Journal Article

PLAU inferred from a correlation network is critical for suppressor function of regulatory T cells

Probst‐Kepper, Michael, Geffers, Robert, del Sol, Antonio, He, Feng, Schughart, Klaus, Eifes, Serge, Balling, Rudi, Chen, Hairong, Zeng, An‐Ping

2012

Overview

Human FOXP3 + CD25 + CD4 + regulatory T cells (Tregs) are essential to the maintenance of immune homeostasis. Several genes are known to be important for murine Tregs, but for human Tregs the genes and underlying molecular networks controlling the suppressor function still largely remain unclear. Here, we describe a strategy to identify the key genes directly from an undirected correlation network which we reconstruct from a very high time‐resolution (HTR) transcriptome during the activation of human Tregs/CD4 + T‐effector cells. We show that a predicted top‐ranked new key gene PLAU (the plasminogen activator urokinase) is important for the suppressor function of both human and murine Tregs. Further analysis unveils that PLAU is particularly important for memory Tregs and that PLAU mediates Treg suppressor function via STAT5 and ERK signaling pathways. Our study demonstrates the potential for identifying novel key genes for complex dynamic biological processes using a network strategy based on HTR data, and reveals a critical role for PLAU in Treg suppressor function. Network‐based analysis of transcriptome dynamics during activation in two human T‐cell subpopulations identifies key regulators, and reveals that PLAU plays a critical role in both human and murine regulatory T‐cell function. Synopsis Network‐based analysis of transcriptome dynamics during activation in two human T‐cell subpopulations identifies key regulators, and reveals that PLAU plays a critical role in both human and murine regulatory T‐cell function. We construct a Treg‐specific correlation network from a high time‐resolution transcriptome of human Tregs versus CD4 + T effector cells measured during their very early activation process. We propose a queen bee‐surrounding principle to predict key candidate genes from the simplified undirected correlation network rather than an advanced directed transcription regulatory network. These potential key genes would have not been easily identified by a differential expression analysis. We show that the plasminogen activator urokinase (PLAU) is critical for suppressor function of both human and murine Tregs. We further demonstrate that PLAU is particularly important for memory Tregs and that PLAU mediates Treg suppressor function via STAT5 and ERK signaling pathways.

• Publisher: Nature Publishing Group UK,John Wiley & Sons, Ltd,EMBO Press,Nature Publishing Group,Springer Nature
• Subject: Animals / Biological activity / CD25 antigen / CD4 antigen / Cytokines - genetics / Cytokines - metabolism / Disease / Down-Regulation - genetics / Effector cells / EMBO19 / EMBO26 / Experiments / Extracellular Signal-Regulated MAP Kinases - metabolism / Forkhead Transcription Factors / Foxp3 protein / Gene expression / Gene Knockdown Techniques / Genes / Genomes / high time‐resolution time series / Homeostasis / human CD4 regulatory T cell / Humans / Hyaluronan Receptors - metabolism / Immunoregulation / infer key genes from undirected gene networks / L-Selectin - metabolism / Lymphocytes / Lymphocytes T / MAP Kinase Signaling System / Mice / Mice, Knockout / Plau knockout mice / Signal Transduction - genetics / Stat5 protein / STAT5 Transcription Factor - metabolism / T-Lymphocytes, Regulatory - enzymology / T-Lymphocytes, Regulatory - metabolism / Time Factors / Transcriptome - genetics / Treg development and suppressor function / U-Plasminogen activator / Urokinase / Urokinase-Type Plasminogen Activator - genetics / Urokinase-Type Plasminogen Activator - metabolism