In this review, we discuss the recent advances with regard to the mammalian target of rapamycin (mTOR) signaling pathway and focus on how this pathway modulates immune responses. Overall, these insights provide important clues in terms of strategically integrating mTOR and metabolic inhibitors into transplantation rejection protocols.
mTOR is regulated by environmental cues and activates diverse downstream pathways to guide cell growth and fate. What has emerged from recent studies is that mechanistically mTOR directs T cell differentiation and function in part by regulating metabolic programs. Such findings not only inform us with regard to the metabolic demands of effector and memory T cells but also elucidate metabolic pathways that might be targeted to selectively regulate immune responses.
Initial studies focused on the ability of the mTOR inhibitor rapamycin to suppress immune responses by inhibiting T cell proliferation. Since then, both pharmacologic and genetic studies have revealed a central role for mTOR in regulating T cell activation, differentiation, and function independent of proliferation. Specifically, it has become clear that mTOR plays an important role in regulating the metabolic machinery necessary for effector, regulatory, and memory T cell generation. As such, direct inhibition of metabolism may emerge as a potent and selective means of preventing graft rejection. This review will discuss new insights regarding the ability of downstream signaling pathways, including mTOR-dependent metabolic pathways in regulating T cell responses. Finally, we will discuss these new insights in the context of developing novel immunoregulatory regimens for transplantation.
aDepartment of Oncology, School of Medicine, Johns Hopkins University, Baltimore, Maryland, USA
bChang-Gung Transplantation Institute, Department of Liver and Transplantation Surgery, Chang-Gung Memorial Hospital, Chang-Gung University College of Medicine, Taoyuan, Taiwan
*These authors contributed equally to the writing of this article.
Correspondence to Dr Jonathan D. Powell, Cancer Research Building 1, Room 443, 1650 Orleans Street, Baltimore, MD 21231, USA. Tel: +410 502 7887; fax: +410 614 9705; e-mail: firstname.lastname@example.org