A PI3Kδ-Foxo1-FasL signaling amplification loop rewires CD4⁺ T helper cell signaling, differentiation and epigenetic remodeling.

ABSTRACT: 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; activating mutations affecting PI3Kδ result in an immunodeficiency with multiple T cell defects. Using mice expressing activated-PI3Kδ, 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 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, ablati

SUBMITTER: Golec DP 

PROVIDER: S-EPMC11722529 | biostudies-literature | 2024 Nov

REPOSITORIES: biostudies-literature