High-linear energy transfer radiation disrupts natural killer cell surveillance of senescent intestinal cells in the mouse intestine

Si-exposed mice showed a significant reduction in NKp46⁺ NK cells and decreased expression of molecules associated with NK activation and epithelial interactions. NK cell subtype analysis further revealed a decline in functionally mature populations involved in recognizing stressed cells. In parallel, intestinal epithelial cells (IECs) displayed altered expression of NK cell regulatory ligands, including reduced activating signals and increased inhibitory signaling associated with Qa-1b (non-classical MHC class Ib). Mechanistically, these changes were linked to activation of p38 Mitogen-Activated Protein Kinase (MAPK) signaling. Using irradiated intestinal organoids, we observed that pharmacological inhibition of the p38 MAPK pathway decreased Qa-1b expression and enhanced NK cell cytotoxic activity. Causality experiments further demonstrated that Qa-1b directly regulates NK cell-mediated cytotoxicity against senescent IECs. Collectively, these findings indicate that high-LET IR compromises intestinal immune surveillance by impairing NK cell function through a p38 MAPK-Qa-1b signaling axis, providing mechanistic insight into radiation-induced immune dysregulation.