c-REL and IκB Govern Common and Independent Steps of Regulatory T Cell Development from Novel CD122-Expressing Pre-Precursors.

Foxp3-expressing regulatory T cells (Tregs) are essential regulators of immune homeostasis and, thus, are prime targets for therapeutic interventions of diseases such as cancer and autoimmunity. c-REL and IκB are important regulators of Foxp3 induction in Treg precursors upon γ-chain cytokine stimulation. In c-REL/IκB double-deficient mice, Treg numbers were dramatically reduced, indicating that together, c-REL and IκB are pivotal for Treg development. However, despite the highly reduced Treg compartment, double-deficient mice did not develop autoimmunity even when aged to more than 1 y, suggesting that c-REL and IκB are required for T cell effector function as well. Analyzing Treg development in more detail, we identified a CD122 subset within the CD25Foxp3 precursor population, which gave rise to classical CD25Foxp3 Treg precursors. Importantly, c-REL, but not IκB, controlled the generation of classical CD25Foxp3 precursors via direct binding to the locus. Thus, we propose that CD4GITRCD122CD25Foxp3 cells represent a Treg pre-precursor population, whose transition into Treg precursors is mediated via c-REL.