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PI3Kd coordinates transcriptional, epigenetic and metabolic changes to promote effector CD8 T cells at the expense of memory
Patients with Activated-PI3Kd Syndrome (APDS) present with sinopulmonary infections, lymphadenopathy and CMV and/or EBV viremia, yet why patients fail to clear certain viral infections remains poorly understood. Using APDS patient samples and a mouse model (Pik3cdE1020K/+ mice), we demonstrate that,...
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Published in: | The Journal of immunology (1950) 2021-05, Vol.206 (1_Supplement), p.52-52.18 |
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Main Authors: | , , , , , , , , , , , , , , , |
Format: | Article |
Language: | English |
Online Access: | Get full text |
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Summary: | Patients with Activated-PI3Kd Syndrome (APDS) present with sinopulmonary infections, lymphadenopathy and CMV and/or EBV viremia, yet why patients fail to clear certain viral infections remains poorly understood. Using APDS patient samples and a mouse model (Pik3cdE1020K/+ mice), we demonstrate that, upon activation, Pik3cdE1020K/+ CD8+ T cells exhibit exaggerated features of short-lived effectors both in vitro and post-viral infection, associated with increased Fas-mediated apoptosis due to sustained phosphorylation of FoxO1 and derepression of FasL. In addition, Pik3cdE1020K/+ CD8+ T cells exhibit enhanced mTORC1 and c-Myc signatures; metabolic perturbations; and reorientation of their chromatin landscape. Conversely, Pik3cdE1020K/+ CD8+ T cells failed to sustain expression of proteins critical for maintenance of long-lived memory cells, including TCF1. Strikingly, activated Pik3cdE1020K/+ CD8+ T cells exhibit altered transcriptional and epigenetic circuits characterized by a pronounced IL-2/STAT5 signature associated with heightened IL-2 responses that prevented differentiation to memory-like cells in the presence of IL-15. Our data position PI3Kd as a central driver integrating multiple signaling circuits that promote terminal CD8+ T cell effector differentiation at the expense of memory and long-lived T cell responses.
This work was funded in part by the Intramural Research Program of NIAID, NIH. |
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ISSN: | 0022-1767 1550-6606 |
DOI: | 10.4049/jimmunol.206.Supp.52.18 |