Abstract
SUMMARYPatients 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 (Pik3cdE1020K/+ mice), we demonstrate that, upon activation, Pik3cdE1020K/+ 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, Pik3cdE1020K/+ CD8+ cells fail to sustain expression of proteins critical for central memory, including TCF1. Strikingly, activated Pik3cdE1020K/+ 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.
Highlights
Following T cell receptor (TCR) ligation and cytokine signals, naive CD8+ T cells proliferate and differentiate into effector cytotoxic T lymphocytes (CTLs) that express cytolytic proteins and help eliminate virus-infected cells and tumors (Stinchcombe and Griffiths, 2007)
We find that a substantial fraction of activated phosphatidylinositol 3-kinase delta (PI3Kd) T cells die via TCR-induced apoptosis (Angulo et al, 2013; Edwards et al, 2019), which we link to impaired FoxO1-mediated repression of Fasl
Similar results were observed with activated T cells from Pik3cdE1020K/+ mice or Pik3cdE1020K/+ OT-I mice expressing a class I major histocompatibility complex (MHC)
Summary
Following T cell receptor (TCR) ligation and cytokine signals, naive CD8+ T cells proliferate and differentiate into effector cytotoxic T lymphocytes (CTLs) that express cytolytic proteins and help eliminate virus-infected cells and tumors (Stinchcombe and Griffiths, 2007). TCM cells, in particular, expand upon rechallenge and maintain long-term immunity. Many studies have enumerated factors critical for T cell memory, including cytokines, transcription factors (TFs), chromatin remodelers, and metabolic regulators. There is considerable overlap between the transcriptomes of CD8+ TCM cells and TCF1+ stem-like progenitor cells that maintain long-term T cell responses in chronic infection and cancer (McLane et al, 2019). Elucidating mechanisms guiding TCM cell generation is important both for understanding memory in acute infection and harnessing immune responses in chronic infection. Whether there is a common theme unifying the regulation of effector/memory cell fate decisions remains unclear
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
