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

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.