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bioRxiv · 10.1101/2025.05.13.653657

PI3Kδ Bridges Microbial Surveillance with Antigen Presentation to Reinforce Intestinal Immunity

Gonzalez Nunez, M.·C. Vasconcellos, L. R.·Garrido Mesa, J.·Cardoso Maciel Costa Silva, R.·Hachani, A.·Bosquet Agudo, A.·Simeoli, R.·Medrano Gonzalez, L.·Filloux, A.·C. E. Welch, H.·Perretti, M.·Vanhaesebroeck, B.·Dombrowicz, D.·Haworth, O.·Kok, K.·Manoury, B.·Aksoy, E.
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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.

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Gonzalez Nunez, M., C. Vasconcellos, L. R., Garrido Mesa, J., Cardoso Maciel Costa Silva, R., Hachani, A., Bosquet Agudo, A., Simeoli, R., Medrano Gonzalez, L., Filloux, A., C. E. Welch, H., Perretti, M., Vanhaesebroeck, B., Dombrowicz, D., Haworth, O., Kok, K., Manoury, B., Aksoy, E.. 2025-05-16. PI3Kδ Bridges Microbial Surveillance with Antigen Presentation to Reinforce Intestinal Immunity. https://doi.org/10.1101/2025.05.13.653657

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