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

Phosphoinositide 3-kinase p110 delta (PI3K p110 delta) is pivotal for CD8(+) T cell immune responses. The current study explores PI3K p110 delta induction and repression of antigen receptor and cytokine regulated programs to inform how PI3K p110 delta directs CD8(+) T cell fate. The studies force a revision of the concept that PI3K p110 delta controls metabolic pathways in T cells and reveal major differences in PI3K p110 delta regulated transcriptional programs between naive 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 p110 delta signalling pathways repress expression of the critical inhibitory receptors CTLA4 and SLAMF6 in CTL. Moreover, in both naive and effector T cells the dominant role for PI3K p110 delta 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 p110 delta 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.