The role of mTOR in memory CD8 T-cell differentiation

Abstract

The mammalian target of rapamycin (mTOR) is an intracellular kinase that regulates cell growth and metabolism. Its specific inhibitor rapamycin is currently used in transplant recipients as an immunosuppressive drug to prevent allograft rejection. Studies have shown complex and diverse mechanisms for the immunosuppressive effects of rapamycin. The drug has been reported to inhibit T-cell proliferation, induce anergy, modulate T-cell trafficking, promote regulatory T cells, and also prevent maturation of dendritic cells as well as production of type I interferon. However, several other studies have paradoxically demonstrated immunostimulatory effects of rapamycin by improving antigen presentation and regulating cytokine production from macrophages and myeloid dendritic cells. Recently, it has been shown that rapamycin also exhibits immunostimulatory effects on memory CD8(+) T-cell differentiation. The drug improved both quantity and quality of memory CD8(+) T cells induced by viral infection and vaccination, showing that mTOR is a major regulator of memory CD8(+) T-cell differentiation. These discoveries have implications for the development of novel vaccine regimens. Here, we review the role of mTOR in memory CD8(+) T-cell differentiation and compare the effect of rapamycin among CD8(+) T cells, CD4(+) T cells, and dendritic cells. Also, we discuss potential application of these findings in a clinical setting.

Fig. 1. Memory CD8⁺ T-cell differentiation

(A) Antigen-specific CD8⁺ T-cell responses after an acute infection. During the expansion phase, naive CD8⁺ T cells proliferate and then become effector cells. After clearance of the pathogen, 90 to 95% of the effector T cells die during a contraction phase. The surviving 5-10% of the antigen-specific T cells become the memory population. (B) Progressive memory CD8⁺ T-cell differentiation and the subsets of effector and memory CD8⁺ T cells. (C) Several key cell surface and intracellular markers for memory CD8⁺ T-cell differentiation. (D) Some of the key phenotypic changes associated with memory CD8⁺ T-cell quality.

Fig. 2

Structure of rapamycin.

Fig. 3. The mTOR signaling cascade

The kinase mTOR forms two distinct complexes: mTOR complex 1 (mTORC1) and mTOR complex 2 (mTORC2). Rapamycin needs to bind to the intracellular partner FKBP12 to exert its effect in the target cell. Rapamycin-FKBP12 complex inhibits activation of mTORC1 by directly binding to mTORC1. mTORC2 is not inhibited directly by rapamycin, but prolonged rapamycin treatment reduces the mTORC2 activity in some cells. Arrows and bars represent activation and inhibition, respectively.

Fig. 4. Rapamycin improves the quantity and quality of memory CD8⁺ T cells

(A) Without rapamycin treatment. (B) Rapamycin treatment during T-cell expansion phase. Rapamycin increases memory precursor effector cells that survive during the contraction phase. Higher quantity of memory T cells is formed compared to control. (C) Rapamycin treatment during T-cell contraction phase. Rapamycin accelerates effector to memory T-cell formation, and improves quality of memory T cells. (D) Rapamycin treatment during both the expansion and contraction phase. Rapamycin improves both quality and quantity of memory CD8⁺ T cells.