title: PLAU inferred from a correlation network is critical for suppressor function of regulatory T cells.
abstract: 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.
authors.affiliation: Department of Infection Genetics, Helmholtz Centre for Infection Research (HZI), University of Veterinary Medicine Hannover, Braunschweig, Germany.
authors.forename: Feng
authors.initials: F
authors.lastname: He
authors.forename: Hairong
authors.initials: H
authors.lastname: Chen
authors.forename: Michael
authors.initials: M
authors.lastname: Probst-Kepper
authors.forename: Robert
authors.initials: R
authors.lastname: Geffers
authors.forename: Serge
authors.initials: S
authors.lastname: Eifes
authors.forename: Antonio
authors.initials: A
authors.lastname: Del Sol
authors.forename: Klaus
authors.initials: K
authors.lastname: Schughart
authors.forename: An-Ping
authors.initials: AP
authors.lastname: Zeng
authors.forename: Rudi
authors.initials: R
authors.lastname: Balling
mesh_terms: D000818:Animals; D016207:Cytokines / Q000235:genetics / Q000378:metabolism; D015536:Down-Regulation / Q000235:genetics; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D051858:Forkhead Transcription Factors; D055785:Gene Knockdown Techniques; D006801:Humans; D018960:Hyaluronan Receptors / Q000378:metabolism; D019041:L-Selectin / Q000378:metabolism; D020935:MAP Kinase Signaling System; D051379:Mice; D018345:Mice, Knockout; D050799:STAT5 Transcription Factor / Q000378:metabolism; D015398:Signal Transduction / Q000235:genetics; D050378:T-Lymphocytes, Regulatory / Q000201:enzymology / Q000378:metabolism*; D013997:Time Factors; D059467:Transcriptome / Q000235:genetics; D014568:Urokinase-Type Plasminogen Activator / Q000235:genetics / Q000378:metabolism*
chemical_list: D016207:Cytokines; C418974:FOXP3 protein, human; D051858:Forkhead Transcription Factors; D018960:Hyaluronan Receptors; D050799:STAT5 Transcription Factor; D019041:L-Selectin; D048049:Extracellular Signal-Regulated MAP Kinases; D014568:Urokinase-Type Plasminogen Activator