Regulatory T cells (T reg cells) are essential for self-tolerance and immune homeostasis. Lack of effector T cell (T eff cell) function and gain of suppressive activity by T reg 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 T reg 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 3ĝ€2 untranslated region. Release of SATB1 from the control of Foxp3 in T reg cells caused loss of suppressive function, establishment of transcriptional T eff cell programs and induction of T eff cell cytokines. Our data support the proposal that inhibition of SATB1-mediated modulation of global chromatin remodeling is pivotal for maintaining T reg cell functionality.
Bibliographical noteFunding Information:
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