mTOR regulates memory CD8 T cell differentiation

By K. Araki, A. Turner, V. Shaffer, Shivaprakash Gangappa, Susanne A. Keller, M. Bachmann, C. Larsen, Rafi Ahmed. Nature, 2009

1,595 citations recorded by the source corpus.

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 tumours. 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. Here we show that mTOR (mammalian target of rapamycin, also known as FRAP1) is a major regulator of memory CD8 T-cell differentiation, and in contrast to what we expected, the immunosuppressive drug rapamycin has immunostimulatory effects on the generation of memory CD8 T cells. Treatment of mice with rapamycin following acute lymphocytic choriomeningitis virus 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 vaccine based on non-replicating virus-like particles. In addition, rapamycin treatment also enhanced memory T-cell responses in non-human primates following vaccination with 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 RNA interference to inhibit expression of mTOR, raptor (also known as 4932417H02Rik) or FKBP12 (also known as FKBP1A) in antigen-specific CD8 T cells showed that mTOR acts intrinsically through the mTORC1 (mTOR complex 1) 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.

Subfields: Immunology

View Paper: https://www.semanticscholar.org/paper/fa0d427543b2a5c7f5862aa463256f6d3677d840

How researchers see this paper

The researchers whose trusted networks rank it highest, strongest advocate first. Every researcher gets a different order.

In Immunology

Citations in the corpus

Cutting Edge: Distinct Glycolytic and Lipid Oxidative Metabolic Programs Are Essential for Effector and Regulatory CD4+ T Cell Subsets (2011, background): “At the conclusion of an immune response, decreased glycolysis and increased lipid oxidation can favor the enrichment of long-lived CD8 memory cells (5, 6).”
Combining Immunotherapy and Targeted Therapies in Cancer Treatment (2012, background): “However, recent evidence suggests that under some conditions mTOR inhibitors may have a stimulatory effect on T cell”
Metabolic Regulation of Immune Responses (2014, background): “Although the metabolic importance of mTORC1 in CD8+ memory T cells remains to be explored, its inhibition by rapamycin has been shown to increase their numbers and enhance their function in both mice and nonhuman primates (105, 106).”
Metabolic Instruction of Immunity (2017, neutral): “However, dampening regulators of glycolytic metabolism, such as mTOR or c-Myc, and increasing mitochondrial FAO-dependent OXPHOS favors the formation of long-lived memory T cells (Araki et al., 2009; Cui et al., 2015; O’Sullivan et al., 2014; Pearce et al., 2009; Pollizzi et al., 2016; van der Windt”
Spermidine in health and disease (2018, result): “Spermidine also directly improves the generation and function of memory lymphocytes, similar to what is known for other autophagy inducers such as rapamycin (107) or metformin (108).”
Fueling Immunity: Insights into Metabolism and Lymphocyte Function (2013, background): “Consistent with this, the drug rapamycin, which also inhibits mTORC1, enhances the generation of CD8 TM cells (17, 19, 20).”
T cell metabolism drives immunity (2015, background): “Inhibiting mTOR with rapamycin boosts memory T cell development in vivo (Araki et al., 2009; Pearce et al., 2009; Rao et al., 2010).”
Metabolic Regulation of T Lymphocytes (2013, background): “Although the mTORC1 inhibitor rapamycin can suppress T cell activation when given early, lower or delayed rapamycin treatment did little to impact the primary T cell response but paradoxically increased CD8+ T cell memory (92, 93).”
Bioenergetic insufficiencies due to metabolic alterations regulated by PD-1 are an early driver of CD8+ T cell exhaustion (2016, background): “This treatmentmildly reduced the number of virus-specific T cells (Figures 4B and 4C) as expected based on the role of mTOR in effector CD8+ T cell expansion (Araki et al., 2009; Pearce et al., 2009).”
From Vaccines to Memory and Back (2010, neutral): “Recent studies identified signaling pathways that appear to be involved in the differentiation of memory stem cells as well as drugs that favor the generation of T CM cells (Araki et al., 2009; Gattinoni et al., 2009; Pearce et al., 2009).”
mTOR Signaling in Growth, Metabolism, and Disease (2017, background): “…T cell maturation, as rapamycin promotes the differentiation and expansion of CD4+FoxP3+ Regulatory T cells and CD8+ memory T cells while suppressing CD8+ and CD4+ effector T cell populations (Araki et al., 2009; Haxhinasto et al., 2008), consistent with the metabolic profiles of these cell types.”
The multifaceted role of CD4+ T cells in the regulation of CD8+ T cell memory maturation (2015, neutral): “Consistent with this, inhibition of mammalian target of rapamycin (mTOR) promotes fatty acid oxidation and increases the formation of memory cells 92 .”