Hyperactive PI3K-delta in Th1 and Th2 differentiation

While inputs regulating CD4+ T helper cell (Th) differentiation are well-defined, the integration of downstream signaling with transcriptional and epigenetic programs that define Th-lineage identity remain incompletely resolved. PI3K signaling is a critical regulator of T-cell function; activating mutations affecting PI3Kd result in an immunodeficiency with multiple T-cell defects. Using mice expressing activated-PI3Kd, we found aberrant expression of proinflammatory Th1-signature genes under Th2-inducing conditions, both in vivo and in vitro. This dysregulation was driven by a PI3Kd-IL-2-Foxo1 signaling amplification loop, fueling Foxo1-inactivation, loss of Th2-lineage restriction and extensive epigenetic reprogramming. Surprisingly, ablation of Fasl, a Foxo1-repressed gene, normalized both Th2 differentiation and TCR signaling. BioID and imaging revealed Fas interactions with TCR-signaling components, which were supported by Fas-mediated potentiation of TCR signaling that could occur in the absence of FADD. Our results highlight Fas-FasL signaling as a critical intermediate in phenotypes driven by activated-PI3Kd, thereby linking two key pathways of immune dysregulation. Overall design: CD45+ cells isolated from lungs in 4 samples. Each sample consists of cells from 3 mice, sequenced as one pool per sample. Comparisons made between WT & MT, & between Naïve & HDM.