An essential role of the Forkhead-box transcription factor Foxo1 in control of T cell homeostasis and tolerance.
Members of the Forkhead box O (Foxo) family of transcription factors are key regulators of cellular responses, but their function in the immune system remains incompletely understood. Here we showed that T cell-specific deletion of Foxo1 gene in mice led to spontaneous T cell activation, effector T cell differentiation, autoantibody production, and the induction of inflammatory bowel disease in a transfer model. In addition, Foxo1 was critical for the maintenance of naive T cells in the peripheral lymphoid organs. Transcriptome analyses of T cells identified Foxo1-regulated genes encoding, among others, cell-surface molecules, signaling proteins, and nuclear factors that control gene expression. Functional studies validated interleukin-7 receptor-alpha as a Foxo1 target gene essential for Foxo1 maintenance of naive T cells. These findings reveal crucial functions of Foxo1-dependent transcription in control of T cell homeostasis and tolerance.
Ouyang
Weiming
W
Immunology Program, Memorial Sloan-Kettering Cancer Center, New York, NY 10065, USA.
Beckett
Omar
O
Flavell
Richard A
RA
Li
Ming O
MO
D000818:Animals; D001483:Base Sequence; D018797:Cell Cycle Proteins / Q000235:genetics; D002478:Cells, Cultured; D003001:Cloning, Molecular; D044783:F-Box Proteins; D005434:Flow Cytometry; D051858:Forkhead Transcription Factors / Q000235:genetics / Q000276:immunology / Q000502:physiology*; D006706:Homeostasis; D006801:Humans; D007108:Immune Tolerance; D051379:Mice; D008969:Molecular Sequence Data; D009419:Nerve Tissue Proteins / Q000235:genetics; D020395:Receptors, Interleukin-7 / Q000378:metabolism; D044843:SKP Cullin F-Box Protein Ligases / Q000235:genetics; D013601:T-Lymphocytes / Q000276:immunology*
D018797:Cell Cycle Proteins; D044783:F-Box Proteins; C485508:FBXO2 protein, human; D051858:Forkhead Transcription Factors; D009419:Nerve Tissue Proteins; D020395:Receptors, Interleukin-7; C479752:FBXO6 protein, human; D044843:SKP Cullin F-Box Protein Ligases