mTOR signaling in the differentiation and function of regulatory and effector T cells

Abstract

The mechanistic target of rapamycin (mTOR) signaling pathway integrates environmental signals and cellular metabolism to regulate T cell development, activation and differentiation. Recent studies reveal the importance of exquisite control of mTOR activity for proper T cell function, and detailed molecular mechanisms that regulate mTOR signaling in different T cell subsets. Here, we review the latest advances in our understanding of the mTOR pathway and its regulation in the differentiation and function of regulatory T cells and effector T cells.

Figure 1

Optimal mTOR activity (Goldilocks mTOR) is required for proper T cell differentiation and function. (Upper panel) Over-activation of mTORC1 destabilizes Tregs and impairs their suppressive function. This abolishes naïve T cell quiescence, disrupts Myc asymmetric distribution, promotes Th9 differentiation, and reduces memory CD8⁺ T cell differentiation. Loss of mTORC1 activity reduces Treg suppressive function, impairs effector CD4⁺ and CD8⁺ T cell differentiation, abolishes Myc asymmetry, and diminishes memory T cell function. However, a modest reduction of mTORC1 activity enhances memory CD8⁺ T cell differentiation and function. It is currently unclear the extent to which the reduction of mTORC1 is beneficial. (Lower panel) Over-activation of mTORC2 promotes Treg instability and impairs Treg-mediated suppression of Th1 and Tfh differentiation. While loss of mTORC2 does not affect Treg function, it increases thymic tTreg generation and reduces Th1 and Tfh differentiation. In CD8⁺ T cells, mTORC2 deficiency does not affect effector T cell generation and function, but enhances memory T cell formation. Finally, loss of both mTORC1 and or mTORC2 enhances iTreg differentiation.

Figure 2

Multiple upstream inputs impinge upon mTOR signaling in T cells under various contexts. There are positive signals, including S1PR1, TLR1, TLR2, TCR, IL-2, ICOS, SEMA4A/PLEXIN B2, CaMK4, RA, and amino acid transporters ASCT2 and System L amino acid transporter (a heterodimer composed of LAT1 and CD98). ASCT2 and System L amino acid transporter mediate uptake of glutamine and leucine, respectively, which potently activate mTORC1. The expression of these amino acid transporters is induced by TCR activation. Negative signals include potassium channel Kv1.3-mediated transport of potassium ion (K⁺) (it engages PP2A), NRP1, SIRT1, autophagy, microRNA (miR)-99a, miR150, miR15b/16, and Foxp3. Please see main texts for details. Abbreviations: RA, retinoic acid; PP2A, protein phosphatase 2A; NRP1, neuropilin-1; S1PR1, sphingosine-1-phosphate receptor 1; PTEN, phosphatase and tensin homolog; TLR, toll-like receptor; Gln, glutamine; Leu, leucine; SEMA4A, semaphorin; CaMK4, calcium/calmodulin-dependent protein kinase IV; SIRT1, sirtuin1.