PI3Kδ Bridges Microbial Surveillance with Antigen Presentation to Reinforce Intestinal Immunity

Abstract

Phosphoinositide 3-kinase delta (PI3K{delta}) is essential for immune cell functions, preventing immunodeficiency and inflammation; however, its role in dendritic cell (DC)-mediated immune regulation remains unknown. Here, we report a key role for DC-intrinsic PI3K{delta} in linking microbial recognition with antigen presentation for effective T-cell priming. Using genetic and functional assays, we demonstrate that PI3K{delta} deficiency in DCs leads to broad dysregulation of intestinal CD4 T-cell immunity, characterized by impaired regulatory T-cell expansion and increased susceptibility to colitis. DC-based studies show that PI3K{delta} links pattern-recognition-receptor signaling to MHC class I- and II-restricted presentation of phagosome-associated antigens by facilitating NOX2-dependent oxidative burst through RAC2, while mitigating inflammasome activation. In contrast, PI3K{delta} deficiency disrupts phagosomal pH balance, leading to accelerated acidification and proteolysis of antigens, impairing T-cell activation. Our study identifies PI3K{delta} as a key coordinator of phagosome dynamics, important for DC adaptive programming that shapes T-cell responses and supports intestinal immune homeostasis.