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

While 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 anti-bacterial 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 the defective anti-bacterial 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.