title: Krüppel-like factor KLF10 regulates transforming growth factor receptor II expression and TGF-β signaling in CD8+ T lymphocytes.
abstract: KLF10 has recently elicited significant attention as a transcriptional regulator of transforming growth factor-β1 (TGF-β1) signaling in CD4(+) T cells. In the current study, we demonstrate a novel role for KLF10 in the regulation of TGF-β receptor II (TGF-βRII) expression with functional relevance in antiviral immune response. Specifically, we show that KLF10-deficient mice have an increased number of effector/memory CD8(+) T cells, display higher levels of the T helper type 1 cell-associated transcription factor T-bet, and produce more IFN-γ following in vitro stimulation. In addition, KLF10(-/-) CD8(+) T cells show enhanced proliferation in vitro and homeostatic proliferation in vivo. Freshly isolated CD8(+) T cells from the spleen of adult mice express lower levels of surface TGF-βRII (TβRII). Congruently, in vitro activation of KLF10-deficient CD8(+) T cells upregulate TGF-βRII to a lesser extent compared with wild-type (WT) CD8(+) T cells, which results in attenuated Smad2 phosphorylation following TGF-β1 stimulation compared with WT CD8(+) T cells. Moreover, we demonstrate that KLF10 directly binds to the TGF-βRII promoter in T cells, leading to enhanced gene expression. In vivo viral infection with Daniel's strain Theiler's murine encephalomyelitis virus (TMEV) also led to lower expression of TGF-βRII among viral-specific KLF10(-/-) CD8(+) T cells and a higher percentage of IFN-γ-producing CD8(+) T cells in the spleen. Collectively, our data reveal a critical role for KLF10 in the transcriptional activation of TGF-βRII in CD8(+) T cells. Thus, KLF10 regulation of TGF-βRII in this cell subset may likely play a critical role in viral and tumor immune responses for which the integrity of the TGF-β1/TGF-βRII signaling pathway is crucial.
authors.affiliation: Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota;
authors.forename: Konstantinos A
authors.initials: KA
authors.lastname: Papadakis
authors.affiliation: Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota;
authors.forename: James
authors.initials: J
authors.lastname: Krempski
authors.affiliation: Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota;
authors.forename: Jesse
authors.initials: J
authors.lastname: Reiter
authors.affiliation: Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota;
authors.forename: Phyllis
authors.initials: P
authors.lastname: Svingen
authors.affiliation: Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota;
authors.forename: Yuning
authors.initials: Y
authors.lastname: Xiong
authors.affiliation: Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota;
authors.forename: Olga F
authors.initials: OF
authors.lastname: Sarmento
authors.affiliation: Division of Immunology and Neurology, Mayo Clinic, Rochester, Minnesota; and.
authors.forename: April
authors.initials: A
authors.lastname: Huseby
authors.affiliation: Division of Immunology and Neurology, Mayo Clinic, Rochester, Minnesota; and.
authors.forename: Aaron J
authors.initials: AJ
authors.lastname: Johnson
authors.affiliation: Epigenetics and Chromatin Dynamics Laboratory, Departments of Medicine and Biochemistry and Molecular Biology, Epigenetic Translational Program, Center for Individualized Medicine, Mayo Clinic, Rochester, Minnesota.
authors.forename: Gwen A
authors.initials: GA
authors.lastname: Lomberk
authors.affiliation: Epigenetics and Chromatin Dynamics Laboratory, Departments of Medicine and Biochemistry and Molecular Biology, Epigenetic Translational Program, Center for Individualized Medicine, Mayo Clinic, Rochester, Minnesota.
authors.forename: Raul A
authors.initials: RA
authors.lastname: Urrutia
authors.affiliation: Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota; faubion.william@mayo.edu.
authors.forename: William A
authors.initials: WA
authors.lastname: Faubion
mesh_terms: D000818:Animals; D018414:CD8-Positive T-Lymphocytes / Q000378:metabolism*; D002478:Cells, Cultured; D051765:Early Growth Response Transcription Factors / Q000172:deficiency / Q000502:physiology*; D005786:Gene Expression Regulation; D006801:Humans; D019169:Jurkat Cells; D051741:Kruppel-Like Transcription Factors / Q000172:deficiency / Q000502:physiology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D017346:Protein Serine-Threonine Kinases / Q000096:biosynthesis*; D000077294:Receptor, Transforming Growth Factor-beta Type II; D018125:Receptors, Transforming Growth Factor beta / Q000096:biosynthesis*; D016212:Transforming Growth Factor beta / Q000096:biosynthesis*
chemical_list: D051765:Early Growth Response Transcription Factors; C569958:KLF10 protein, mouse; D051741:Kruppel-Like Transcription Factors; D018125:Receptors, Transforming Growth Factor beta; D016212:Transforming Growth Factor beta; D017346:Protein Serine-Threonine Kinases; D000077294:Receptor, Transforming Growth Factor-beta Type II
keywords: KLF10; Krüppel-like factor; T regulatory cell; TGF-β receptor II