c-REL and IκBNS 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 IκBNS are important regulators of Foxp3 induction in Treg precursors upon γ-chain cytokine stimulation. In c-REL/IκBNS double-deficient mice, Treg numbers were dramatically reduced, indicating that together, c-REL and IκBNS 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 IκBNS are required for T cell effector function as well. Analyzing Treg development in more detail, we identified a CD122(+) subset within the CD25(-)Foxp3(-) precursor population, which gave rise to classical CD25(+)Foxp3(-) Treg precursors. Importantly, c-REL, but not IκBNS, controlled the generation of classical CD25(+)Foxp3(-) precursors via direct binding to the Cd25 locus. Thus, we propose that CD4(+)GITR(+)CD122(+)CD25(-)Foxp3(-) cells represent a Treg pre-precursor population, whose transition into Treg precursors is mediated via c-REL.

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