mTOR regulates memory CD8 T-cell differentiation

Abstract

Memory CD8 T cells are a critical component of protective immunity and inducing effective memory T cell responses is a major goal of vaccines against chronic infections and tumors 1-3. Considerable effort has gone into designing vaccine regimens that will increase the magnitude of the memory response but there has been minimal emphasis on developing strategies to improve the functional qualities of memory T cells 4. In this study we show that mTOR, the mammalian target of rapamycin 5, is a major regulator of memory CD8 T cell differentiation and in contrast to what we expected the mTOR specific inhibitor rapamycin, an immunosuppressive drug, had surprising immunostimulatory effects on the generation of memory CD8 T cells. Treatment of mice with rapamycin following acute lymphocytic choriomeningitis virus (LCMV) infection enhanced not only the quantity but also the quality of virus specific CD8 T cells. Similar effects were seen after immunization of mice with a non-replicating VLP based vaccine. In addition, rapamycin treatment also enhanced memory T cell responses in non-human primates following vaccination with MVA (modified vaccinia virus - Ankara). Rapamycin was effective during both the expansion and contraction phases of the T cell response; during the expansion phase it increased the number of memory precursors and during the contraction phase (effector to memory transition) it accelerated the memory T cell differentiation program. Experiments using RNAi to inhibit mTOR, raptor or FKBP12 expression in antigen specific CD8 T cells showed that mTOR acts intrinsically through the mTORC1 pathway to regulate memory T cell differentiation. Thus, these studies identify a molecular pathway regulating memory formation and provide an effective strategy for improving the functional qualities of vaccine or infection induced memory T cells.

Combination of dual mTORC1/2 inhibition and immune-checkpoint blockade potentiates anti-tumour immunity

“…To our knowledge, this data represents the first evidence of a dose-dependent immune potentiating impact of mTOR signalling in primary effector T-cells. These findings are in keeping with evidence that rapamycin promotes the accumulation of T-cell memory cells during viral infection or vaccination, 36,48 and that mTOR plays a generalized role to limit biological lifespan. 49 In addition, given that mTOR inhibition is known to promote autophagy, 50 our results may extend findings by Xu et al., who linked autophagy to enhanced effector T-cell survival and differentiation during immune responses to chronic viral infection, 51 Further study will be required to delineate the contributions of downstream mTOR-dependent processes that limit intratumoral immunity.…”

“…5C). Whilst a pro-survival phenotype following mTOR inhibition has been previously reported in memory precursor cells, 36 this represented an unexpected finding in freshly activated T-effector cells. To better understand the mechanism underlying vistusertib-dependent CD8 T-effector cell survival, we examined the expression of a panel of pro- and anti-apoptotic factors that have been previously associated with T-cell population dynamics in the thymus.…”

Contrasting effects of chronic, systemic treatment with mTOR inhibitors rapamycin and metformin on adult neural progenitors in mice

“…Scale bar=100 μm. Data are presented as representative of ≥5 mice per group rapamycin was selected to match previously reported dosage that enhanced CD8 memory T cell generation (Araki et al 2009). The high rapamycin dosage was selected to match the concentration reported to extend life span (Miller et al 2011).…”

Chronic mTOR inhibition in mice with rapamycin alters T, B, myeloid, and innate lymphoid cells and gut flora and prolongs life of immune‐deficient mice

“…As much work also supports rapamycin‐mediated improvements in T‐cell functions (Ferrer et al ., 2010), including improved antigen‐specific T‐cell memory (Araki et al ., 2009), much additional investigation is merited. Our demonstrations of preserved naïve phenotypes in B and T cells in aged mice on eRapa support potential benefits for antigen‐specific immunity and could be related to its reported rejuvenating effect on hematopoietic stem cells (Chen et al ., 2009).…”

“…However, mTOR also mediates profound functional and differentiation effects on major immune cell populations, including CD8 + T cells (Araki et al ., 2009), CD4 + regulatory and nonregulatory T cells (Chi, 2012), and myeloid and B cells (Weichhart & Saemann, 2009). Immunosuppression is a major concern with long‐term mTOR inhibition, but recent data show that rapamycin can boost antipathogen (Keating et al ., 2013) and antitumor immunity (Diken et al ., 2013) and was not detrimentally immunosuppressive in a mouse organ transplant model (Ferrer et al ., 2010).…”