Disruption of TSC1/2 signaling complex reveals a checkpoint governing thymic CD4+CD25+Foxp3+, regulatory T-cell development in mice

Thymic-derived CD4(+)CD25(+)Foxp3(+) natural regulatory T (nT(reg)) cells are essential for the maintenance of peripheral immune tolerance. Signaling pathways that drive immature thymic progenitors to differentiate into CD4(+)CD25(+)Foxp3(+) nT(reg) cells need to be elucidated. The precise role of the TSC1/2 complex, a critical negative regulator of mammalian target of rapamycin (mTOR), in thymic CD4(+)CD25(+)Foxp3(+) nT(reg)-cell development remains elusive. In the present study, we found that the percentage and cell number of thymic CD4(+)CD25(+)Foxp3(+) nT(reg) cells were significantly increased in T-cell-specific TSC1-knockout (TSC1KO) mice. Nevertheless, the levels of CD4(+)CD25(+)Foxp3(-) nT(reg) precursors in TSC1KO thymus were indistinguishable from those in wild-type mice. TSC1KO CD4(+)CD25(+)Foxp3(+) nT(reg) cells showed normal cell death but enhanced proliferative response to IL-2 in a STAT5-dependent manner. Rapamycin (Rapa) treatment failed to rescue but rather increased the frequency of CD4(+)CD25(+)Foxp3(+) nT(reg) cells in TSC1KO and RictorKO mice. The percentage and cell number of thymic CD4(+)CD25(+)Foxp3(+) nT(reg) cells were significantly increased in T-cell-specific RictorKO mice but not in PtenKO mice. Collectively, our studies suggest that TSC1 plays an important role in regulating thymic CD4(+)CD25(+)Foxp3(+) nT(reg)-cell development via a Rapa-resistant and mTORC2-dependent signaling pathway.Chen, H, Zhang, L., Zhang, H., Xiao, Y., Shao, L., Li, H., Yin, H., Wang, R., Liu, G., Corley, D., Yang, Z., Zhao, Y. Disruption of TSC1/2 signaling complex reveals a checkpoint governing thymic CD4(+)CD25(+)Foxp3(+) regulatory T-cell development in mice.