TOR in the immune system

Abstract

The target of rapamycin (TOR) is a crucial intracellular regulator of the immune system. Recent studies have suggested that immunosuppression by TOR inhibition may be mediated by modulating differentiation of both effector and regulatory CD4 T cell subsets. However, it was paradoxically shown that inhibiting TOR signaling has immunostimulatory effects on the generation of long-lived memory CD8 T cells. Beneficial effects of TOR inhibition have also been observed with dendritic cells and hematopoietic stem cells. This immune modulation may contribute to lifespan extension seen in mice with mTOR inhibition. Here, we review recent findings on TOR modulation of innate and adaptive immune responses, and discuss potential applications of regulating TOR to provide longer and healthier immunity.

Fig. 1. The mTOR signaling pathway

mTOR regulates many cellular activities through two distinct complexes; mTORC1 and mTORC2. mTORC1 is inhibited by the rapamycin-FKBP12 complex. mTORC2 is usually insensitive to rapamycin, but prolonged treatment decreases the mTORC2 activity in some cells. The ribosome is recently found to regulate activation of mTORC2 [68]. Arrows and bars represent activation and inhibition, respectively.

Fig. 2. mTORC1 regulates memory CD8 T cell differentiation

mTORC1 signaling is required for initial T cell proliferation as well as generation of effector T cells. Reducing mTORC1 signaling with rapamycin enhances induction of memory precursor effector cells, resulting in increased number of memory CD8 T cells. It also accelerates memory CD8 T cell differentiation, and improves memory T cell quality than normally found.

Fig. 3. The role of mTOR in differentiation of helper and regulatory T cell subsets

Sufficient mTOR activity induces effector CD4 T helper subsets. On the other hand, a complete or strong block of the signaling prevents the generation of these effector cells, instead promotes Treg differentiation. The effects of partial inhibition of mTOR activity in vivo on effector versus regulatory T cell differentiation are not fully understood. The role of mTOR pathway in development of Tfh as well as memory CD4 T cells is yet to be defined.