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¹ Swiss Institute of Allergy and Asthma Research Davos, University of Zurich, CH-7270 Davos-Platz, Switzerland
² Howard Hughes Medical Institute, The Kimmel Center for Biology and Medicine of the Skirball Institute, New York University School of Medicine, New York, NY 10016

CORRESPONDENCE Cezmi A. Akdis: akdisac{at}siaf.uzh.ch

Forkhead box P3 (FOXP3)⁺CD4⁺CD25⁺ inducible regulatory T (iT reg) cells play an important role in immune tolerance and homeostasis. In this study, we show that the transforming growth factor-β (TGF-β) induces the expression of the Runt-related transcription factors RUNX1 and RUNX3 in CD4⁺ T cells. This induction seems to be a prerequisite for the binding of RUNX1 and RUNX3 to three putative RUNX binding sites in the FOXP3 promoter. Inactivation of the gene encoding RUNX cofactor core-binding factor-β (CBFβ) in mice and small interfering RNA (siRNA)-mediated suppression of RUNX1 and RUNX3 in human T cells resulted in reduced expression of Foxp3. The in vivo conversion of naive CD4⁺ T cells into Foxp3⁺ iT reg cells was significantly decreased in adoptively transferred Cbfb^F/F CD4-cre naive T cells into Rag2^–/– mice. Both RUNX1 and RUNX3 siRNA silenced human T reg cells and Cbfb^F/F CD4-cre mouse T reg cells showed diminished suppressive function in vitro. Circulating human CD4⁺ CD25^high CD127^– T reg cells significantly expressed higher levels of RUNX3, FOXP3, and TGF-β mRNA compared with CD4⁺CD25^– cells. Furthermore, FOXP3 and RUNX3 were colocalized in human tonsil T reg cells. These data demonstrate Runx transcription factors as a molecular link in TGF-β–induced Foxp3 expression in iT reg cell differentiation and function.

Abbreviations used: AML, acute myeloid leukemia; CBF, core-binding factor; ChIP, chromatin immunoprecipitation; iT reg, inducible T reg; NFAT, nuclear factor of activated T cells; nT reg, natural T reg; PEBP2, polyoma enhancer-binding protein-2; siRNA, small interfering RNA; T reg, regulatory T; TSS, transcription start site.

© 2009 Klunker et al.
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