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3' Untranslated Regions/genetics/immunology Animals Cell Differentiation/drug effects Chromatin Assembly and Disassembly/drug effects/*immunology Flow Cytometry Forkhead Transcription Factors/genetics/*immunology/metabolism Gene Expression Profiling *Gene Expression Regulation Genome, Human Genome-Wide Association Study Humans Lentivirus Lymphocyte Activation/drug effects Matrix Attachment Region Binding Proteins/genetics/*immunology/metabolism Mice Mice, Inbred C57BL Mice, Knockout MicroRNAs/immunology/metabolism/pharmacology RNA Interference RNA, Small Interfering/immunology/metabolism/pharmacology Reverse Transcriptase Polymerase Chain Reaction *Self Tolerance/drug effects/genetics/immunology T-Lymphocytes, Regulatory/cytology/*immunology/metabolism Transduction, Genetic
Abstract:
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 3' 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.
