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• W2079413281 abstract "Memory CD8+ T cells can provide exceptionally long-term immunity against re-infection, which is in part because of their enhanced longevity and maintenance of a high proliferative capacity. During a viral infection, the activated CD8+ T cells undergo a vigorous wave of proliferation and differentiate into cytotoxic killer T cells that eliminate infected cells. However, after pathogen clearance, the antiviral CD8+ T cells ‘gear down’ by halting cell division and the production of effector molecules.1 Most of the activated CD8+ T cells die after infection, but a minority of the cells become long-lived and develop into memory T cells that are poised to rapidly respond to reinfection. Between these two phases of the immune response, the antiviral T cells undergo a dramatic metabolic switch from an activated effector to a resting memory cell,2 but how this switch is regulated is unclear. In addition, little is known about the nature of the metabolic state that confers longevity in memory T cells and their precursors. Recently, two studies in Nature3, 4 have shed some light on this interesting question and show that two central regulators of cellular metabolism—the stress-sensing adenosine monophosphate (AMP) kinase (AMPK) and the nutrient-sensing mammalian target of rapamycin (mTOR)—control the effector → memory transition and are integrally involved in the differentiation of memory T cells. These studies found that treatment of mice during acute viral or bacterial infection with two metabolically active drugs, rapamycin and metformin, increased effector CD8+ T cell survival after infection, and that rapamycin also hastened the development of memory T cells from the effector population.3, 4 In the case of rapamycin, this was especially surprising given that it is a common immunosuppressant used to prevent T-cell proliferation and rejection of solid organ transplants. An interesting intersection is that both of these drugs inhibit the target of rapamycin complex 1 (TORC1), indicating an unanticipated role for this complex in memory cell development. At the heart of the TORC1 complex lies the rapamycin-sensitive serine/threonine kinase mTOR, and in response to a variety of environmental cues, such as increased nutrient availability and growth factors (including T-cell receptor (TCR) and common-gamma chain cytokine signaling, in the case of T cells), this complex promotes cell growth, protein synthesis and proliferation.2, 5 In activated T cells, TCR and phosphoinositide 3-kinase/AKT signaling pathways activate TORC1 to induce anabolic metabolism and glycolysis, which provide the necessary macromolecules for clonal expansion and effector cell differentiation, and actively repress catabolic processes such as fatty acid oxidation (FAO) and autophagy.2 In the face of cellular stress, such as nutrient or glucose deprivation, cytokine withdrawal or low energy levels (for example, increased AMP:ATP ratio), AMPK is activated and inhibits TORC1, permitting cells to utilize other energy-producing pathways that diminish cell stress.6 Thus, these two kinases work in opposition to maintain cellular homeostasis by appropriately coordinating a cell's metabolism with its surroundings. Following clonal expansion and pathogen clearance, effector T cells are believed to contract because they are deprived of critical growth factors (such as interleukin (IL)-2).1 The recent work of Pearce et al.4 suggests that this activates AMPK and is necessary for robust memory T-cell generation. This finding came to light while trying to determine why T cells lacking the molecule TRAF6 (TRAF6KO) are unable to form memory T cells, despite the normal expansion of effector T cells. Comparing gene expression profiles between wild-type (WT) and TRAF6KO CD8+ T cells, the authors identified that TRAF6KO T cells have reduced expression of enzymes involved in FAO. Indeed, activated TRAF6KO T cells were deficient in AMPK activation and unable to up-regulate FAO after IL-2 withdrawal in vitro.4 Finally, the authors showed that in vivo administration of the drugs metformin (which activates AMPK and FAO and is therapeutic for type II diabetes) and rapamycin not only rescued formation of protective memory T cells in the TRAF6KO cells, but also enhanced the recall responses of WT memory CD8+ T cells. Interestingly, other recent studies show that the AMPK and mTOR pathways may not simply govern the metabolism of activated T cells, but that these pathways also influence T-cell differentiation.3, 7, 8, 9 In the same issue of Nature, Araki et al.3 treated mice with a relatively low dose of rapamycin during different phases of the immune response to lymphocytic choriomeningitis virus. Treatment of mice during and after infection, or even just during the first week resulted in the formation of significantly greater numbers of memory CD8+ T cells. Moreover, rapamycin treatment substantially increased the proportion of effector CD8+ T cells that resembled memory precursor cells and had increased expression of IL-7R, bcl-2, CD62L and