Showing papers by "Hyun-Dong Chang published in 2007"
TL;DR: The data suggest that expression of Foxp3 must be stabilized by epigenetic modification to allow the development of a permanent suppressor cell lineage, a finding of significant importance for therapeutic applications involving induction or transfer of Tregs and for the understanding of long-term cell lineage decisions.
Abstract: Compelling evidence suggests that the transcription factor Foxp3 acts as a master switch governing the development and function of CD4+ regulatory T cells (Tregs). However, whether transcriptional control of Foxp3 expression itself contributes to the development of a stable Treg lineage has thus far not been investigated. We here identified an evolutionarily conserved region within the foxp3 locus upstream of exon-1 possessing transcriptional activity. Bisulphite sequencing and chromatin immunoprecipitation revealed complete demethylation of CpG motifs as well as histone modifications within the conserved region in ex vivo isolated Foxp3+CD25+CD4+ Tregs, but not in naive CD25−CD4+ T cells. Partial DNA demethylation is already found within developing Foxp3+ thymocytes; however, Tregs induced by TGF-β in vitro display only incomplete demethylation despite high Foxp3 expression. In contrast to natural Tregs, these TGF-β–induced Foxp3+ Tregs lose both Foxp3 expression and suppressive activity upon restimulation in the absence of TGF-β. Our data suggest that expression of Foxp3 must be stabilized by epigenetic modification to allow the development of a permanent suppressor cell lineage, a finding of significant importance for therapeutic applications involving induction or transfer of Tregs and for the understanding of long-term cell lineage decisions.
1,147 citations
TL;DR: A potential anti‐inflammatory role for IL‐12 in Th1 recall responses is defined, while in primary Th1 responses IL‐ 12 is required to induce expression of the pro‐inflammatory cytokine IFN‐γ, in secondary Th1Responses IFN'γ re‐expression is independent ofIL‐12, which still is able to induceexpression of the anti‐ inflammatory cytokine IL‐10.
Abstract: In Th1 and Th2 memory lymphocytes, the genes for the cytokines interleukin (IL)-4 and interferon-gamma (IFN-gamma) are imprinted for expression upon restimulation. This cytokine memory is based on expression of the transcription factors T-bet for IFN-gamma, and GATA-3 for IL-4, and epigenetic modification of the cytokine genes. In Th2 cells, expression of the cytokine IL-10 is also induced by GATA-3. Here, we show that this induction is initially not accompanied by epigenetic modification of the IL-10 gene. Only after repeated restimulation of a memory Th2 cell in the presence of IL-4, extensive histone acetylation of the IL-10 gene is detectable. This epigenetic imprinting correlates with the development of a memory for IL-10 in repeatedly restimulated Th2 cells. In Th1 cells, IL-10 expression is induced by IL-12, but the IL-10 gene lacks detectable histone acetylation. Accordingly, IL-10 expression in restimulated memory Th1 cells remains conditional on the presence of IL-12. This finding defines a potential anti-inflammatory role for IL-12 in Th1 recall responses. While in primary Th1 responses IL-12 is required to induce expression of the pro-inflammatory cytokine IFN-gamma, in secondary Th1 responses IFN-gamma re-expression is independent of IL-12, which still is able to induce expression of the anti-inflammatory cytokine IL-10.
111 citations
TL;DR: The data indicate that IL10 does not become epigenetically marked in human memory Th cells unlike effector cytokine genes such as IFNG, which may reflect the need for appropriate regulation of IL-10 secretion, due to its potent immunoregulatory potential.
Abstract: Epigenetic modifications, including DNA methylation, profoundly influence gene expression of CD4(+) Th-specific cells thereby shaping memory Th cell function. We demonstrate here a correlation between a lacking fixed potential of human memory Th cells to re-express the immunoregulatory cytokine gene IL10 and its DNA methylation status. Memory Th cells secreting IL-10 or IFN-gamma were directly isolated ex vivo from peripheral blood of healthy volunteers, and the DNA methylation status of IL10 and IFNG was assessed. Limited difference in methylation was found for the IL10 gene locus in IL-10-secreting Th cells, as compared with Th cells not secreting IL-10 isolated directly ex vivo or from in vitro-established human Th1 and Th2 clones. In contrast, in IFN-gamma(+) memory Th cells the promoter of the IFNG gene was hypomethylated, as compared with IFN-gamma-nonsecreting memory Th cells. In accordance with the lack of epigenetic memory, almost 90% of ex vivo-isolated IL-10-secreting Th cells lacked a functional memory for IL-10 re-expression after restimulation. Our data indicate that IL10 does not become epigenetically marked in human memory Th cells unlike effector cytokine genes such as IFNG. The exclusion of IL-10, but not effector cytokines, from the functional memory of human CD4(+) T lymphocytes ex vivo may reflect the need for appropriate regulation of IL-10 secretion, due to its potent immunoregulatory potential.
51 citations
TL;DR: It has been demonstrated that Th1 cells are potent inducers of inflammation, however, in the chronic phase of such inflammation, the regulatory potential of IL-12 and Th 1 cells themselves may play an important role in limiting immunopathology.
Abstract: The differentiation of T-helper (Th) lymphocytes into various types of T-helper effector and memory cells with distinct functions depending on the type of concomitant signals they receive upon activation is a critical event determining the course of an immune reaction. Th1 cells characterized by the expression of IFN-gamma and the recently described Th17 cells promote inflammation and are critically involved in the induction and maintenance of autoimmunity, whereas the secretion of IL-4 is a hallmark of Th2 cells mediating protection from parasites and allergy. Original stimulation in the presence of IL-12 results in the imprinting of Th1 memory cells for the expression of IFN-gamma by expression of the transcription factor T-bet and epigenetic modification of the ifngamma gene. It has been demonstrated that Th1 cells are potent inducers of inflammation. However, in the chronic phase of such inflammation, the regulatory potential of IL-12 and Th1 cells themselves may play an important role in limiting immunopathology.
2 citations