Journal
JOURNAL OF EXPERIMENTAL MEDICINE
Volume 210, Issue 2, Pages 417-432Publisher
ROCKEFELLER UNIV PRESS
DOI: 10.1084/jem.20111717
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Funding
- National Institutes of Health [R56AI089828, R01HL109102, R01DA026065, R01GM08078]
- Dana Foundation
- Burroughs Wellcome Fund [CABS 1006173]
- University of California San Francisco Program for Breakthrough Biomedical Research
- Sandler Asthma Basic Research Center
- German Research Foundation (DFG) [HE 3359/3-1]
- National Science Foundation [2009057510]
- Boehringer Ingelheim Foundation
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Activation induces extensive changes in the gene expression program of naive CD4(+) T cells, promoting their differentiation into helper T cells that coordinate immune responses. MicroRNAs (miRNAs) play a critical role in this process, and miRNA expression also changes dramatically during T cell differentiation. Quantitative analyses revealed that T cell activation induces global posttranscriptional miRNA down-regulation in vitro and in vivo. Argonaute (Ago) proteins, the core effector proteins of the miRNA-induced silencing complex (miRISC), were also posttranscriptionally down-regulated during T cell activation. Ago2 was inducibly ubiquitinated in activated T cells and its down-regulation was inhibited by the proteasome inhibitor MG132. Therefore, activation-induced miRNA down-regulation likely occurs at the level of miRISC turnover. Measurements of miRNA-processing intermediates uncovered an additional layer of activation-induced, miRNA-specific transcriptional regulation. Thus, transcriptional and posttranscriptional mechanisms cooperate to rapidly reprogram the miRNA repertoire in differentiating T cells. Altering Ago2 expression in T cells revealed that Ago proteins are limiting factors that determine miRNA abundance. Naive T cells with reduced Ago2 and miRNA expression differentiated more readily into cytokine-producing helper T cells, suggesting that activation-induced miRNA down-regulation promotes acquisition of helper T cell effector functions by relaxing the repression of genes that direct T cell differentiation.
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