Context-Specific Function of S6K2 in Th Cell Differentiation

The mammalian target of rapamycin (mTOR) is essential for Th cell proliferation and effector differentiation, making the mTOR signaling network an attractive immunomodulatory target for autoimmune-related diseases. Although direct targeting of mTOR complex-1 (mTORC1) with rapamycin can provide clinical benefit, targeting downstream enzymes has the potential to offer more selective immunosuppression. In this study, we evaluated p70 ribosomal protein S6 Kinase 2 (S6K2), a downstream effector of mTORC1, for its role in T cell function and autoimmunity. S6K2 is a direct substrate of mTORC1, with a potential role in Th17 differentiation suggested by biochemical studies. Using a genetic approach with S6K2 knockout mice, we found that S6K2 loss reduces Th17 skewing and increases regulatory T cell differentiation in vitro when cultured in RPMI 1640 media. However, S6K2 was dispensable for Th17 differentiation in IMDM. In an in vivo experimental autoimmune encephalomyelitis model in which rapamycin suppresses disease, S6K2 knockout mice did not exhibit differences in clinical score or Th17 differentiation. These results suggest that S6K2 is dispensable for Th17-driven autoimmunity and highlight how distinct experimental conditions can produce significantly different results in T cell differentiation.