mTOR: A Target for Enhancing Memory T-Cell Generation

Rapamycin, a natural bacterial product first found on Easter Island (Rapa Nui), was originally studied as an antifungal agent, but it was soon found to have potent anti-proliferative and immunosuppressive properties. It is now used to promote graft tolerance in solid organ transplantation, prevent graft-versus-host disease after hematopoietic stem cell transplantation, and prevent re-stenosis after angioplasty. Two rapamycin derivatives have recently been approved as anti-cancer agents. Rapamycin inhibits a protein known as mammalian target of rapamycin (mTOR), which is a central node that integrates input from many signaling pathways, including nutrient-sensing pathways, to control mRNA translation and cell proliferation. Initially, rapamycin was thought to cause immunosuppression through inhibition of antigen-specific T-cell proliferation; however, more recent studies have shown that it also promotes differentiation of regulatory T cells¹  and modulates innate immune cell responses.² 

With this background, observations that rapamycin enhances formation of memory T cells, as reported by the labs of Yongwon Choi at the University of Pennsylvania and Rafi Ahmed at Emory University, were unexpected. Using different approaches, they demonstrated that alterations in cellular metabolism are critical for memory T-cell development. Pearce et al. studied tumor necrosis factor receptor-associated factor 6 (TRAF6)-deficient mice. These mice mounted a normal effector response to viral infection but then failed to develop memory T cells. Using microarray analysis, they found that TRAF6-deficient mice failed to up-regulate genes required for fatty acid oxidation (FAO). Treatment of TRAF6-deficient mice with rapamycin reversed the FAO defect and rescued memory T-cell development. Metformin, which activates an inhibitory kinase that blocks mTOR and promotes FAO, also rescued memory T-cell generation. Interestingly, both drugs markedly increased memory T-cell development in both TRAF6-deficient and normal mice, enhancing recall responses to secondary infections and even tumor challenge. Araki et al. performed similar studies in murine and primate models and found that rapamycin treatment during the initial viral infection and subsequent expansion phase led to increased numbers of memory T cells, while treatment during the contraction phase after the peak of the T-cell response accelerated memory T-cell differentiation, with the resultant memory T cells showing enhanced recall ability.