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Phosphoinositide 3-Kinase p110 Delta Differentially Restrains and Directs Naive Versus Effector CD8⁺ T Cell Transcriptional Programs.

ABSTRACT: Phosphoinositide 3-kinase p110 delta (PI3K p110δ) is pivotal for CD8⁺ T cell immune responses. The current study explores PI3K p110δ induction and repression of antigen receptor and cytokine regulated programs to inform how PI3K p110δ directs CD8⁺ T cell fate. The studies force a revision of the concept that PI3K p110δ controls metabolic pathways in T cells and reveal major differences in PI3K p110δ regulated transcriptional programs between naïve and effector cytotoxic T cells (CTL). These differences include differential control of the expression of cytolytic effector molecules and costimulatory receptors. Key insights from the work include that PI3K p110δ signalling pathways repress expression of the critical inhibitory receptors CTLA4 and SLAMF6 in CTL. Moreover, in both naïve and effector T cells the dominant role for PI3K p110δ is to restrain the production of the chemokines that orchestrate communication between adaptive and innate immune cells. The study provides a comprehensive resource for understanding how PI3K p110δ uses multiple processes mediated by Protein Kinase B/AKT, FOXO1 dependent and independent mechanisms and mitogen-activated protein kinases (MAPK) to direct CD8⁺ T cell fate.

SUBMITTER: Spinelli L

PROVIDER: S-EPMC8250422 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Phosphatidylinositol-3-kinase p110 delta differentially restrains and directs naïve versus effector CD8+ T cell transcriptional programs Phosphatidylinositol-3-kinase p110 delta differentially restrains and directs naïve versus effector CD8+ T cell transcriptional programs

Project description:Phosphatidylinositol-3-kinase p110 delta (PI3Kp110δ) is pivotal for CD8+ T cell immune responses. To inform how PI3Kp110δ regulates CD8+ T cells, the current study focuses on PI3Kp110δ controlled transcriptional programs and reveals how PI3Kp110δ selectively induces and represses expression of key genes that create a cytotoxic T cell (CTL). The data identify differences in PI3Kp110δ regulated transcriptional programs between naïve and cytotoxic T cells including differential control of cytolytic effector molecules, costimulatory receptors and the critical inhibitory receptors CTLA4 and SLAMF6. However, common to both naïve and effector cells is PI3Kp110δ control of the production of chemokines and cytokines that orchestrate communication between the adaptive and innate immune system. The study provides a comprehensive resource for understanding how PI3Kp110δ uses multiple mechanisms dependent on Protein Kinase B/AKT, FOXO1 dependent and independent mechanisms and mitogen-activated protein kinases (MAPK) to direct CD8+ T cell fate.

2021-06-14 | PXD025046 | Pride

Phosphatidylinositol-3-kinase p110 delta differentially restrains and directs naïve versus effector CD8+ T cell transcriptional programs

2021-06-14 | PXD025061 | Pride

Phosphoinositide acyl chain saturation drives CD8+ effector T cell signaling and function.

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SATB1 ensures appropriate transcriptional programs within naive CD8+ T cells.

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Selective inhibition of phosphoinositide 3-kinase p110? preserves lymphocyte function.

Project description:Class IA phosphoinositide 3-kinase (PI3K) is essential for clonal expansion, differentiation, and effector function of B and T lymphocytes. The p110? catalytic isoform of PI3K is highly expressed in lymphocytes and plays a prominent role in B and T cell responses. Another class IA PI3K catalytic isoform, p110?, is a promising drug target in cancer but little is known about its function in lymphocytes. Here we used highly selective inhibitors to probe the function of p110? in lymphocyte responses in vitro and in vivo. p110? inhibition partially reduced B cell receptor (BCR)-dependent AKT activation and proliferation, and diminished survival supported by the cytokines BAFF and IL-4. Selective p110? inhibition suppressed B cell responses much more strongly, yet maximal suppression was achieved by targeting multiple PI3K isoforms. In mouse and human T cells, inhibition of single class IA isoforms had little effect on proliferation, whereas pan-class I inhibition did suppress T cell expansion. In mice, selective p110? inhibition using the investigational agent MLN1117 (previously known as INK1117) did not disrupt the marginal zone B cell compartment and did not block T cell-dependent germinal center formation. In contrast, the selective p110? inhibitor IC87114 strongly suppressed germinal center formation and reduced marginal zone B cell numbers, similar to a pan-class I inhibitor. These findings show that although acute p110? inhibition partially diminishes AKT activation, selective p110? inhibitors are likely to be less immunosuppressive in vivo compared with p110? or pan-class I inhibitors.

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Phosphoinositide 3-kinase signaling pathway mediated by p110? regulates invadopodia formation.

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CXCR3 Identifies Human Naive CD8+ T Cells with Enhanced Effector Differentiation Potential.

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