Figure 1. Reciprocal consequences of mTOR activation in APCs and T cells may be host protective or disease promotive.

Innate (e.g. TLRs) or adaptive signals (e.g. CD40) trigger the PI3 kinase-Akt-mTOR signaling cascade in the APCs. Activation of mTORc1 leads to the phosphorylation of 4E-BP1/2 and initiation of protein translation. Pathogenic virulence factors such as Gp63 and antibiotic rapamycin (RAPA) inhibit mTOR activation and hence downregulate translation of type I interferons and iNOS (inducible nitric oxide synthase). Inhibition of 4E-BP1/2 can selectively upregulate translation and hence may be an attractive drug target. mTOR activation can also upregulate anti-inflammatory molecule IL-10 and inhibits the proinflammatory molecules, such as IL-12. IL-10 may skew Th0 cells to the disease-promoting Th2/Treg cells, whereas IL-12 and other proinflammatory cytokines can enhance the Th1/Th17 axis. Activation of mTOR signaling by inhibition of TSC1/TSC2 (tuberous sclerosis complex) or inhibition of Rictor (rapamycin-insensitive companion of mTOR, an essential component of mTORc1 signaling), especially at the early stage of an infection, can boost the propensity of these cells to be skewed towards Th1 phenotype. mTOR inhibition of Treg cells by rapamycin can augment expansion of Treg cells with increased suppressive capacity. This can be prevented by the activation of mTOR by inhibiting TSC1/2 or PTEN (Phosphatase and TENsin homolog) and may be a lucrative drug target at the later stages of an infection. On the other hand, inhibition of mTOR signaling in memory cells can improve the memory cell differentiation. Blockade of mTOR by pharmacological and genetic ablation enhances the quality and quantity of surviving memory. Targeted inhibition of mTOR in memory cells can thus be an attractive drug target especially at the later stage of infection.