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-kappa B. In Tconv cells, NF-kappa B regulates expression of genes essential for T cell activation, proliferation, and function. However the role of NF-kappa B in Treg function remains unclear. We conditionally deleted canonical NF-kappa B 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-kappa B p65 binding analyses demonstrated a lineage specific, NF-kappa B-dependent transcriptional program, enabled by enhanced chromatin accessibility. These dual roles of canonical NF-kappa B in Tconv and Treg cells highlight the functional plasticity of the NF-kappa B signaling pathway and underscores the need for more selective strategies to therapeutically target NF-kappa B.