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 develop ment 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. FASEB J. 27, 3979–3990 (2013). www.fasebj.org