title: Kruppel-like factor KLF10 targets transforming growth factor-beta1 to regulate CD4(+)CD25(-) T cells and T regulatory cells.
abstract: CD4(+)CD25(+) regulatory T cells (T regs) play a major role in the maintenance of self-tolerance and immune suppression, although the mechanisms controlling T reg development and suppressor function remain incompletely understood. Herein, we provide evidence that Kruppel-like factor 10 (KLF10/TIEG1) constitutes an important regulator of T regulatory cell suppressor function and CD4(+)CD25(-) T cell activation through distinct mechanisms involving transforming growth factor (TGF)-beta1 and Foxp3. KLF10 overexpressing CD4(+)CD25(-) T cells induced both TGF-beta1 and Foxp3 expression, an effect associated with reduced T-Bet (Th1 marker) and Gata3 (Th2 marker) mRNA expression. Consistently, KLF10(-/-) CD4(+)CD25(-) T cells have enhanced differentiation along both Th1 and Th2 pathways and elaborate higher levels of Th1 and Th2 cytokines. Furthermore, KLF10(-/-) CD4(+)CD25(-) T cell effectors cannot be appropriately suppressed by wild-type T regs. Surprisingly, KLF10(-/-) T reg cells have reduced suppressor function, independent of Foxp3 expression, with decreased expression and elaboration of TGF-beta1, an effect completely rescued by exogenous treatment with TGF-beta1. Mechanistic studies demonstrate that in response to TGF-beta1, KLF10 can transactivate both TGF-beta1 and Foxp3 promoters, implicating KLF10 in a positive feedback loop that may promote cell-intrinsic control of T cell activation. Finally, KLF10(-/-) CD4(+)CD25(-) T cells promoted atherosclerosis by approximately 2-fold in ApoE(-/-)/scid/scid mice with increased leukocyte accumulation and peripheral pro-inflammatory cytokines. Thus, KLF10 is a critical regulator in the transcriptional network controlling TGF-beta1 in both CD4(+)CD25(-) T cells and T regs and plays an important role in regulating atherosclerotic lesion formation in mice.
authors: Department of Medicine, Cardiovascular Division, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA.
authors: Zhuoxiao
authors: Z
authors: Cao
authors: Akm Khyrul
authors: AK
authors: Wara
authors: Basak
authors: B
authors: Icli
authors: Xinghui
authors: X
authors: Sun
authors: René R S
authors: RR
authors: Packard
authors: Fehim
authors: F
authors: Esen
authors: Christopher J
authors: CJ
authors: Stapleton
authors: Malayannan
authors: M
authors: Subramaniam
authors: Karsten
authors: K
authors: Kretschmer
authors: Irina
authors: I
authors: Apostolou
authors: Harald
authors: H
authors: von Boehmer
authors: Göran K
authors: GK
authors: Hansson
authors: Thomas C
authors: TC
authors: Spelsberg
authors: Peter
authors: P
authors: Libby
authors: Mark W
authors: MW
authors: Feinberg
mesh_terms: D000818:Animals; D050197:Atherosclerosis / Q000097:blood / Q000378:metabolism; D015496:CD4-Positive T-Lymphocytes / Q000378:metabolism*; D002469:Cell Separation; D016207:Cytokines / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000378:metabolism*; D005434:Flow Cytometry; D053645:Interleukin-2 Receptor alpha Subunit / Q000096:biosynthesis*; D051379:Mice; D008822:Mice, Transgenic; D008954:Models, Biological; D034741:RNA, Small Interfering / Q000378:metabolism; D050378:T-Lymphocytes, Regulatory / Q000378:metabolism*; D014157:Transcription Factors / Q000378:metabolism*; D053773:Transforming Growth Factor beta1 / Q000378:metabolism; D051741:Kruppel-Like Transcription Factors; D051765:Early Growth Response Transcription Factors
chemical_list: D016207:Cytokines; D004268:DNA-Binding Proteins; D053645:Interleukin-2 Receptor alpha Subunit; D034741:RNA, Small Interfering; D014157:Transcription Factors; D053773:Transforming Growth Factor beta1; C569958:KLF10 protein, mouse; D051741:Kruppel-Like Transcription Factors; D051765:Early Growth Response Transcription Factors