Tuning PI3K: striking the right balance for optimal CD8 T-cell responses

CD8 cytolytic T cells are key players in fighting viral infections and other intracellular pathogens. In response to signals from the TCR, costimulatory molecules, and cytokines, CD8 T cells differentiate into populations of cytolytic effectors that can efficiently kill infected and tumor cells, as well as memory precursors that can develop into memory cells that respond to subsequent infection. The class I phosphatidylinositol 3-kinases (PI3Ks) are key components of signaling pathways that dictate and shape CD8 T-cell responses during acute viral infection, as well as during CD8 T-cell exhaustion, a state of hyporesponsiveness driven by prolonged antigen exposure in chronic infection and cancer. In this review, we highlight the role of PI3Kδ in CD8 T-cell activation, differentiation, and function, with a focus on downstream effectors and lessons learned from activating and inhibitory mutants affecting these pathways in mouse models and primary immunodeficiencies.