An NF-κB Transcription-Factor-Dependent Lineage-Specific Transcriptional Program Promotes Regulatory T Cell Identity and Function

• Published in: Immunity (Cambridge, Mass.) Mass.), 2017-09, Vol.47 (3), p.450-465.e5
• Main Authors: Oh, Hyunju, Grinberg-Bleyer, Yenkel, Liao, Will, Maloney, Dillon, Wang, Pingzhang, Wu, Zikai, Wang, Jiguang, Bhatt, Dev M., Heise, Nicole, Schmid, Roland M., Hayden, Matthew S., Klein, Ulf, Rabadan, Raul, Ghosh, Sankar
• Format: Article
• Language: English
• Subjects: Animals; Autoimmunity - genetics; Autoimmunity - immunology; Binding Sites; Bioinformatics; Biomarkers; Cell activation; Cell Differentiation; Cell Lineage - genetics; Cell proliferation; Cell Survival - genetics; Cell Survival - immunology; Chromatin; Cluster Analysis; Cytokines - metabolism; Functional plasticity; Gene Deletion; Gene expression; Gene Expression Profiling; Gene Expression Regulation; Genomes; Homeostasis; Homeostasis - genetics; Homeostasis - immunology; Immune Tolerance; Immunological tolerance; Immunophenotyping; Inflammation - genetics; Inflammation - immunology; Inflammation - metabolism; Lymphocyte Activation; Lymphocytes; Lymphocytes T; Mice; Mice, Transgenic; NF-kappa B - genetics; NF-kappa B - metabolism; NF-κB protein; Nucleotide Motifs; Phenotype; Protein Binding; Roles; Signal Transduction; T cell receptors; T-Lymphocytes, Regulatory - cytology; T-Lymphocytes, Regulatory - immunology; T-Lymphocytes, Regulatory - metabolism; Thymus; Transcription Factor RelA - genetics; Transcription Factor RelA - metabolism; Transcription factors; Transcription, Genetic; Transcriptome
• ISSN: 1074-7613; 1097-4180
• DOI: 10.1016/j.immuni.2017.08.010

Both conventional T (Tconv) cells and regulatory T (Treg) cells are activated through ligation of the T cell receptor (TCR) complex, leading to the induction of the transcription factor NF-κB. In Tconv cells, NF-κB regulates expression of genes essential for T cell activation, proliferation, and function. However the role of NF-κB in Treg function remains unclear. We conditionally deleted canonical NF-κB members p65 and c-Rel in developing and mature Treg cells and found they have unique but partially redundant roles. c-Rel was critical for thymic Treg development while p65 was essential for mature Treg identity and maintenance of immune tolerance. Transcriptome and NF-κB p65 binding analyses demonstrated a lineage specific, NF-κB-dependent transcriptional program, enabled by enhanced chromatin accessibility. These dual roles of canonical NF-κB in Tconv and Treg cells highlight the functional plasticity of the NF-κB signaling pathway and underscores the need for more selective strategies to therapeutically target NF-κB. [Display omitted] •Canonical NF-κB signaling promotes regulatory T (Treg) cell development•Conditional deletions reveal that c-Rel and p65 play unique but partly redundant roles•NF-κB maintains Treg cell homeostasis and immune tolerance•NF-κB establishes Treg cell transcriptional identity NF-κB regulates genes essential for conventional T cell activation and function, but its role in Treg cell function remains unclear. Oh et al. use Treg cell-specific conditional deletions of canonical NF-κB subunits to demonstrate central roles for p65 and c-Rel in orchestrating Treg cell development, suppressive function, and molecular identity.