Work

A PI3Kd-Foxo1-FasL signaling amplification loop rewires CD4+ T helper cell signaling, differentiation and epigenetic remodeling 4854

Year: 2025

Type: article

Abstract: Description 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 unresolved. PI3K signaling is a critical regulator of T cell function; activated PI3Kδ syndrome (APDS) is an inborn error of immunity caused by heterozygous activating mutations in PI3Kδ. APDS patients have recurrent respiratory infections (Th1-type) and develop allergic (Th2-type) diseases; we therefore hypothesized that activated-PI3Kδ (Pik3cdE1020K) signaling may alter CD4 T cell differentiation. Using mice expressing activated-PI3Kδ, we found aberrant expression of proinflammatory Th1-signature genes under Th2-inducing conditions, following both house dust mite induced asthma in vivo and CD4 T cell polarization in vitro. This dysregulation was driven by a robust PI3Kδ-IL-2-Foxo1 signaling loop, fueling Foxo1-inactivation, loss of Th2-lineage restriction, altered chromatin accessibility and global impairment of CTCF-DNA interactions. Surprisingly, ablation of Fasl, a Foxo1-repressed gene, restored normal Th2 differentiation, TCR signaling and CTCF expression. BioID proximity labeling revealed Fas interactions with TCR-signaling components, which were supported by Fas-mediated potentiation of TCR signaling. Our results highlight Fas-FasL signaling as a critical intermediate in phenotypes driven by activated-PI3Kδ, thereby linking two key pathways of immune dysregulation. Funding Sources This work was supported by the Division of Intramural Research of NIAID, NIH. Topic Categories Lymphocyte Differentiation and Peripheral Maintenance (LYM)

Source: The Journal of Immunology

DOI: 10.1093/jimmun/vkaf283.2464