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* 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;
Institut National de la Santé et de la Recherche Médicale, U567, Paris, France;
Department of Molecular Biology and Biochemistry, and Center for Immunology, University of California, Irvine, CA 92697;
Proteomic unit, Centro de Investigacion Cooperativa en Biociencias, Derio, Spain;
¶ Département de la Recherche Clinique et du Développement de l’Assistance Publique, Hôpitaux de Paris, Paris, France; and
|| Unité de Génomique Fonctionnelle, Institut Gustave Roussy, Villejuif, France
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.
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1 This work was supported by grants from Ligue Nationale contre le Cancer, Institut National de la Santé et de la Recherche Médicale, and Centre National de la Recherche Scientifique. S.F. was supported by a Ligue Nationale contre le Cancer Fellowship and F.C. by a Ministère de l’Education Nationale et de La Recherche doctoral Fellowship.
2 S.F. and F.C. contributed equally to this work.
3 Address correspondence and reprint requests to Dr. Georges Bismuth, Institut Cochin, 22 rue Méchain, 75014, Paris, France. E-mail address: bismuth{at}cochin inserm.fr
4 Abbreviations used in this paper: FOXO, forkhead box O; PTEN, phosphatase and tensin homolog; CFP, cyan fluorescent protein; ChIP, chromatin immunoprecipitation; sCD62L, soluble CD62L.
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  R. M. Hinman, W. A. Nichols, T. M. Diaz, T. D. Gallardo, D. H. Castrillon, and A. B. Satterthwaite Foxo3-/- mice demonstrate reduced numbers of pre-B and recirculating B cells but normal splenic B cell sub-population distribution Int. Immunol., July 1, 2009; 21(7): 831 - 842. [Abstract] [Full Text] [PDF]
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