title: The transcription factor Foxp1 is a critical negative regulator of the differentiation of follicular helper T cells.
abstract: CD4(+) follicular helper T cells (T(FH) cells) are essential for germinal center (GC) responses and long-lived antibody responses. Here we report that naive CD4(+) T cells deficient in the transcription factor Foxp1 'preferentially' differentiated into T(FH) cells, which resulted in substantially enhanced GC and antibody responses. We found that Foxp1 used both constitutive Foxp1A and Foxp1D induced by stimulation of the T cell antigen receptor (TCR) to inhibit the generation of T(FH) cells. Mechanistically, Foxp1 directly and negatively regulated interleukin 21 (IL-21); Foxp1 also dampened expression of the costimulatory molecule ICOS and its downstream signaling at early stages of T cell activation, which rendered Foxp1-deficient CD4(+) T cells partially resistant to blockade of the ICOS ligand (ICOSL) during T(FH) cell development. Our findings demonstrate that Foxp1 is a critical negative regulator of T(FH) cell differentiation.
authors.affiliation: The Wistar Institute, Philadelphia, Pennsylvania, USA.
authors.forename: Haikun
authors.initials: H
authors.lastname: Wang
authors.affiliation: 1] The Wistar Institute, Philadelphia, Pennsylvania, USA. [2].
authors.forename: Jianlin
authors.initials: J
authors.lastname: Geng
authors.affiliation: 1] The Wistar Institute, Philadelphia, Pennsylvania, USA. [2].
authors.forename: Xiaomin
authors.initials: X
authors.lastname: Wen
authors.affiliation: The Wistar Institute, Philadelphia, Pennsylvania, USA.
authors.forename: Enguang
authors.initials: E
authors.lastname: Bi
authors.affiliation: The Wistar Institute, Philadelphia, Pennsylvania, USA.
authors.forename: Andrew V
authors.initials: AV
authors.lastname: Kossenkov
authors.affiliation: The Wistar Institute, Philadelphia, Pennsylvania, USA.
authors.forename: Amaya I
authors.initials: AI
authors.lastname: Wolf
authors.affiliation: Whitehead Institute for Biomedical Research, Cambridge, Massachusetts, USA.
authors.forename: Jeroen
authors.initials: J
authors.lastname: Tas
authors.affiliation: La Jolla Institute for Allergy & Immunology, La Jolla, California, USA.
authors.forename: Youn Soo
authors.initials: YS
authors.lastname: Choi
authors.affiliation: The Wistar Institute, Philadelphia, Pennsylvania, USA.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Takata
authors.affiliation: The Wistar Institute, Philadelphia, Pennsylvania, USA.
authors.forename: Timothy J
authors.initials: TJ
authors.lastname: Day
authors.affiliation: The Wistar Institute, Philadelphia, Pennsylvania, USA.
authors.forename: Li-Yuan
authors.initials: LY
authors.lastname: Chang
authors.affiliation: The Wistar Institute, Philadelphia, Pennsylvania, USA.
authors.forename: Stephanie L
authors.initials: SL
authors.lastname: Sprout
authors.affiliation: The Wistar Institute, Philadelphia, Pennsylvania, USA.
authors.forename: Emily K
authors.initials: EK
authors.lastname: Becker
authors.affiliation: The Wistar Institute, Philadelphia, Pennsylvania, USA.
authors.forename: Jessica
authors.initials: J
authors.lastname: Willen
authors.affiliation: The Wistar Institute, Philadelphia, Pennsylvania, USA.
authors.forename: Lifeng
authors.initials: L
authors.lastname: Tian
authors.affiliation: The Wistar Institute, Philadelphia, Pennsylvania, USA.
authors.forename: Xinxin
authors.initials: X
authors.lastname: Wang
authors.affiliation: Department of Immunology and Microbial Science, The Scripps Research Institute, La Jolla, California, USA.
authors.forename: Changchun
authors.initials: C
authors.lastname: Xiao
authors.affiliation: The Wistar Institute, Philadelphia, Pennsylvania, USA.
authors.forename: Ping
authors.initials: P
authors.lastname: Jiang
authors.affiliation: La Jolla Institute for Allergy & Immunology, La Jolla, California, USA.
authors.forename: Shane
authors.initials: S
authors.lastname: Crotty
authors.affiliation: Whitehead Institute for Biomedical Research, Cambridge, Massachusetts, USA.
authors.forename: Gabriel D
authors.initials: GD
authors.lastname: Victora
authors.affiliation: The Wistar Institute, Philadelphia, Pennsylvania, USA.
authors.forename: Louise C
authors.initials: LC
authors.lastname: Showe
authors.affiliation: Department of Molecular Genetics and The Institute for Cellular and Molecular Biology, The University of Texas at Austin, Texas, USA.
authors.forename: Haley O
authors.initials: HO
authors.lastname: Tucker
authors.affiliation: The Wistar Institute, Philadelphia, Pennsylvania, USA.
authors.forename: Jan
authors.initials: J
authors.lastname: Erikson
authors.affiliation: The Wistar Institute, Philadelphia, Pennsylvania, USA.
authors.forename: Hui
authors.initials: H
authors.lastname: Hu
mesh_terms: D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D002454:Cell Differentiation; D051858:Forkhead Transcription Factors / Q000502:physiology*; D060889:Inducible T-Cell Co-Stimulator Protein / Q000235:genetics; D007378:Interleukins / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D011948:Receptors, Antigen, T-Cell / Q000502:physiology; D012097:Repressor Proteins / Q000502:physiology*; D006377:T-Lymphocytes, Helper-Inducer / Q000166:cytology*; D000098546:Interleukin-21
chemical_list: D051858:Forkhead Transcription Factors; C432917:Foxp1 protein, mouse; C556694:Icos protein, mouse; D060889:Inducible T-Cell Co-Stimulator Protein; D007378:Interleukins; D011948:Receptors, Antigen, T-Cell; D012097:Repressor Proteins; D000098546:Interleukin-21