Regulatory T cells (Treg cells) are essential for self-tolerance and immune homeostasis. Lack of effector T cell (Teff cell) function and gain of suppressive activity by Treg cells are dependent on the transcriptional program induced by Foxp3. Here we report that repression of SATB1, a genome organizer that regulates chromatin structure and gene expression, was crucial for the phenotype and function of Treg cells. Foxp3, acting as a transcriptional repressor, directly suppressed the SATB1 locus and indirectly suppressed it through the induction of microRNAs that bound the SATB1 3′ untranslated region. Release of SATB1 from the control of Foxp3 in Treg cells caused loss of suppressive function, establishment of transcriptional Teff cell programs and induction of Teff cell cytokines. Our data support the proposal that inhibition of SATB1-mediated modulation of global chromatin remodeling is pivotal for maintaining Treg cell functionality.
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We thank M. Mai, M. Kraut, S. Keller, N. Kuhn, J. Birke, I. Büchmann, A. Dolf and P. Wurst for technical assistance; M. Hoch, M. Pankratz, S. Burgdorf, A. Popov and A. Staratschek-Jox, as well as all other laboratory members, for discussions; and J. Oldenburg for blood samples from healthy subjects. Supported by the German Research Foundation (Sonderforschungsbereich 832, SFB 704, INST 217/576-1 and INST 217/577-1 to J.L.S. and M.B.), the Wilhelm-Sander-Foundation (J.L.S. and M.B.), the German Cancer Aid (J.L.S.), the German Jose-Carreras-Foundation (J.L.S. and M.B.), the Federal Ministry of Education and Research (Nationale Genomforschungsnetz 2 to J.L.S.), the Humboldt Foundation (J.L.S.), the Leukemia and Lymphoma Society of America (R6029-07 to B.R.B. and K.L.H.), the Juvenile Diabetes Research Foundation (16-2008-643 to X.Z., S.L.B.-B. and J.A.B.), the University of California, San Francisco, Autoimmunity Center of Excellence (X.Z., S.L.B.-B. and J.A.B.), the National Health and Medical Research Council (339123, 565314 to S.C.B.), the German Research Foundation (SCHE 1562 and SFB832 to B.S.), the Juvenile Diabetes Research Foundation Collaborative Centers for Cell Therapy (S.B., T.G. and J.L.R.) and the Juvenile Diabetes Research Foundation Center on Cord Blood Therapies for Type 1 Diabetes (S.B., T.G. and J.L.R.).
Research support to J.L.S. and M.B. has been provided in part by Becton Dickinson; R.B. is employed by Becton Dickinson; S.C. is employed by Miltenyi Biotech; and J.L.S., M.B. and R.B. have applied for several US and international patents on Treg cell biology.
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