title: The transcription factor KLF2 restrains CD4⁺ T follicular helper cell differentiation.
abstract: T follicular helper (Tfh) cells are essential for efficient B cell responses, yet the factors that regulate differentiation of this CD4(+) T cell subset are incompletely understood. Here we found that the KLF2 transcription factor serves to restrain Tfh cell generation. Induced KLF2 deficiency in activated CD4(+) T cells led to increased Tfh cell generation and B cell priming, whereas KLF2 overexpression prevented Tfh cell production. KLF2 promotes expression of the trafficking receptor S1PR1, and S1PR1 downregulation is essential for efficient Tfh cell production. However, KLF2 also induced expression of the transcription factor Blimp-1, which repressed transcription factor Bcl-6 and thereby impaired Tfh cell differentiation. Furthermore, KLF2 induced expression of the transcription factors T-bet and GATA3 and enhanced Th1 differentiation. Hence, our data indicate KLF2 is pivotal for coordinating CD4(+) T cell differentiation through two distinct and complementary mechanisms: via control of T cell localization and by regulation of lineage-defining transcription factors.
authors.affiliation: Center for Immunology, University of Minnesota Medical School, Minneapolis, MN 55414, USA; Department of Laboratory Medicine and Pathology, University of Minnesota Medical School, Minneapolis, MN 55414, USA.
authors.forename: June-Yong
authors.initials: JY
authors.lastname: Lee
authors.affiliation: Center for Immunology, University of Minnesota Medical School, Minneapolis, MN 55414, USA; Department of Laboratory Medicine and Pathology, University of Minnesota Medical School, Minneapolis, MN 55414, USA.
authors.forename: Cara N
authors.initials: CN
authors.lastname: Skon
authors.affiliation: Center for Immunology, University of Minnesota Medical School, Minneapolis, MN 55414, USA; Department of Laboratory Medicine and Pathology, University of Minnesota Medical School, Minneapolis, MN 55414, USA.
authors.forename: You Jeong
authors.initials: YJ
authors.lastname: Lee
authors.affiliation: Howard Hughes Medical Institute; Department of Medicine, School of Medicine, University of California, San Diego, La Jolla, CA 92093, USA.
authors.forename: Soohwan
authors.initials: S
authors.lastname: Oh
authors.affiliation: Center for Immunology, University of Minnesota Medical School, Minneapolis, MN 55414, USA; Department of Microbiology, University of Minnesota Medical School, Minneapolis, MN 55414, USA.
authors.forename: Justin J
authors.initials: JJ
authors.lastname: Taylor
authors.affiliation: Center for Immunology, University of Minnesota Medical School, Minneapolis, MN 55414, USA; Department of Microbiology, University of Minnesota Medical School, Minneapolis, MN 55414, USA.
authors.forename: Deepali
authors.initials: D
authors.lastname: Malhotra
authors.affiliation: Center for Immunology, University of Minnesota Medical School, Minneapolis, MN 55414, USA; Department of Microbiology, University of Minnesota Medical School, Minneapolis, MN 55414, USA.
authors.forename: Marc K
authors.initials: MK
authors.lastname: Jenkins
authors.affiliation: Howard Hughes Medical Institute; Department of Medicine, School of Medicine, University of California, San Diego, La Jolla, CA 92093, USA.
authors.forename: M Geoffrey
authors.initials: MG
authors.lastname: Rosenfeld
authors.affiliation: Center for Immunology, University of Minnesota Medical School, Minneapolis, MN 55414, USA; Department of Laboratory Medicine and Pathology, University of Minnesota Medical School, Minneapolis, MN 55414, USA.
authors.forename: Kristin A
authors.initials: KA
authors.lastname: Hogquist
authors.affiliation: Center for Immunology, University of Minnesota Medical School, Minneapolis, MN 55414, USA; Department of Laboratory Medicine and Pathology, University of Minnesota Medical School, Minneapolis, MN 55414, USA. Electronic address: james024@umn.edu.
authors.forename: Stephen C
authors.initials: SC
authors.lastname: Jameson
mesh_terms: D019264:Adoptive Transfer; D000818:Animals; D015703:Antigens, CD / Q000096:biosynthesis; D000945:Antigens, Differentiation, T-Lymphocyte / Q000096:biosynthesis; D001402:B-Lymphocytes / Q000276:immunology; D002454:Cell Differentiation / Q000276:immunology*; D004268:DNA-Binding Proteins / Q000096:biosynthesis; D015536:Down-Regulation; D050990:GATA3 Transcription Factor / Q000096:biosynthesis; D055786:Gene Knockout Techniques; D051741:Kruppel-Like Transcription Factors / Q000096:biosynthesis / Q000235:genetics / Q000276:immunology*; D037181:Lectins, C-Type / Q000096:biosynthesis; D008213:Lymphocyte Activation / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D000074462:Positive Regulatory Domain I-Binding Factor 1; D051560:Proto-Oncogene Proteins c-bcl-6; D049349:Receptors, Lysosphingolipid / Q000096:biosynthesis / Q000378:metabolism; D000081025:Sphingosine-1-Phosphate Receptors; D020825:T-Box Domain Proteins / Q000096:biosynthesis; D018417:Th1 Cells / Q000166:cytology* / Q000276:immunology*; D014157:Transcription Factors / Q000096:biosynthesis / Q000378:metabolism; D000098815:T-bet Transcription Factor; D000099192:CD69 Antigens
chemical_list: D015703:Antigens, CD; D000945:Antigens, Differentiation, T-Lymphocyte; D004268:DNA-Binding Proteins; D050990:GATA3 Transcription Factor; D051741:Kruppel-Like Transcription Factors; D037181:Lectins, C-Type; D000074462:Positive Regulatory Domain I-Binding Factor 1; D051560:Proto-Oncogene Proteins c-bcl-6; D049349:Receptors, Lysosphingolipid; D000081025:Sphingosine-1-Phosphate Receptors; D020825:T-Box Domain Proteins; D014157:Transcription Factors; D000098815:T-bet Transcription Factor; D000099192:CD69 Antigens; C490010:Bcl6 protein, mouse; C494748:Gata3 protein, mouse; C498314:Klf2 protein, mouse; C513258:Prdm1 protein, mouse; C556330:S1pr1 protein, mouse