Abstract
MicroRNAs have emerged as key regulators in T cell development, activation, and differentiation, with miR-181a having a prominent function. By targeting several signaling pathways, miR-181a is an important rheostat controlling T cell receptor (TCR) activation thresholds in thymic selection as well as peripheral T cell responses. A decline in miR-181a expression, due to reduced transcription of pri-miR-181a, accounts for T cell activation defects that occur with older age. Here we examine the transcriptional regulation of miR-181a expression and find a putative pri-miR-181a enhancer around position 198,904,300 on chromosome 1, which is regulated by a transcription factor complex including YY1. The decline in miR-181a expression correlates with reduced transcription of YY1 in older individuals. Partial silencing of YY1 in T cells from young individuals reproduces the signaling defects seen in older T cells. In conclusion, YY1 controls TCR signaling by upregulating miR-181a and dampening negative feedback loops mediated by miR-181a targets.
Highlights
MicroRNAs have emerged as key regulators in T cell development, activation, and differentiation, with miR-181a having a prominent function
Based on our initial findings that naïve CD4 T cells from older individuals have reduced extracellular signal-related kinase (ERK) phosphorylation upon T cell receptor (TCR) stimulation, we have focused on miR181a. miR-181a is highly expressed in T cells and is dynamically regulated during activation and differentiation[28]
We had found a decline in miR-181a in naïve and, to a lesser extent, memory CD4 T cells with age impairing TCR sensitivity to respond to antigen stimulation[34]
Summary
MicroRNAs have emerged as key regulators in T cell development, activation, and differentiation, with miR-181a having a prominent function. By targeting several signaling pathways, miR-181a is an important rheostat controlling T cell receptor (TCR) activation thresholds in thymic selection as well as peripheral T cell responses. A decline in miR-181a expression, due to reduced transcription of pri-miR-181a, accounts for T cell activation defects that occur with older age. A single dominant functional defect, such as cellular senescence has not been found, and the overriding aging signature in cell biological studies of naïve and central memory T cells from older individuals is dominated by markers of accelerated differentiation[18]. MicroRNAs are known to be an important driver of differentiation Because they concomitantly reduce expression of many target molecules, their concerted activity may have a major influence the effect size on each of this molecules is small[26,27]. The decline in YY1 expression with age results in reduced miR-181a expression and concomitantly increased expression of DUSP6 and SIRT1 and the corresponding loss in TCR sensitivity to respond to stimulation
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
