title: Krüppel-like factor 4 (KLF4) directly regulates proliferation in thymocyte development and IL-17 expression during Th17 differentiation.
abstract: Krüppel-like factor 4 (KLF4), a transcription factor, plays a key role in the pluripotency of stem cells. We sought to determine the function of KLF4 in T-cell development and differentiation by using T-cell-specific Klf4-knockout (KO) mice. We found that KLF4 was highly expressed in thymocytes and mature T cells and was rapidly down-regulated in mature T cells after activation. In Klf4-KO mice, we observed a modest reduction of thymocytes (27%) due to the reduced proliferation of double-negative (DN) thymocytes. We demonstrated that a direct repression of Cdkn1b by KLF4 was a cause of decreased DN proliferation. During in vitro T-cell differentiation, we observed significant reduction of IL-17-expressing CD4(+) T cells (Th17; 24%) but not in other types of Th differentiation. The reduction of Th17 cells resulted in a significant attenuation of the severity (35%) of experimental autoimmune encephalomyelitis in vivo in Klf4-KO mice as compared with the Klf4 wild-type littermates. Finally, we demonstrated that KLF4 directly binds to the promoter of Il17a and positively regulates its expression. In summary, these findings identify KLF4 as a critical regulator in T-cell development and Th17 differentiation.
authors.affiliation: Laboratory of Molecular Biology and Immunology, National Institutes of Health, Baltimore, Maryland, USA.
authors.forename: Jie
authors.initials: J
authors.lastname: An
authors.forename: Susanne
authors.initials: S
authors.lastname: Golech
authors.forename: Jettanong
authors.initials: J
authors.lastname: Klaewsongkram
authors.forename: Yongqing
authors.initials: Y
authors.lastname: Zhang
authors.forename: Kalpana
authors.initials: K
authors.lastname: Subedi
authors.forename: Gail E
authors.initials: GE
authors.lastname: Huston
authors.forename: William H
authors.initials: WH
authors.lastname: Wood
authors.forename: Robert P
authors.initials: RP
authors.lastname: Wersto
authors.forename: Kevin G
authors.initials: KG
authors.lastname: Becker
authors.forename: Susan L
authors.initials: SL
authors.lastname: Swain
authors.forename: Nanping
authors.initials: N
authors.lastname: Weng
mesh_terms: D000818:Animals; D049109:Cell Proliferation; D050760:Cyclin-Dependent Kinase Inhibitor p27 / Q000235:genetics / Q000378:metabolism; D005786:Gene Expression Regulation / Q000502:physiology; D020381:Interleukin-17 / Q000235:genetics / Q000378:metabolism*; D000090062:Kruppel-Like Factor 4; D051741:Kruppel-Like Transcription Factors / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D058504:Th17 Cells / Q000166:cytology* / Q000378:metabolism*; D013950:Thymus Gland / Q000166:cytology*
chemical_list: C493961:Cdkn1b protein, mouse; C098680:Il17a protein, mouse; D020381:Interleukin-17; C000715468:Klf4 protein, mouse; D000090062:Kruppel-Like Factor 4; D051741:Kruppel-Like Transcription Factors; D050760:Cyclin-Dependent Kinase Inhibitor p27