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

ABSTRACT: 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.

SUBMITTER: Cannons JL

PROVIDER: S-EPMC8582080 | biostudies-literature | 2021 Oct

REPOSITORIES: biostudies-literature

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Publications

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

Cannons Jennifer L JL Villarino Alejandro V AV Kapnick Senta M SM Preite Silvia S Shih Han-Yu HY Gomez-Rodriguez Julio J Kaul Zenia Z Shibata Hirofumi H Reilley Julie M JM Huang Bonnie B Handon Robin R McBain Ian T IT Gossa Selamawit S Wu Tuoqi T Su Helen C HC McGavern Dorian B DB O'Shea John J JJ McGuire Peter J PJ Uzel Gulbu G Schwartzberg Pamela L PL

Cell reports 20211001 2

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 (Pik3cdE1020K/+ mice), we demonstrate that, upon activation, Pik3cdE1020K/+ CD8+ T cells exhibit exaggerated features of eff ...[more]

PMID: 34644563

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Project description:BackgroundRadiotherapy enhances antitumor immunity. However, it also induces immunosuppressive responses, which are major hurdles for an effective treatment. Thus, targeting the immunosuppressive tumor microenvironment is essential for enhancing the antitumor immunity after radiotherapy. Retrospective studies show that a blockade of PI3Kδ and/or γ, which are abundant in leukocytes, exhibits antitumor immune response by attenuating activity of immune suppressive cells, however, the single blockade of PI3Kδ or γ is not sufficient to completely eliminate solid tumor.MethodsWe used BR101801, PI3Kδ/γ inhibitor in the CT-26 syngeneic mouse model with a subcutaneously implanted tumor. BR101801 was administered daily, and the target tumor site was locally irradiated. We monitored the tumor growth regularly and evaluated the immunological changes using flow cytometry, ELISpot, and transcriptional analysis.ResultsThis study showed that BR101801 combined with irradiation promotes systemic antitumor immunity and abscopal response by attenuating the activity of immune suppressive cells in the CT-26 tumor model. BR101801 combined with irradiation systemically reduced the proliferation of regulatory T cells (Tregs) and enhanced the number of tumor-specific CD8α+ T cells in the tumor microenvironment, thereby leading to tumor regression. Furthermore, the high ratio of CD8α+ T cells to Tregs was maintained for 14 days after irradiation, resulting in remote tumor regression in metastatic lesions, the so-called abscopal effect. Moreover, our transcriptomic analysis showed that BR101801 combined with irradiation promoted the immune-stimulatory tumor microenvironment, suggesting that the combined therapy converts immunologically cold tumors into hot one.ConclusionsOur data suggest the first evidence that PI3Kδ/γ inhibition combined with irradiation promotes systemic antitumor immunity against solid tumors, providing the preclinical result of the potential use of PI3Kδ/γ inhibitor as an immune-regulatory radiosensitizer.

Dataset Information

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

Publications

PI3Kδ coordinates transcriptional, chromatin, and metabolic changes to promote effector CD8<sup>+</sup> T cells at the expense of central memory.

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