Paradoxical Aspects of Rapamycin Immunobiology in Transplantation

In the early 1970’s on Easter Island, the compound now known as rapamycin was isolated from Streptomyces hygroscopicus and subsequently found to potently inhibit cell proliferation (1). In the 40 years since its discovery, rapamycin has been shown to have myriad effects on many different cell types in mammals. It is now known that rapamycin mediates these effects by forming a complex with FK506-binding protein 12 (FKBP-12), which binds to and inactivates mammalian target of rapamycin (mTOR) (Figure 1A) (1). mTOR is a serine/threonine protein kinase which is widely expressed among many cell types, and is an important component of several intracellular signaling pathways in naive, effector, and regulatory T cells, involving the PI3K/Akt pathway (Figure 1A) (2). While great strides have been made in the last few years to understand the impact of rapamycin on T cell metabolism, differentiation, and lineage commitment, our current understanding of the effects of rapamycin on T cell biology is encumbered by an unusually high number of paradoxical effects, the mechanisms underlying most of which have yet to be elucidated. Figure 1 Differential effects of rapamycin therapy on antigen-specific CD8+ T cell responses following infection or transplantation