Insight into the role of mTOR and metabolism in T cells reveals new potential approaches to preventing graft rejection

Abstract

Purpose of review In this review, we discuss the recent advances with regard to the 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. Recent findings 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. Summary 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.

Preventing Allograft Rejection by Targeting Immune Metabolism

“…Further, even though we observed 100% heart graft survival (Figure 4D) while the mice were being treated, preliminary studies indicate that stopping therapy resulted in the eventual rejection of the hearts approximately 80 days later (data not shown). To this end, we are actively pursuing integrating tolerance inducing therapy such as costimulatory blockade with our anti-metabolic regimen (Bestard et al, 2011; Lo et al, 2014; Oderup et al, 2006; Pilon et al, 2014). …”

Feeding an army: The metabolism of T cells in activation, anergy, and exhaustion

“…This compound (also known as sirolimus) is a potent immunosuppressant that could result in tolerance and has been used extensively in transplantation [40-42]. Study of its downstream target, the mechanistic target of rapamycin (mTOR), revealed that costimulation, the net sum of positive costimulatory and negative coinhibitory signals, was routed in part through mTOR.…”

BK Polyomavirus and the Transplanted Kidney

“…It also has an impact on effector T cell metabolic programming and TReg generation and maintenance. 124 In addition, Sirolimus was shown in vitro to reduce LT antigen replication but not BK virus DNA replication. 125 This could also occur in vivo and provide direct antiviral effects.…”