title: Gfi1-Foxo1 axis controls the fidelity of effector gene expression and developmental maturation of thymocytes.
abstract: Double-positive (DP) thymocytes respond to intrathymic T-cell receptor (TCR) signals by undergoing positive selection and lineage differentiation into single-positive (SP) mature cells. Concomitant with these well-characterized events is the acquisition of a mature T-cell gene expression program characterized by the induction of the effector molecules IL-7Rα, S1P1, and CCR7, but the underlying mechanism remains elusive. We report here that transcription repressor Growth factor independent 1 (Gfi1) orchestrates the fidelity of the DP gene expression program and developmental maturation into SP cells. Loss of Gfi1 resulted in premature induction of effector genes and the transcription factors forkhead box protein O1 (Foxo1) and Klf2 in DP thymocytes and the accumulation of postselection intermediate populations and accelerated transition into SP cells. Strikingly, partial loss of Foxo1 function, but not restored survival fitness, rectified the dysregulated gene expression and thymocyte maturation in Gfi1-deficient mice. Our results establish the Gfi1-Foxo1 axis and the transcriptional circuitry that actively maintain DP identity and shape the proper generation of mature T cells.
authors.affiliation: Department of Immunology, St. Jude Children's Research Hospital, Memphis, TN 38105.
authors.forename: Lewis Zhichang
authors.initials: LZ
authors.lastname: Shi
authors.affiliation: Department of Immunology, St. Jude Children's Research Hospital, Memphis, TN 38105.
authors.forename: Jordy
authors.initials: J
authors.lastname: Saravia
authors.affiliation: Department of Immunology, St. Jude Children's Research Hospital, Memphis, TN 38105.
authors.forename: Hu
authors.initials: H
authors.lastname: Zeng
authors.affiliation: Department of Immunology, St. Jude Children's Research Hospital, Memphis, TN 38105.
authors.forename: Nishan S
authors.initials: NS
authors.lastname: Kalupahana
authors.affiliation: Department of Immunology, St. Jude Children's Research Hospital, Memphis, TN 38105.
authors.forename: Clifford S
authors.initials: CS
authors.lastname: Guy
authors.affiliation: Hartwell Center for Bioinformatics and Biotechnology, St. Jude Children's Research Hospital, Memphis, TN 38105.
authors.forename: Geoffrey
authors.initials: G
authors.lastname: Neale
authors.affiliation: Department of Immunology, St. Jude Children's Research Hospital, Memphis, TN 38105; hongbo.chi@stjude.org.
authors.forename: Hongbo
authors.initials: H
authors.lastname: Chi
mesh_terms: D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology* / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000166:cytology* / Q000276:immunology; D002454:Cell Differentiation / Q000235:genetics*; D004268:DNA-Binding Proteins / Q000235:genetics* / Q000378:metabolism; D000071161:Forkhead Box Protein O1 / Q000235:genetics* / Q000378:metabolism; D005786:Gene Expression Regulation / Q000235:genetics / Q000276:immunology*; D051741:Kruppel-Like Transcription Factors / Q000235:genetics* / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D011948:Receptors, Antigen, T-Cell / Q000276:immunology; D013950:Thymus Gland / Q000166:cytology; D014157:Transcription Factors / Q000235:genetics* / Q000378:metabolism; D014158:Transcription, Genetic / Q000235:genetics; D015533:Transcriptional Activation / Q000235:genetics
chemical_list: D004268:DNA-Binding Proteins; D000071161:Forkhead Box Protein O1; C467200:Foxo1 protein, mouse; C079873:Gfi1 protein, mouse; C498314:Klf2 protein, mouse; D051741:Kruppel-Like Transcription Factors; D011948:Receptors, Antigen, T-Cell; D014157:Transcription Factors
keywords: Foxo1; Gfi1; apoptosis; thymocyte maturation; transcription repressor