PP2A catalytic subunit alpha is critically required for CD8+ T-cell homeostasis and antibacterial responses

Although the functions of tyrosine phosphatases in T-cell biology have been extensively studied, our knowledge on the contribution of serine/threonine phosphatases in T cells remains poor. Protein phosphatase 2A (PP2A) is one of the most abundantly expressed serine/threonine phosphatases. It is important in thymocyte development and CD4⁺ T-cell differentiation. Utilizing a genetic model in which its catalytic subunit alpha isoform (PP2A Cα) is deleted in T cells, we investigated its contribution to CD8⁺ T-cell homeostasis and effector functions. Our results demonstrate that T-cell intrinsic PP2A Cα is critically required for CD8⁺ T-cell homeostasis in secondary lymphoid organs and intestinal mucosal site. Importantly, PP2A Cα–deficient CD8⁺ T cells exhibit reduced proliferation and survival. CD8⁺ T-cell antibacterial response is strictly dependent on PP2A Cα. Expression of Bcl2 transgene rescues CD8⁺ T-cell homeostasis in spleens, but not in intestinal mucosal site, nor does it restore defective antibacterial responses. Finally, proteomics and phosphoproteomics analyses reveal potential targets dependent on PP2A Cα, including mTORC1 and AKT. Thus, PP2A Cα is a key modulator of CD8⁺ T-cell homeostasis and effector functions.