Treg-derived IκBζ promotes their conversion into Th2-like effectors and drives type 2 inflammation via BATF

Abstract Regulatory T cells (Treg cells) maintain peripheral immune tolerance but display considerable plasticity in peripheral tissues. The molecular mechanisms governing their function and plasticity, particularly under inflammatory conditions, remain poorly defined. Here, we identify the NF-κB-associated transcriptional cofactor IκBζ as a critical regulator of Treg cell plasticity and function. Enforced expression of IκBζ in Treg cells triggered the excessive expansion of functionally impaired Treg cells, resulting in lymphadenopathy, splenomegaly, and systemic type 2 inflammation, most prominently in the lung. Mechanistically, IκBζ modified BATF expression and function, thereby driving the cell-intrinsic production of Th2-associated cytokines by Treg cells. Conversely, Treg-specific deletion of IκBζ constrained IL-33-mediated expansion of tissue Treg cells and surprisingly attenuated type 2 inflammation. Thus, IκBζ functions as a molecular switch that reprograms regulatory T cells into Th2-like Treg cells, thereby perturbing peripheral immune tolerance. Graphical Abstract