Zeng, H.; Zhou, X.; Li, M.; Ai, M.; Li, Y.; Zhu, X.; Hansen, M. J.; Zhong, J.; Johnson, K. L.; Zenka, R.; Pandey, A.; Pease, L. R.

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 C) 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 C is critically required for CD8+ T cell homeostasis in secondary lymphoid organs and intestinal mucosal site. Importantly, PP2A C deficient CD8+ T cells exhibit reduced proliferation and survival. CD8+ T cell anti-bacterial response is strictly dependent on PP2A C. 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 C, including mTORC1 and AKT. Thus, PP2A C is a key modulator of CD8+ T cell homeostasis and effector functions.