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Cao, Z.* ; Wara, A.K.* ; Icli, B.* ; Sun, X.* ; Packard, R.R.* ; Esen, F.* ; Stapleton, C.J.* ; Subramaniam, M.* ; Kretschmer, K.* ; Apostolou, I.* ; von Boehmer, H.* ; Hansson, G.K.* ; Spelsberg, T.C.* ; Libby, P.* ; Feinberg, M.W.*

Kruppel-like factor KLF10 targets transforming growth factor-beta1 to regulate CD4+ CD25- T cells and T regulatory cells.

J. Biol. Chem. 284, 24914-24924 (2009)
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Open Access Green as soon as Postprint is submitted to ZB.
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.
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Publication type Article: Journal article
Document type Scientific Article
ISSN (print) / ISBN 0021-9258
e-ISSN 1083-351X
Quellenangaben Volume: 284, Issue: 37, Pages: 24914-24924 Article Number: , Supplement: ,
Publisher American Society for Biochemistry and Molecular Biology
Reviewing status Peer reviewed
Institute(s) Institute for Pancreatic Beta Cell Research (IPI)