An Oscillatory Switch in mTOR Kinase Activity Sets Regulatory T Cell Responsiveness

Procaccini, Claudio; Rosa, Veronica De; Galgani, Mario; Abanni, Luisa; Calı̀, Gaetano; Porcellini, Antonio; Carbone, Fortunata; Fontana, Silvia; Horváth, Tamas L.; Cava, Antonio La; Matarese, Giuseppe

doi:10.1016/j.immuni.2010.11.024

Cited by 313 publications

(347 citation statements)

References 42 publications

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“…The Idd9 interval also includes other genes of interest such as p110d and mTOR, known to be involved in Treg differentiation and function (50)(51)(52), as well as several zinc finger proteins containing Kr€ uppel-associated box domains, which can be involved in cell differentiation and development. Therefore, careful dissection of the Idd9 region is essential to pinpoint the genes of interest.…”

Section: Discussionmentioning

confidence: 99%

Reduced Regulatory T Cell Diversity in NOD Mice Is Linked to Early Events in the Thymus

Ferreira

Palmer

Blake

et al. 2014

The Journal of Immunology

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The thymic natural regulatory T cell (Treg) compartment of NOD mice is unusual in having reduced TCR diversity despite normal cellularity. In this study, we show that this phenotype is attributable to perturbations in early and late stages of thymocyte development and is controlled, at least in part, by the NOD Idd9 region on chromosome 4. Progression from double negative 1 to double negative 2 stage thymocytes in NOD mice is inefficient; however, this defect is compensated by increased proliferation of natural Tregs (nTregs) within the single positive CD4 thymocyte compartment, accounting for recovery of cellularity accompanied by loss of TCR diversity. This region also underlies the known attenuation of ERK-MAPK signaling, which may preferentially disadvantage nTreg selection. Interestingly, the same genetic region also regulates the rate of thymic involution that is accelerated in NOD mice. These findings highlight further complexity in the control of nTreg repertoire diversity.

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Section: Discussionmentioning

confidence: 99%

Reduced Regulatory T Cell Diversity in NOD Mice Is Linked to Early Events in the Thymus

Ferreira

Palmer

Blake

et al. 2014

The Journal of Immunology

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“…A key player in this cellular control is mammalian target of rapamycin (mTOR), an evolutionarily conserved 289-kDa serine/threonine protein kinase inhibited by rapamycin (2-4) that directly influences T cell differentiation and proliferation by integrating environmental cues, including nutrients, energy stores, and growth factors (5-7). The central role of mTOR in T cell metabolism and function is reinforced by recent findings that it influences the generation of regulatory T cells (Tregs) (8)(9)(10), the generation of CD8 + memory cells (11), and the choice between T cell activation and anergy (12,13).…”

Section: N Aive Cd4mentioning

confidence: 99%

Leptin-Induced mTOR Activation Defines a Specific Molecular and Transcriptional Signature Controlling CD4+ Effector T Cell Responses

Procaccini

Rosa

Galgani

et al. 2012

The Journal of Immunology

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The sensing by T cells of metabolic and energetic changes in the microenvironment can determine the differentiation, maturation, and activation of these cells. Although it is known that mammalian target of rapamycin (mTOR) gauges nutritonal and energetic signals in the extracellular milieu, it is not known how mTOR and metabolism influence CD4+CD25−FOXP3− effector T cell (Teff) responses. In this article, we show that leptin-induced activation of mTOR, which, in turn, controls leptin production and signaling, causes a defined cellular, biochemical, and transcriptional signature that determine the outcome of Teff responses, both in vitro and in vivo. The blockade of leptin/leptin receptor signaling, induced by genetic means or by starvation, leads to impaired mTOR activity that inhibits the proliferation of Teffs in vivo. Notably, the transcriptional signature of Teffs in the presence of leptin blockade appears similar to that observed in rapamycin-treated Teffs. These results identify a novel link between nutritional status and Teff responses through the leptin–mTOR axis and define a potential target for Teff modulation in normal and pathologic conditions.

