Regulation and function of mTOR signalling in T cell fate decisions

Abstract

The kinase mTOR (mammalian target of rapamycin) is part of an evolutionarily conserved pathway that couples cell growth and metabolism to inputs from the environment in all eukaryotes. mTOR exists in two multiprotein complexes in metazoans, mTOR complex 1 (mTORC1) and mTORC2, which have distinct molecular compositions, cellular actions and physiological functions. T cells depend on mTOR signalling to sense and integrate immune signals from dendritic cells (including antigenic signals, co-stimulatory molecules and cytokines), environmental cues derived from growth factors and immunoregulatory factors, and nutrients. Under steady-state conditions, mTOR activity is tightly controlled by multiple inhibitory molecules — in particular the tumour suppressors PTEN (phosphatase and tensin homologue), TSC1 (tuberous sclerosis 1) and LKB1 (liver kinase B1) — to enforce the normal homeostasis of T cells. Loss of these control mechanisms disrupts the development and maintenance of T cells. Antigen recognition triggers robust mTOR activation, which drives the differentiation of naive CD4⁺ T cells into the T helper 1 (T_H1), T_H2 and T_H17 cell effector lineages, while inhibiting the induction of regulatory T cells and T cell anergy. mTOR also promotes an effector fate over a memory fate for CD8⁺ T cells in infection and tumour immunity. mTOR serves as a signalling node to activate several downstream effector pathways, including immune receptor signalling, metabolic programmes and migratory activity. The coordination of these pathways by mTOR is important to achieve a productive immune response. Inhibition of mTOR induces immunosuppression in transplant rejections and autoimmune disorders, but also represents a promising strategy for vaccine development to boost immunity against pathogens and tumours. More potent and selective inhibitors of mTOR and mTOR-associated pathways are being developed for clinical and research purposes.