FOXO1 regulates L-Selectin and a network of human T cell homing molecules downstream of phosphatidylinositol 3-kinase.
In T cells, the PI3K pathway promotes proliferation and survival induced by Ag or growth factors, in part by inactivating the FOXO transcription factor 1. We now report that FOXO1 controls the expression of L-selectin, an essential homing molecule, in human T lymphocytes. This control is already operational in unprimed T cells and involves a transcriptional regulation process that requires the FOXO1 DNA-binding domain. Using transcriptional profiling, we demonstrate that FOXO1 also increases transcripts of EDG1 and EDG6, two sphingosine-1-phosphate receptors that regulate lymphocyte trafficking. Additionally, FOXO1 binds the promoter of the cell quiescence and homing regulator Krüppel-like factor 2 and regulates its expression. Together, these results reveal a new function of FOXO1 in the immune system and suggest that PI3K controls a coordinated network of transcription factors regulating both cell quiescence and homing of human T lymphocytes.
Fabre
Stéphanie
S
Institut Cochin, Université Paris Descartes, Centre National de la Recherche Scientifique (Unité Mixte de Recherche 8104), Equipe labellisée par la Ligue Nationale contre le Cancer, Paris, France.
Carrette
Florent
F
Chen
Jing
J
Lang
Valérie
V
Semichon
Monique
M
Denoyelle
Christine
C
Lazar
Vladimir
V
Cagnard
Nicolas
N
Dubart-Kupperschmitt
Anne
A
Mangeney
Marianne
M
Fruman
David A
DA
Bismuth
Georges
G
D002478:Cells, Cultured; D002634:Chemotaxis, Leukocyte / Q000276:immunology*; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors / Q000276:immunology / Q000502:physiology*; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D006801:Humans; D051741:Kruppel-Like Transcription Factors / Q000235:genetics; D019041:L-Selectin / Q000235:genetics*; D019869:Phosphatidylinositol 3-Kinases / Q000502:physiology*; D014176:Protein Biosynthesis; D049349:Receptors, Lysosphingolipid / Q000235:genetics; D013601:T-Lymphocytes / Q000166:cytology*
C085126:FOXO1 protein, human; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors; C096161:KLF2 protein, human; D051741:Kruppel-Like Transcription Factors; D049349:Receptors, Lysosphingolipid; D019041:L-Selectin; D019869:Phosphatidylinositol 3-Kinases