mTOR signaling at the crossroads of environmental signals and T-cell fate decisions

Abstract

The evolutionarily conserved serine/threonine kinase mTOR (mechanistic target of rapamycin) forms the distinct protein complexes mTORC1 and mTORC2 and integrates signals from the environment to coordinate downstream signaling events and various cellular processes. T cells rely on mTOR activity for their development and to establish their homeostasis and functional fitness. Here, we review recent progress in our understanding of the upstream signaling and downstream targets of mTOR. We also provide an updated overview of the roles of mTOR in T-cell development, homeostasis, activation, and effector-cell fate decisions, as well as its important impacts on the suppressive activity of regulatory T cells. Moreover, we summarize the emerging roles of mTOR in T-cell exhaustion and transdifferentiation. A better understanding of the contribution of mTOR to T-cell fate decisions will ultimately aid in the therapeutic targeting of mTOR in human disease.

Keywords: T cell; Treg cell; iNKT cell; mTOR; metabolism.

Fig. 1. Regulation of mTOR signaling pathways in T cells.

Multiple signals from the TCR, co-stimulatory receptors, cytokines, growth factors, nutrients (amino acids, glucose, and nucleotides), oxygen, and DNA damage tune mTOR activation in T cells. In this figure, positive regulators are shown in ovals, and negative regulators are shown in squares; genes whose effects have been studied in genetic deletion systems are in red. Black solid arrows indicate an activating event, and black flat-ended arrows indicate an inhibitory event.

Fig. 2. The mTOR signaling pathway and its role in metabolic programs and differentiation of T-cell subsets.

A| mTORC1 and mTORC2 integrate nutrient-sensing and signaling pathways to coordinate multiple biological processes. mTORC1 activates protein synthesis through S6 and eIF4E, stimulates nucleotide synthesis through CAD, and promotes mitochondrial biogenesis through PGC-1α. mTORC2 activates AKT, which inhibits apoptosis in part by phosphorylating and inactivating pro-apoptotic factors, such as BAD, BIM, and FAS. In addition, mTORC2 influences T-cell trafficking through CD62L, CCR7, and S1P₁. B| T-cell differentiation requires changes in mTOR-dependent metabolic programs. Th1, Th2, Th17, and effector CD8⁺ T cells use glycolysis (together with amino acid and mitochondria-dependent metabolism) to meet their energy and biosynthetic demands; Treg and memory CD8⁺ T cells exhibit a higher dependency on lipid oxidative phosphorylation in some contexts. mTORC1 activation facilitates the generation of Th1, Th2, Th17, and effector CD8⁺ T cells, whereas mTORC2 activation promotes the generation of Th2 and memory CD8⁺ T cells. The absence of both mTORC1 and mTORC2 activity leads to iTreg cell generation. Both mTORC1 and mTORC2 contribute to Tfh cell differentiation through distinct mechanisms: mTORC1 deficiency reduces the proliferation and expression of ICOS that are necessary for Tfh cell differentiation; in contrast, mTORC2 deficiency impairs Tfh cell differentiation by inhibiting AKT activation and TCF-1 expression.

Fig. 3. mTORC1 signaling in mature effector T-cell maintenance, function, and transdifferentiation.

A mTOR and other signaling pathways during effector-to-memory transition and memory cell maintenance. Upon antigen recognition, naïve CD8⁺ T cells enter cell-division cycles and differentiate to effector CD8⁺ T cells. The transition from effector cells to memory cells and the subsequent maintenance and self-renewal of memory cells are active processes that rely on the interplay between multiple signaling pathways, including the inhibition of mTORC1 activity. Loss of signaling mediated by FOXO1, P2RX7, and AMPK will inhibit the persistence of memory cells either by blocking memory cell programming or fitness. B| mTORC1 activity is critical for tTreg cell–mediated immune tolerance. To maintain their suppressive functions, tTreg cells require continuous stimulation from TCR, co-stimulatory receptors, cytokines (IL-2), and nutrients (amino acids). Diverse mTORC1 components that work in concert or individually orchestrate metabolic pathways and suppressive programs by integrating upstream stimuli to strengthen tTreg-cell function. C| mTORC1 activity instructs Th17-cell transdifferentiation. In the presence of IL-6 and TGF-β, naïve CD4⁺ T cells differentiate to Th17 cells when proper mTORC1 and HIF-1α activity exist. In the model of experimental autoimmune encephalomyelitis (EAE), there are two subsets of Th17 cells, with the one that expresses CD27 and TCF-1 displaying higher stemness features and low anabolic metabolism, and the other one that expresses T-bet showing features of terminal differentiation and metabolic activity. mTORC1 activity controls the transdifferentiation of the CD27⁺TCF-1⁺ subset into the terminal T-bet⁺ Th17 subset to establish EAE.