Dataset Information

Decreased ERK and JNK signaling contribute to gene overexpression in "senescent" CD4+CD28- T cells through epigenetic mechanisms.

ABSTRACT: An inflammatory and cytotoxic CD4+CD28- T cell subset infiltrates atherosclerotic plaques and is implicated in plaque rupture and myocardial infarctions. This pathologic subset develops with replicative stress and is found in patients with chronic inflammatory diseases such as RA as well as with aging. CD4+CD28- cells overexpress genes normally suppressed by DNA methylation in CD4+CD28+ T cells, such as KIR, perforin, and CD70. How this subset over expresses methylation-sensitive genes is unknown. DNA methylation patterns are maintained in proliferating cells by Dnmts, which are up-regulated during mitosis by the ERK and JNK signaling pathways. We hypothesized that defects in these signaling pathways contribute to altered gene expression in human CD4+CD28- cells through effects on DNA methylation. We report that signaling through the ERK and JNK pathways is decreased in CD4+CD28- relative to CD4+CD28+ cells from the same individuals and that ERK and JNK pathway inhibition decreases Dnmt1 and -3a levels, which in turn, causes demethylation and overexpression of the TNFSF7 (CD70) gene. We also report that CD4+CD28- T cells overexpress PP5, a stress-induced inhibitor of the ERK and JNK signaling pathways that may contribute to the signaling defects. We conclude that decreased ERK and JNK signaling in the CD4+CD28- subset, arising with replicative stress, can lead to the overexpression of normally suppressed genes through effects on Dnmts and consequently, chromatin structure.

SUBMITTER: Chen Y

PROVIDER: S-EPMC2801623 | biostudies-literature | 2010 Jan

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Decreased ERK and JNK signaling contribute to gene overexpression in "senescent" CD4+CD28- T cells through epigenetic mechanisms.

Chen Yingxuan Y Gorelik Gabriela J GJ Strickland Faith M FM Richardson Bruce C BC

Journal of leukocyte biology 20091020 1

An inflammatory and cytotoxic CD4+CD28- T cell subset infiltrates atherosclerotic plaques and is implicated in plaque rupture and myocardial infarctions. This pathologic subset develops with replicative stress and is found in patients with chronic inflammatory diseases such as RA as well as with aging. CD4+CD28- cells overexpress genes normally suppressed by DNA methylation in CD4+CD28+ T cells, such as KIR, perforin, and CD70. How this subset over expresses methylation-sensitive genes is unknow ...[more]

PMID: 19843577

Similar Datasets

Project description:UnlabelledPlasmacytoid dendritic cells (pDCs) are the major source of type I IFN (IFN-I) in response to human immunodeficiency virus type 1 (HIV-1) infection. pDCs are rapidly activated during HIV-1 infection and are implicated in reducing the early viral load, as well as contributing to HIV-1-induced pathogenesis. However, most cell-free HIV-1 isolates are inefficient in activating human pDCs, and the mechanisms of HIV-1 recognition by pDCs and pDC activation are not clearly defined. In this study, we report that two genetically similar HIV-1 variants (R3A and R3B) isolated from a rapid progressor differentially activated pDCs to produce alpha interferon (IFN-?). The highly pathogenic R3A efficiently activated pDCs to induce robust IFN-? production, while the less pathogenic R3B did not. The viral determinant for efficient pDC activation was mapped to the V1V2 region of R3A Env, which also correlated with enhanced CD4 binding activity. Furthermore, we showed that the Nef protein was also required for the activation of pDCs by R3A. Analysis of a panel of R3A Nef functional mutants demonstrated that Nef domains involved in CD4 downregulation were necessary for R3A to activate pDCs. Our data indicate that R3A-induced pDC activation depends on (i) the high affinity of R3A Env for binding the CD4 receptor and (ii) Nef activity, which is involved in CD4 downregulation. Our findings provide new insights into the mechanism by which HIV-1 induces IFN-? in pDCs, which contributes to pathogenesis.ImportancePlasmacytoid dendritic cells (pDCs) are the major type I interferon (IFN-I)-producing cells, and IFN-I actually contributes to pathogenesis during chronic viral infections. How HIV-1 activates pDCs and the roles of pDCs/IFN-I in HIV-1 pathogenesis remain unclear. We report here that the highly pathogenic HIV R3A efficiently activated pDCs to induce IFN-? production, while most HIV-1 isolates are inefficient in activating pDCs. We have discovered that R3A-induced pDC activation depends on (i) the high affinity of R3A Env for binding the CD4 receptor and (ii) Nef activity, which is involved in CD4 downregulation. Our findings thus provide new insights into the mechanism by which HIV-1 induces IFN-? in pDCs and contributes to HIV-1 pathogenesis. These novel findings will be of great interest to those working on the roles of IFN and pDCs in HIV-1 pathogenesis in general and on the interaction of HIV-1 with pDCs in particular.

Dataset Information

Decreased ERK and JNK signaling contribute to gene overexpression in "senescent" CD4+CD28- T cells through epigenetic mechanisms.

Publications

Decreased ERK and JNK signaling contribute to gene overexpression in "senescent" CD4+CD28- T cells through epigenetic mechanisms.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets