Indispensable role of the Runx1-Cbfbeta transcription complex for in vivo-suppressive function of FoxP3+ regulatory T cells.
Naturally arising regulatory T (Treg) cells express the transcription factor FoxP3, which critically controls the development and function of Treg cells. FoxP3 interacts with another transcription factor Runx1 (also known as AML1). Here, we showed that Treg cell-specific deficiency of Cbfbeta, a cofactor for all Runx proteins, or that of Runx1, but not Runx3, induced lymphoproliferation, autoimmune disease, and hyperproduction of IgE. Cbfb-deleted Treg cells exhibited impaired suppressive function in vitro and in vivo, with altered gene expression profiles including attenuated expression of FoxP3 and high expression of interleukin-4. The Runx complex bound to more than 3000 gene loci in Treg cells, including the Foxp3 regulatory regions and the Il4 silencer. In addition, knockdown of RUNX1 showed that RUNX1 is required for the optimal regulation of FoxP3 expression in human T cells. Taken together, our results indicate that the Runx1-Cbfbeta heterodimer is indispensable for in vivo Treg cell function, in particular, suppressive activity and optimal expression of FoxP3.
Kitoh
Akihiko
A
Department of Experimental Pathology, Institute for Frontier Medical Sciences, Graduate School of Medicine, Kyoto University, Kyoto 606-8507, Japan.
Ono
Masahiro
M
Naoe
Yoshinori
Y
Ohkura
Naganari
N
Yamaguchi
Tomoyuki
T
Yaguchi
Hiroko
H
Kitabayashi
Issay
I
Tsukada
Toshihiko
T
Nomura
Takashi
T
Miyachi
Yoshiki
Y
Taniuchi
Ichiro
I
Sakaguchi
Shimon
S
D000818:Animals; D001327:Autoimmune Diseases / Q000276:immunology* / Q000378:metabolism; D003106:Colon / Q000276:immunology / Q000473:pathology; D050676:Core Binding Factor Alpha 2 Subunit / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D050658:Core Binding Factor beta Subunit / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D051858:Forkhead Transcription Factors / Q000276:immunology / Q000378:metabolism*; D015870:Gene Expression / Q000235:genetics / Q000276:immunology; D020869:Gene Expression Profiling; D007073:Immunoglobulin E / Q000096:biosynthesis / Q000276:immunology; D015847:Interleukin-4 / Q000096:biosynthesis / Q000276:immunology; D051379:Mice; D008807:Mice, Inbred BALB C; D016513:Mice, SCID; D013270:Stomach / Q000276:immunology / Q000473:pathology; D050378:T-Lymphocytes, Regulatory / Q000276:immunology* / Q000378:metabolism
C493693:Cbfb protein, mouse; D050676:Core Binding Factor Alpha 2 Subunit; D050658:Core Binding Factor beta Subunit; D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; C493726:Runx1 protein, mouse; D015847:Interleukin-4; D007073:Immunoglobulin E