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- Nestor, Colm, et al.
(författare)
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5-Hydroxymethylcytosine Remodeling Precedes Lineage Specification during Differentiation of Human CD4(+) T Cells
- 2016
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Ingår i: Cell Reports. - : CELL PRESS. - 2211-1247. ; 16:2, s. 559-570
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Tidskriftsartikel (refereegranskat)abstract
- 5-methylcytosine (5mC) is converted to 5-hydroxymethylcytosine (5hmC) by the TET family of enzymes as part of a recently discovered active DNA de-methylation pathway. 5hmC plays important roles in regulation of gene expression and differentiation and has been implicated in T cell malignancies and autoimmunity. Here, we report early and widespread 5mC/5hmC remodeling during human CD4(+) T cell differentiation ex vivo at genes and cell-specific enhancers with known T cell function. We observe similar DNA de-methylation in CD4(+) memory T cells in vivo, indicating that early remodeling events persist long term in differentiated cells. Underscoring their important function, 5hmC loci were highly enriched for genetic variants associated with T cell diseases and T-cell-specific chromosomal interactions. Extensive functional validation of 22 risk variants revealed potentially pathogenic mechanisms in diabetes and multiple sclerosis. Our results support 5hmC-mediated DNA de-methylation as a key component of CD4(+) T cell biology in humans, with important implications for gene regulation and lineage commitment.
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- Yang, M., et al.
(författare)
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Regulatory T cells control epitope spreading in autoimmune arthritis independent of cytotoxic T-lymphocyte antigen-4 VOL EA, 1995, IMMUNITY, V3, P541
- 2018
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Ingår i: Immunology. - : Wiley. - 0019-2805 .- 1365-2567. ; 155:4, s. 446-457
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Tidskriftsartikel (refereegranskat)abstract
- CD4(+) Foxp3(+) regulatory T (Treg) cells can control both cellular and humoral immune responses; however, when and how Treg cells play a predominant role in regulating autoimmune disease remains elusive. To deplete Treg cells in vivo at given time-points, we used a mouse strain, susceptible to glucose-6-phosphate isomerase peptide-induced arthritis (GIA), in which the deletion of Treg cells can be controlled by diphtheria toxin treatment. By depleting Treg cells in the GIA mouse model, we found that a temporary lack of Treg cells at both priming and onset exaggerated disease development. Ablation of Treg cells led to the expansion of antigen-specific CD4(+) T cells including granulocyte-macrophage colony-stimulating factor, interferon-gamma and interleukin-17-producing T cells, and promoted both T-cell and B-cell epitope spreading, which perpetuated arthritis. Interestingly, specific depletion of cytotoxic T-lymphocyte antigen-4 (CTLA-4) on Treg cells only, was sufficient to protect mice from GIA, due to the expansion of CTLA-4(-) Treg cells expressing alternative suppressive molecules. Collectively, our findings suggest that Treg cells, independently of CTLA-4, act as the key driving force in controlling autoimmune arthritis development.
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