Transcription factors RUNX1 and RUNX3 in the induction and suppressive function of Foxp3+ inducible regulatory T cells.
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-beta (TGF-beta) 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-beta (CBFbeta) 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-beta 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-beta-induced Foxp3 expression in iT reg cell differentiation and function.
Klunker
Sven
S
Swiss Institute of Allergy and Asthma Research Davos, University of Zurich, CH-7270 Davos-Platz, Switzerland.
Chong
Mark M W
MM
Mantel
Pierre-Yves
PY
Palomares
Oscar
O
Bassin
Claudio
C
Ziegler
Mario
M
Rückert
Beate
B
Meiler
Flurina
F
Akdis
Mübeccel
M
Littman
Dan R
DR
Akdis
Cezmi A
CA
D000818:Animals; D002454:Cell Differentiation / Q000235:genetics / Q000276:immunology; D050676:Core Binding Factor Alpha 2 Subunit / Q000235:genetics / Q000276:immunology*; D050677:Core Binding Factor Alpha 3 Subunit / Q000235:genetics / Q000276:immunology*; D050658:Core Binding Factor beta Subunit / Q000235:genetics / Q000276:immunology; D051858:Forkhead Transcription Factors / Q000235:genetics / Q000276:immunology*; D020868:Gene Silencing; D006801:Humans; D007108:Immune Tolerance / Q000502:physiology*; D051379:Mice; D018345:Mice, Knockout; D014066:Palatine Tonsil / Q000276:immunology; D011401:Promoter Regions, Genetic / Q000235:genetics / Q000276:immunology; D034741:RNA, Small Interfering; D050378:T-Lymphocytes, Regulatory / Q000276:immunology*; D016212:Transforming Growth Factor beta / Q000235:genetics / Q000276:immunology
C493692:CBFB protein, human; C493693:Cbfb protein, mouse; D050676:Core Binding Factor Alpha 2 Subunit; D050677:Core Binding Factor Alpha 3 Subunit; D050658:Core Binding Factor beta Subunit; C418974:FOXP3 protein, human; D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; D034741:RNA, Small Interfering; C493728:RUNX1 protein, human; C493726:Runx1 protein, mouse; C493729:Runx3 protein, human; C493730:Runx3 protein, mouse; D016212:Transforming Growth Factor beta