title: ICOS coreceptor signaling inactivates the transcription factor FOXO1 to promote Tfh cell differentiation.
abstract: T follicular helper (Tfh) cells are essential in the induction of high-affinity, class-switched antibodies. The differentiation of Tfh cells is a multi-step process that depends upon the co-receptor ICOS and the activation of phosphoinositide-3 kinase leading to the expression of key Tfh cell genes. We report that ICOS signaling inactivates the transcription factor FOXO1, and a Foxo1 genetic deletion allowed for generation of Tfh cells with reduced dependence on ICOS ligand. Conversely, enforced nuclear localization of FOXO1 inhibited Tfh cell development even though ICOS was overexpressed. FOXO1 regulated Tfh cell differentiation through a broad program of gene expression exemplified by its negative regulation of Bcl6. Final differentiation to germinal center Tfh cells (GC-Tfh) was instead FOXO1 dependent as the Foxo1(-/-) GC-Tfh cell population was substantially reduced. We propose that ICOS signaling transiently inactivates FOXO1 to initiate a Tfh cell contingency that is completed in a FOXO1-dependent manner.
authors.affiliation: Department of Cellular and Molecular Medicine, School of Medicine, University of California, San Diego, 9500 Gilman Dr., La Jolla, CA 92093-0377, USA.
authors.forename: Erica L
authors.initials: EL
authors.lastname: Stone
authors.affiliation: Department of Immunology, University of Washington, 750 Republican Street, Seattle, WA 98109, USA.
authors.forename: Marion
authors.initials: M
authors.lastname: Pepper
authors.affiliation: Department of Cellular and Molecular Medicine, School of Medicine, University of California, San Diego, 9500 Gilman Dr., La Jolla, CA 92093-0377, USA.
authors.forename: Carol D
authors.initials: CD
authors.lastname: Katayama
authors.affiliation: Department of Cellular and Molecular Medicine, School of Medicine, University of California, San Diego, 9500 Gilman Dr., La Jolla, CA 92093-0377, USA.
authors.forename: Yann M
authors.initials: YM
authors.lastname: Kerdiles
authors.affiliation: Department of Cellular and Molecular Medicine, School of Medicine, University of California, San Diego, 9500 Gilman Dr., La Jolla, CA 92093-0377, USA.
authors.forename: Chen-Yen
authors.initials: CY
authors.lastname: Lai
authors.affiliation: College of Life Sciences, University of Dundee, Dow Street, Dundee, DD1 5EH, Scotland, UK.
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Emslie
authors.affiliation: Molecular Biology Section, Division of Biological Sciences, University of California San Diego, 9500 Gilman Dr., La Jolla, CA 92093-0377, USA.
authors.forename: Yin C
authors.initials: YC
authors.lastname: Lin
authors.affiliation: Molecular Biology Section, Division of Biological Sciences, University of California San Diego, 9500 Gilman Dr., La Jolla, CA 92093-0377, USA.
authors.forename: Edward
authors.initials: E
authors.lastname: Yang
authors.affiliation: Molecular Biology Section, Division of Biological Sciences, University of California San Diego, 9500 Gilman Dr., La Jolla, CA 92093-0377, USA.
authors.forename: Ananda W
authors.initials: AW
authors.lastname: Goldrath
authors.affiliation: Immunology Program, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, NY 10065, USA.
authors.forename: Ming O
authors.initials: MO
authors.lastname: Li
authors.affiliation: College of Life Sciences, University of Dundee, Dow Street, Dundee, DD1 5EH, Scotland, UK.
authors.forename: Doreen A
authors.initials: DA
authors.lastname: Cantrell
authors.affiliation: Department of Cellular and Molecular Medicine, School of Medicine, University of California, San Diego, 9500 Gilman Dr., La Jolla, CA 92093-0377, USA; Molecular Biology Section, Division of Biological Sciences, University of California San Diego, 9500 Gilman Dr., La Jolla, CA 92093-0377, USA. Electronic address: shedrick@ucsd.edu.
authors.forename: Stephen M
authors.initials: SM
authors.lastname: Hedrick
mesh_terms: D000818:Animals; D002454:Cell Differentiation / Q000276:immunology*; D004268:DNA-Binding Proteins / Q000096:biosynthesis*; D004789:Enzyme Activation; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors / Q000235:genetics* / Q000276:immunology; D005786:Gene Expression Regulation; D060889:Inducible T-Cell Co-Stimulator Protein / Q000276:immunology*; D008213:Lymphocyte Activation / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D051560:Proto-Oncogene Proteins c-bcl-6; D015398:Signal Transduction; D006377:T-Lymphocytes, Helper-Inducer / Q000166:cytology* / Q000276:immunology
chemical_list: C490010:Bcl6 protein, mouse; D004268:DNA-Binding Proteins; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors; C467200:Foxo1 protein, mouse; C556694:Icos protein, mouse; D060889:Inducible T-Cell Co-Stimulator Protein; D051560:Proto-Oncogene Proteins c-bcl-6; D019869:Phosphatidylinositol 3-Kinases