mTOR: A Target for Enhancing Memory T-Cell Generation

Mary Philip MD, PhD, and Michael Linenberger, MD

2010-01-01

Drs. Philip and Linenberger indicated no relevant conflicts of interest.

Pearce EL, Walsh MC, Cejas PJ, et al. Enhancing CD8 T-cell memory by modulating fatty acid metabolism. Nature. 2009; 460:103-7.

Araki K, Turner AP, Shaffer VO, et al. mTOR regulates memory CD8 T-cell differentiation. Nature.2009;460:108-12.

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.

Previous work has shown that naïve, quiescent T cells display a catabolic metabolic signature, generating energy mainly through oxidative phosphorylation.3 Upon stimulation, activated T cells shift to anabolic metabolism, relying on a high rate of glycolysis. The studies by Pearce et al. and Araki et al. complete the circle by demonstrating that a shift back to catabolic metabolism is necessary for effector cells to differentiate into memory T cells. Moreover, the observation that rapamycin increases memory T-cell generation and secondary immune responses raises the exciting prospect that manipulation of the mTOR pathway could augment memory T-cell responses to vaccinations. To recapitulate this activity in humans, derivatives of rapamycin or more specific downstream inhibitors may be required. It will also be important to define the pleiotropic effects of mTOR inhibitors on regulatory and memory T-cell development and graft tolerance, especially in transplant patients. Meeting these challenges, however, could have a profound clinical impact if modulation of this molecular pathway leads to more effective immunotherapeutic approaches against infectious diseases and malignancies.

  1. Delgoffe GM, Kole TP, Zheng Y, et al. The mTOR kinase differentially regulates effector and regulatory T cell lineage commitment. Immunity. 2009;30:832-44.
  2. Thomson AW, Turnquist HR, Raimondi G. Immunoregulatory functions of mTOR inhibition. Nat Rev Immunol. 2009;9:324-37.
  3. Jones RG, Thompson CB. Revving the engine: signal transduction fuels T cell activation. Immunity. 2007;27:173-78.

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