Abstract
The posttranscriptional mechanisms by which RNA binding proteins (RBPs) regulate T-cell differentiation and cytokine production in vivo remain unclear. The RBP HuR binds to labile mRNAs, usually leading to increases in mRNA stability and/or translation. Previous work demonstrated that HuR binds to the mRNAs encoding the Th2 transcription factor trans-acting T-cell-specific transcription factor (GATA-3) and Th2 cytokines interleukin (IL)-4 and IL-13, thereby regulating their expression. By using a novel conditional HuR knockout (KO) mouse in which HuR is deleted in activated T cells, we show that Th2-polarized cells from heterozygous HuR conditional (OX40-Cre HuR(fl/+)) KO mice had decreased steady-state levels of Gata3, Il4 and Il13 mRNAs with little changes at the protein level. Surprisingly, Th2-polarized cells from homozygous HuR conditional (OX40-Cre HuR(fl/fl)) KO mice showed increased Il2, Il4 and Il13 mRNA and protein via different mechanisms. Specifically, Il4 was transcriptionally upregulated in HuR KO T cells, whereas Il2 and Il13 mRNA stabilities increased. Additionally, when using the standard ovalbumin model of allergic airway inflammation, HuR conditional KO mice mounted a robust inflammatory response similar to mice with wild-type HuR levels. These results reveal a complex differential posttranscriptional regulation of cytokines by HuR in which gene dosage plays an important role. These findings may have significant implications in allergies and asthma, as well as autoimmune diseases and infection.
Highlights
The process of naive T-cell activation and differentiation toward polarized effector T cells tailors specific immunity against pathogens, while allowing tolerance against harmless allergens, commensal organisms or self-antigens in a healthy individual [1]
In our study, using this novel knockout mouse, we demonstrate that deleting HuR in activated T cells during Th2 polarization leads to paradoxical increases in IL-2, IL-4 and IL-13 cytokine production, targets that HuR normally positively regulates
Because of the described role of HuR in regulating cell growth and proliferation, we performed counting assays to assess the proliferative capabilities of HuR-depleted T cells and found that the absence of HuR had no effect on the ability of T cells to proliferate (Figure 1E)
Summary
The process of naive T-cell activation and differentiation toward polarized effector T cells tailors specific immunity against pathogens, while allowing tolerance against harmless allergens, commensal organisms or self-antigens in a healthy individual [1]. Certain diseases arise as a direct consequence of aberrant effector T-cell cytokine production or alterations in immune homeostasis [2]. Understanding the mechanisms involved in T-cell differentiation is critical. During T-cell activation, the cell undergoes rapid and dynamic changes with up to 50% of the changes in cell-specific gene expression occurring at the posttranscriptional level [3,4]. Chromatin remodeling and transcriptional activation are highly integrated with posttranscriptional mechanisms, which regulate the rate of mRNA transport, turnover and transla-
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