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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...
Autores principales: | , , , , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
2021
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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 |
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. |
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