Dataset Information

Accumulation of NFAT mediates IL-2 expression in memory, but not naive, CD4+ T cells.

ABSTRACT: In contrast to naïve CD4+ T cells, memory CD4+ T cells rapidly express high levels of effector cytokines in response to antigen stimulation. The molecular mechanism for this specific behavior is not well understood. The nuclear factor of activated T cells (NFAT) family of transcription factors plays an important role in the transcription of many cytokine genes. Here we show that memory CD4+ T cells rapidly induce NFAT-mediated transcription upon T cell receptor ligation whereas NFAT activation in naïve CD4+ T cells requires longer periods of stimulation. The difference in kinetics correlates with the low levels of NFATc1 and NFATc2 proteins present in naïve CD4+ T cells and their high levels in memory CD4+ T cells. Accordingly, IL-2 expression requires NFAT activation only in memory CD4+ T cells whereas it is NFAT-independent in naïve CD4+ T cells. Thus, the accumulation of NFATc1 and NFATc2 in memory CD4+ T cells represents a previously uncharacterized regulatory mechanism for the induction of early gene expression after antigen stimulation.

SUBMITTER: Dienz O

PROVIDER: S-EPMC1855411 | biostudies-other | 2007 Apr

REPOSITORIES: biostudies-other

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Accumulation of NFAT mediates IL-2 expression in memory, but not naïve, CD4+ T cells.

Dienz Oliver O Eaton Sheri M SM Krahl Troy J TJ Diehl Sean S Charland Colette C Dodge John J Swain Susan L SL Budd Ralph C RC Haynes Laura L Rincon Mercedes M

Proceedings of the National Academy of Sciences of the United States of America 20070416 17

In contrast to naïve CD4+ T cells, memory CD4+ T cells rapidly express high levels of effector cytokines in response to antigen stimulation. The molecular mechanism for this specific behavior is not well understood. The nuclear factor of activated T cells (NFAT) family of transcription factors plays an important role in the transcription of many cytokine genes. Here we show that memory CD4+ T cells rapidly induce NFAT-mediated transcription upon T cell receptor ligation whereas NFAT activation i ...[more]

PMID: 17438271

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Project description:BACKGROUND:CD4+ T cells can be broadly divided into naïve and memory subsets, each of which are differentially impaired by the aging process. It is unclear if and how these differences are reflected at the transcriptomic level. We performed microarray profiling on RNA derived from naïve (CD44low) and memory (CD44high) CD4+ T cells derived from young (2-3 month) and old (28 month) mice, in order to better understand the mechanisms of age-related functional alterations in both subsets. We also performed follow-up bioinformatic analyses in order to determine the functional consequences of gene expression changes in both of these subsets, and identify regulatory factors potentially responsible for these changes. RESULTS:We found 185 and 328 genes differentially expressed (FDR???0.05) in young vs. old naïve and memory cells, respectively, with 50 genes differentially expressed in both subsets. Functional annotation analyses highlighted an increase in genes involved in apoptosis specific to aged naïve cells. Both subsets shared age-related increases in inflammatory signaling genes, along with a decrease in oxidative phosphorylation genes. Cis-regulatory analyses revealed enrichment of multiple transcription factor binding sites near genes with age-associated expression, in particular NF-?B and several forkhead box transcription factors. Enhancer associated histone modifications were enriched near genes down-regulated in naïve cells. Comparison of our results with previous mouse and human datasets indicates few overlapping genes overall, but suggest consistent up-regulation of Casp1 and Il1r2, and down-regulation of Foxp1 in both mouse and human CD4+ T cells. CONCLUSIONS:The transcriptomes of naïve and memory CD4+ T cells are distinctly affected by the aging process. However, both subsets exhibit a common increase inflammatory genes and decrease in oxidative phosphorylation genes. NF-?B, forkhead box, and Myc transcription factors are implicated as upstream regulators of these gene expression changes in both subsets, with enhancer histone modifications potentially driving unique changes unique to naïve cells. Finally we conclude that there is little overlap in age-related gene expression changes between humans and mice; however, age-related alterations in a small subset of genes may be conserved.

Dataset Information

Accumulation of NFAT mediates IL-2 expression in memory, but not naive, CD4+ T cells.

Publications

Accumulation of NFAT mediates IL-2 expression in memory, but not naïve, CD4+ T cells.

Similar Datasets

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