Quantity and quality control by mTOR

The immunosuppressive effects of the drug rapamycin, which inhibits Akt–mTOR (mammalian target of rapamycin) signalling, have been attributed to the modulation of many immune cell types. Three new studies clarify T cell-intrinsic roles for mTOR as a regulator of both CD4⁺ and CD8⁺ T cell differentiation.

Delgoffe et al. generated mice with a conditional deletion of Frap1 (the gene encoding mTOR) in T cells. CD4⁺ T cells from these T-Frap1^−/− mice failed to differentiate into T helper 1 (T_H1), T_H2 or T_H17 effector cells in the presence of appropriate polarizing cytokines in vitro or in vivo. Despite expressing appropriate receptors for these polarizing cytokines, T-Frap1^−/− CD4⁺ T cells had decreased phosphorylation of the downstream signal transducer and activator of transcription (STAT) factors in response to these cytokines and failed to upregulate lineage-specific transcription factors. Instead, the activation of T-Frap1^−/− T cells resulted in the generation of a larger number of CD4⁺CD25⁺FOXP3⁺ regulatory T (T_Reg) cells compared with activation of wild-type T cells, and these FOXP3⁺ T cells had potent suppressive activity in vitro. T-Frap1^−/− T cells had increased baseline levels of phosphorylation of SMAD3, which increased further with the addition of transforming growth factor-β (TGFβ).

These results indicate that mTOR controls the differentiation of effector versus regulatory CD4⁺ T cells in the periphery by regulating cytokine receptor signalling. In the absence of mTOR, the default pathway is the generation of T_Reg cells through hypersensitivity to TGFβ-induced SMAD3 phosphorylation and inhibition of STAT phosphorylation.

Liu et al. have shown a similar inhibitory role for Akt–mTOR, activated by sphingosine 1-phosphate (S1P) signalling, in both the differentiation and suppressive activity of natural T_Reg cells derived from the thymus. In this study, mice with a conditional deletion of S1PR1 (a receptor for S1P) in T cells had an increased number of thymic T_Reg cells, whereas mice with increased expression of S1PR1 in T cells had fewer thymic T_Reg cells than wild-type mice. These results were due to an inhibitory effect of S1P on the differentiation of thymic T_Reg cells rather than to effects of S1P on their trafficking from the thymus. Moreover, S1pr1-transgenic T_Reg cells also had impaired suppressive activity both in vitro and in vivo, leading to a breakdown of T_Reg cell-mediated immune tolerance and the development of autoimmunity. S1PR1 overexpression in T cells was associated with increased activation of the Akt–mTOR signalling pathway, and pharmacological inhibition of mTOR with rapamycin restored the generation and suppressive activity of S1pr1-transgenic T_Reg cells.

Araki et al. have extended the role of mTOR to the differentiation of CD8⁺ T cells. They showed that mice treated with rapamycin during infection with lymphocytic choriomeningitis virus (LCMV) had increased generation of memory CD8⁺ T cell precursors during the expansion phase of the T cell response and increased survival and memory T cell differentiation of antigen-specific CD8⁺ T cells during the contraction phase of the response. This resulted in an increased number of memory CD8⁺ T cells with improved function. Similar results were obtained in mice and non-human primates using both live and inactivated virus vaccines, and the inhibitory role of mTOR in memory CD8⁺ T cell differentiation was shown to be a T cell-intrinsic effect by comparing T cells with or without expression of mTOR that were adoptively transferred into the same mouse.

The insight provided by these three studies into the role of mTOR in regulating both the quantity and quality of effector, regulatory and memory T cells will be relevant to the design of better immunomodulatory protocols to boost protective immune responses through vaccination or to inhibit autoimmunity and transplant rejection.