mTORC1 and mTORC2 selectively program distinct CD4 helper T-cell lineages.
| Evidence tier | C Animal in vivo |
| Study type | 4 - Animal Study |
| Model system | Mouse |
| Journal | Nature immunology |
| Year | 2011 |
| Peer reviewed | Yes |
| Source | DOI 10.1038/ni.2005 · PMID 21358638 · Free full text (PMC3077821) |
The kinase mTOR has emerged as an important regulator of the differentiation of helper T cells. Here we demonstrate that differentiation into the T(H)1 and T(H)17 subsets of helper T cells was selectively regulated by signaling from mTOR complex 1 (mTORC1) that was dependent on the small GTPase Rheb. Rheb-deficient T cells failed to generate T(H)1 and T(H)17 responses in vitro and in vivo and did not induce classical experimental autoimmune encephalomyelitis (EAE). However, they retained their ability to become T(H)2 cells. Alternatively, when mTORC2 signaling was deleted from T cells, they failed to generate T(H)2 cells in vitro and in vivo but preserved their ability to become T(H)1 and T(H)17 cells. Our data identify mechanisms by which two distinct signaling pathways downstream of mTOR regulate helper cell fate in different ways. These findings define a previously unknown paradigm that links T cell differentiation with selective metabolic signaling pathways.
| Intervention | Genetic (Rheb/mTORC1; mTORC2) |
| Target | mTORC1 (Rheb) & mTORC2 |
| Model | Mouse |
| Effect | mTORC1 (Rheb-dependent) selectively drives Th1/Th17 differentiation while mTORC2 controls Th2 |