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PI3Kδ coordinates transcriptional, chromatin, and metabolic changes to promote effector CD8(+) T cells at the expense of central memory

Patients with activated phosphatidylinositol 3-kinase delta (PI3Kδ) syndrome (APDS) present with sinopulmonary infections, lymphadenopathy, and cytomegalvirus (CMV) and/or Epstein-Barr virus (EBV) viremia, yet why patients fail to clear certain chronic viral infections remains incompletely understoo...

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Detalles Bibliográficos
Autores principales: Cannons, Jennifer L., Villarino, Alejandro V., Kapnick, Senta M., Preite, Silvia, Shih, Han-Yu, Gomez-Rodriguez, Julio, Kaul, Zenia, Shibata, Hirofumi, Reilley, Julie M., Huang, Bonnie, Handon, Robin, McBain, Ian T., Gossa, Selamawit, Wu, Tuoqi, Su, Helen C., McGavern, Dorian B., O’Shea, John J., McGuire, Peter J., Uzel, Gulbu, Schwartzberg, Pamela L.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8582080/
https://www.ncbi.nlm.nih.gov/pubmed/34644563
http://dx.doi.org/10.1016/j.celrep.2021.109804
Descripción
Sumario:Patients with activated phosphatidylinositol 3-kinase delta (PI3Kδ) syndrome (APDS) present with sinopulmonary infections, lymphadenopathy, and cytomegalvirus (CMV) and/or Epstein-Barr virus (EBV) viremia, yet why patients fail to clear certain chronic viral infections remains incompletely understood. Using patient samples and a mouse model (Pik3cd(E1020K/+) mice), we demonstrate that, upon activation, Pik3cd(E1020K/+) CD8(+) T cells exhibit exaggerated features of effector populations both in vitro and after viral infection that are associated with increased Fas-mediated apoptosis due to sustained FoxO1 phosphorylation and Fasl derepression, enhanced mTORC1 and c-Myc signatures, metabolic perturbations, and an altered chromatin landscape. Conversely, Pik3cd(E1020K/+) CD8(+) cells fail to sustain expression of proteins critical for central memory, including TCF1. Strikingly, activated Pik3cd(E1020K/+) CD8(+) cells exhibit altered transcriptional and epigenetic circuits characterized by pronounced interleukin-2 (IL-2)/STAT5 signatures and heightened IL-2 responses that prevent differentiation to memory-like cells in IL-15. Our data position PI3Kδ as integrating multiple signaling nodes that promote CD8(+) T cell effector differentiation, providing insight into phenotypes of patients with APDS.