ABSTRACT
Adaptive immunity relies on specialized effector functions elicited by lymphocytes, yet how antigen recognition activates appropriate effector responses through nonspecific signaling intermediates is unclear. Here we examined the role of chromatin priming in specifying the functional outputs of effector T cells and found that most of the cis-regulatory landscape active in effector T cells was poised early in development before the expression of the T cell antigen receptor. We identified two principal mechanisms underpinning this poised landscape: the recruitment of the nucleosome remodeler mammalian SWItch/Sucrose Non-Fermentable (mSWI/SNF) by the transcription factors RUNX1 and PU.1 to establish chromatin accessibility at T effector loci; and a 'relay' whereby the transcription factor BCL11B succeeded PU.1 to maintain occupancy of the chromatin remodeling complex mSWI/SNF together with RUNX1, after PU.1 silencing during lineage commitment. These mechanisms define modes by which T cells acquire the potential to elicit specialized effector functions early in their ontogeny and underscore the importance of integrating extrinsic cues to the developmentally specified intrinsic program.
Subject(s)
Core Binding Factor Alpha 2 Subunit , Proto-Oncogene Proteins , Repressor Proteins , Trans-Activators , Transcription Factors , Tumor Suppressor Proteins , Proto-Oncogene Proteins/metabolism , Animals , Trans-Activators/metabolism , Trans-Activators/genetics , Mice , Core Binding Factor Alpha 2 Subunit/metabolism , Core Binding Factor Alpha 2 Subunit/genetics , Repressor Proteins/metabolism , Repressor Proteins/genetics , Transcription Factors/metabolism , Transcription Factors/genetics , Tumor Suppressor Proteins/metabolism , Tumor Suppressor Proteins/genetics , Mice, Inbred C57BL , Chromosomal Proteins, Non-Histone/metabolism , T-Lymphocytes/immunology , T-Lymphocytes/metabolism , Mice, Knockout , Chromatin Assembly and Disassembly , Cell Differentiation/immunologyABSTRACT
The emergence of antigen receptor diversity in clonotypic lymphocytes drove the evolution of a novel gene, Aire, that enabled the adaptive immune system to discriminate foreign invaders from self-constituents. AIRE functions in the epithelial cells of the thymus to express genes highly restricted to alternative cell lineages. This somatic plasticity facilitates the selection of a balanced repertoire of T cells that protects the host from harmful self-reactive clones, yet maintains a wide range of affinities for virtually any foreign antigen. Here, we review the latest understanding of AIRE's molecular actions with a focus on its interplay with chromatin. We argue that AIRE is a multi-valent chromatin effector that acts late in the transcription cycle to modulate the activity of previously poised non-coding regulatory elements of tissue-specific genes. We postulate a role for chromatin instability-caused in part by ATP-dependent chromatin remodeling-that variably sets the scope of the accessible landscape on which AIRE can act. We highlight AIRE's intrinsic repressive function and its relevance in providing feedback control. We synthesize these recent advances into a putative model for the mechanistic modes by which AIRE triggers ectopic transcription for immune repertoire selection.