CD27, and decreased expression of KLRG1.3, 10, 11 When mice were treated with rapamycin after the first week of infection (during the contraction phase), it did not greatly augment memory T-cell survival but did significantly accelerate the process by which high-functioning, central memory T cells develop from the effector population. Similar to that seen by Pearce et al.,4 these rapamycin-treated memory CD8+ T cells produced more potent and protective responses against secondary infections. These effects of rapamycin were intrinsic to the CD8+ T cells because the authors showed similar effects by using short hairpin RNA interference to knock down components of TORC1 in the virus-specific CD8+ T cells.3 Thus, the surprising positive effects of rapamycin seem to be tied to limiting or reversing the terminal differentiation of effector CD8+ T cells during infection, thereby inducing or maximizing the survival of effector/memory T cells of a ‘higher fitness level’ (Figure 1). Whether metformin has similar effects on effector and memory CD8+ T-cell differentiation remains to be tested. The role of mTOR in T-cell differentiation is becoming more prominent as other recent reports7, 8, 9 have shown that mTOR is necessary for Th1, Th2 and Th17 effector CD4 T-cell development, yet it represses the development of regulatory CD4 T cells (Tregs). Specifically, activated CD4 T cells lacking mTOR (or treated with rapamycin) were unable to induce expression of the appropriate lineage-determining transcription factor, such as T-bet, GATA3 or rorγt, to adopt the respective Th1, Th2 or Th17 cell fates. Instead, the cells upregulated FoxP3 and differentiated into Tregs. With regard to T-bet, it is likely that a similar scenario is occurring in CD8+ T cells because lowered expression of T-bet permits development of memory precursor effector cells whereas higher expression induces terminal differentiation of effector cells with a shortened life span, and rapamycin treatment enhanced the formation of long-lived memory precursor cells.3, 10 On this note, it is salient to point out that the TORC1 complex is an important mediator of the aging process. For example, inactivating mutations in the key subunits of this complex or rapamycin treatment increases the life span of flies, worms and mice.12, 13, 14 By analogy, it appears that a reduction in mTOR and/or an increase in AMPK activity extends the life span of activated T cells, perhaps by diminishing cell stress and regulating mitochondrial function.15, 16 The discovery of the effects of rapamycin and metformin on T-cell differentiation, survival and function will likely lead to new ways to improve or modulate T-cell function for generating more effective vaccines and immunotherapies aimed at infectious diseases, cancer and autoimmunity. Given that these drugs are already currently approved for clinical use, such interventions may be achievable in the not-so-distant future. Role of mammalian target of rapamycin (mTOR) in the effector to memory CD8+ T-cell transition during infection. (a) On activation, CD8+ T cells acquire an anabolic mode of metabolism to synthesize all the necessary macromolecules for rapid cell proliferation and synthesis of antiviral cytokines and cytotoxic molecules needed to eliminate intracellular microbes. Target of rapamycin complex 1 (TORC1) is activated by the T-cell receptor and phosphoinositide 3-kinase/Akt pathways in response to stimulation from antigen and newly-made-available T-cell growth factors (such as interleukin-2 and other cytokines). TORC1 activation causes the cells to become glycolytic and promotes their terminal differentiation into short-lived effector CD8+ T cells (possibly by regulating the expression of T-bet and eomesodermin). Following clearance of the pathogen, antigen and T-cell growth factors decline, inducing a state of stress in the effector CD8+ T cells that activates adenosine monophosphate kinase (AMPK). This causes the CD8+ T cells to switch to a catabolic mode of metabolism in order to generate adenosine triphosphate from other pathways, including FAO. Consequently, the function of mTOR declines and this contributes to the formation of mature central memory T cells (TCM) that provide rapid and potent protection against reinfection. (b) Effects of rapamycin on the differentiation of effector and memory CD8+ T cells. Low doses of rapamycin during clonal expansion reduces the frequency of terminally differentiated effector CD8+ T cells and increases the number of memory precursor effector cells. It also hastens the maturation of the memory CD8+ T-cell population, resulting in faster development of TCM cells and more responsive memory CD8+ T cells than normally found." @default.
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• W2079413281 date "2009-09-22" @default.
• W2079413281 modified "2023-09-27" @default.
• W2079413281 title "Decreasing the TORC on memory CD8 T‐cell formation" @default.
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• W2079413281 doi "https://doi.org/10.1038/icb.2009.72" @default.
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