Sustained PI3K activation destabilized tTreg (BA15P.227)

Abstract

Abstract Regulatory T cells (Treg) play a central role in immune homeostasis, whose dysfunction has been implicated in autoimmune disease pathogenesis. Two subsets Tregs have been defined in vivo: thymus derived tTregs and peripherally derived pTreg. The plasticity of Treg, especially the thymically derived tTreg remains considerable controversial. Since the conserved non-coding sequence 1(CNS1) of Foxp3 gene is only critical for the generation of induced pTreg cells, we generated a new BAC-transgenic mouse expressing a thy1.1 2A Cre fusion protein driven from the CNS1 deleted Foxp3 promoter (del CNS1 Foxp3-thy1.1-Cre). Characterization of these mice demonstrated the thy1.1 2A Cre fusion protein expressed exclusively in the Nrp1+Foxp3+ peripheral tTreg subset. Moreover, thy1.1 expression in the thymus was delayed compare with endogenous Foxp3. Stability of thy1.1+ Treg was tested by breeding the thy1.1 2A Cre Tg mouse line to a conditional YFP knock-in reporter mouse, termed ROSA26-stop-YFP. A subset range from 2% to 8% Cre mapped cells spontaneously lost Foxp3 expression in healthy animals, thus even the late developed tTreg cells have some extent of plasticity. Final, we found sustained PI3K activation by breeding with a conditional active PI3K Rosa26 knockin mouse, can significant destabilized late developed tTreg and generated pathogenic exFoxp3 cells in the homeostatic condition.