Protein Phosphatase 2A Promotes CD8+ T Cell Effector Function through the Augmentation of CD28 Costimulation

Abstract

Protein phosphatase 2A (PP2A) is one of the most abundant serine/threonine phosphatases and plays critical roles in regulating cell fate and function. We previously showed that PP2A regulates the differentiation of CD4⁺ T cells and the development of thymocytes. Nevertheless, its role in CD8⁺ T cells remains elusive. By ablating the catalytic subunit α (Cα) of PP2A in CD8⁺ T cells, we revealed the essential role of PP2A in promoting the effector functions of CD8⁺ T cells. Notably, PP2A Cα-deficient CD8⁺ T cells exhibit reduced proliferation and decreased cytokine production upon stimulation in vitro. In vivo, mice lacking PP2A Cα in T cells displayed defective immune responses against lymphocytic choriomeningitis virus infection, associated with reduced CD8⁺ T cell expansion and decreased cytokine production. Consistently, the ablation of the PP2A Cα subunit in CD8⁺ T cells results in attenuated antitumor activity in mice. There is a notable decrease in the infiltration of PP2A Cα-deficient CD8⁺ T cells within the tumor microenvironment, and the cells that do infiltrate exhibit diminished effector functions. Mechanistically, PP2A Cα deficiency impedes CD28-induced AKT Ser⁴⁷³ phosphorylation, thus impairing CD8⁺ T cell costimulation signal. Collectively, our findings underscore the critical role of phosphatase PP2A as a propeller for CD28-mediated costimulation signaling in CD8⁺ T cell effector function by fine-tuning T cell activation.