Runx-CBFβ regulates the development of tolerogenic Thetis cells

Peripherally induced regulatory T (pT_reg) cells play an essential role in establishing immune tolerance to gut microbiota and food antigens. A subset of RORγt-expressing antigen-presenting cells, Thetis cell subset IV (TC IV), plays an essential role in intestinal tolerance. However, the transcription factors governing the differentiation of this subset remain unclear. Here we show that Runx-CBFβ complexes regulate the development of specific TC subsets. Mice lacking CBFβ2 exhibited loss of TC II, III and IV, with loss of RORγt⁺ pT_reg cells. Transgenic CBFβ2 expression by Cd11c-Cre restored TC IV and RORγt⁺ pT_reg cell differentiation in CBFβ2-deficient mice. Conditional inactivation of Runx1 and Runx3 by Cd11c-Cre selectively impaired TC III and IV. Conversely Cd11c-Cre-driven transgenic Runx expression enhanced TC IV differentiation and thus RORγt⁺ pT_reg cell induction. These findings establish a critical pathway for TC IV differentiation and provide new insights into therapeutic interventions to promote RORγt⁺ pT_reg cell induction in autoimmune diseases.