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“…This difference was associated with impairment in the in vivo proliferation of thymusderived Treg cells shown by significantly reduced ex vivo expression of the proliferating cell nuclear antigen (PCNA) in AgRPSirt1 KO mice. Because we have previously shown that the mammalian target of rapamycin (mTOR) kinase plays a key role in the metabolic control of Treg cell responsiveness (17)(18)(19)(20), we also analyzed S6 phosphorylation levels, a measure of mTOR pathway activity in the thymic Treg cell subset. In accordance with previous findings, impaired in vivo proliferation of thymic Treg cells in the AgRP-Sirt1 KO mice was associated with lower activity of mTOR pathway compared with controls ( Fig.…”

Section: Resultsmentioning

confidence: 99%

Hunger-promoting hypothalamic neurons modulate effector and regulatory T-cell responses

Matarese

Procaccini

Menale

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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Whole-body energy metabolism is regulated by the hypothalamus and has an impact on diverse tissue functions. Here we show that selective knockdown of Sirtuin 1 Sirt1 in hypothalamic Agouti-related peptide-expressing neurons, which renders these cells less responsive to cues of low energy availability, significantly promotes CD4 + T-cell activation by increasing production of T helper 1 and 17 proinflammatory cytokines via mediation of the sympathetic nervous system. These phenomena were associated with an impaired thymic generation of forkhead box P3 (FoxP3 + ) naturally occurring regulatory T cells and their reduced suppressive capacity in the periphery, which resulted in increased delayed-type hypersensitivity responses and autoimmune disease susceptibility in mice. These observations unmask a previously unsuspected role of hypothalamic feeding circuits in the regulation of adaptive immune response.immune system | sirtuins H ypothalamic Agouti-related peptide-expressing (AgRP) neurons are mandatory for feeding and survival (1, 2) and they mediate effects of the hystone deacetylase Sirtuin 1 (Sirt1) on energy metabolism (3, 4). Behavioral and metabolic adaptations to low energy availability are enabled by AgRP neurons, but it is unknown whether these neurons are involved in the regulation of other tissue functions key to survival, such as adaptive immune responses. Sirtuins are NAD + -dependent class-III deacetylases that are highly conserved across species (5). Nutrient deprivation up-regulates Sirt1 in several tissues (6, 7), which is important for the metabolic shift that occurs during negative energy balance (8), a metabolic state in which energy expenditure is higher than energy intake. Evidence suggests that the effects of sirtuins may mediate the beneficial effects of calorie restriction, the only known physiological intervention that promotes a longer, healthier lifespan across species (9-14). However, the site of action of sirtuins in these physiological processes remains ill-defined.The CNS was previously recognized as an immune-privileged site with lack of immunosurveillance. However, accumulating evidence has shown that a mutual interaction between the immune system and CNS exists both in physiological and pathological situations (15). The CNS influences and controls the immune system at least partly through the autonomic nervous system (15). Lymphocytes express the receptors for different neurotransmitters, which enable the brain to properly coordinate the immune system and to maintain the homeostasis of the whole body by responding to environmental changes, such as infections, in an appropriate manner. In this context, we and others have shown that nutritional status can affect T helper 1 (Th1) proinflammatory immune responses through a series of adipose-tissue-derived hormones including leptin, which mediates its effects on immune cells either directly by activating leptin receptors on T cells or indirectly by its effect on autonomic nervous system.

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An Oscillatory Switch in mTOR Kinase Activity Sets Regulatory T Cell Responsiveness

Cited by 313 publications

References 42 publications

Reduced Regulatory T Cell Diversity in NOD Mice Is Linked to Early Events in the Thymus

Reduced Regulatory T Cell Diversity in NOD Mice Is Linked to Early Events in the Thymus

Leptin-Induced mTOR Activation Defines a Specific Molecular and Transcriptional Signature Controlling CD4+ Effector T Cell Responses

Hunger-promoting hypothalamic neurons modulate effector and regulatory T-cell responses

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