collectively, the data presented here show that the unique environment during autoimmune CD4 T cell priming allows T cells to finetune TCF1 expression to maintain long-term survival and function.
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Project description:Integrative molecular profiling of autoreactive CD4 T cells in autoimmune hepatitis
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