Key roles of autophagy in regulating T‐cell function

Botbol, Yaïr; Guerrero-Ros, Ignacio; Macian, Fernando

doi:10.1002/eji.201545955

Cited by 68 publications

(66 citation statements)

References 94 publications

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“…It allows the orderly degradation of surplus or dysfunctional cellular components . In T cells, it is considered as an important mechanism regulating levels of signaling proteins and modulating cellular metabolism . For example, autophagy deficiency upregulates the metabolic regulators mTORC1 and c‐Myc, and glycolysis, which contribute to defective Treg‐cell function .…”

Section: Introductionmentioning

confidence: 99%

Metabolic programming in chronically stimulated T cells: Lessons from cancer and viral infections

2016

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T-cell metabolism is central to the shaping of a successful immune response. However, there are pathological situations where T cells are rendered dysfunctional and incapable of eliminating infected or transformed cells. Here, we review the current knowledge on T-cell metabolism and how persistent antigenic stimulation, in the form of cancer and chronic viral infection, modifies both metabolic and functional pathways in T cells. Keywords: Cancer r Chronic infection r Metabolism r Negative regulatory receptors r T cells IntroductionQuiescent naive or memory T cells need to increase their cellular energy supply substantially in order to satisfy metabolic demands after antigen stimulation. This is usually achieved by enhancing their capacity for oxidative phosphorylation (OXPHOS), as well as by switching glucose metabolism toward aerobic glycolysis, thereby providing increased supplies of energy and metabolic intermediates necessary for cellular function and proliferation [1]. A successful T-cell response is usually sufficient to clear the antigen. However, there are pathological situations, such as viral infection or cancer, which could lead to T-cell dysfunction due to chronic stimulation by virus-or tumor-derived antigens. The recent observation that chronically stimulated T cells are regulated by specific cell surface inhibitory receptors [2][3][4] has fostered the search for therapies aimed at restoring T-cell function. Whether metabolic reprogramming is also required for restoring T-cell function under chronic antigenic exposure is currently unknown. In this review, we present and discuss the current knowledge about the metabolic requirements of chronically stimulated T cells, with a special emphasis on responses restored after the neutralization of programmed death receptor 1 (PD-1)/PD-Ligand interaction. Metabolism of T cells: At rest and after stimulationWhen resting naive T cells exit the thymus; they have low metabolic requirements that serve to maintain most housekeeping (Fig. 1). To maintain this basal energy-generating metabolism, naive T cells require cell extrinsic signals. The cytokine IL-7, a hematopoietic growth hormone important for T-cell homeostasis, has been shown to promote basal T-cell survival and nutrient uptake [8,9]. IL-7 promotes glucose uptake via a signaling mechanism in which STAT5 transcriptional activity promotes AKT activation to regulate GLUT1 trafficking and glucose uptake that is critical to prevent T-cell death and maintain homeostasis [ 9]. TCR signals are also essential to sustain quiescent naive T cells (Fig. 1). It is generally believed that these cells need to interact with low affinity self MHC/peptide complexes to ensure long-term survival in the periphery [10]. In the absence of TCR ligation, T cells have been shown to rapidly downregulate GLUT1 and limit glucose uptake [11]. This process induces a decrease in mitochondrial potential, cellular ATP production, and glucose-derived metabolic substrates, which leads to apoptosis and progressive contraction of T-cell num...

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Section: Introductionmentioning

confidence: 99%

Metabolic programming in chronically stimulated T cells: Lessons from cancer and viral infections

2016

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“…Unfortunately, most of the effective drugs are immunosuppressants that shut down the entire immune system (reviewed in [39]). Interestingly, several studies demonstrated that autophagy (macroautophagy and CMA) are important for the differentiation and activation of lymphocytes [39,[111][112][113][114][115][116][117][118]. In accordance, autophagy dysregulation has been described in various autoimmune diseases and some of the current treatment suggestions include autophagy regulators [39].…”

Section: Autoimmune Diseasesmentioning

confidence: 91%

Assessing Autophagy in Archived Tissue or How to Capture Autophagic Flux from a Tissue Snapshot

Humbert

Morán

Cruz‐Ojeda

et al. 2020

Biology

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Autophagy is a highly conserved degradation mechanism that is essential for maintaining cellular homeostasis. In human disease, autophagy pathways are frequently deregulated and there is immense interest in targeting autophagy for therapeutic approaches. Accordingly, there is a need to determine autophagic activity in human tissues, an endeavor that is hampered by the fact that autophagy is characterized by the flux of substrates whereas histology informs only about amounts and localization of substrates and regulators at a single timepoint. Despite this challenging task, considerable progress in establishing markers of autophagy has been made in recent years. The importance of establishing clear-cut autophagy markers that can be used for tissue analysis cannot be underestimated. In this review, we attempt to summarize known techniques to quantify autophagy in human tissue and their drawbacks. Furthermore, we provide some recommendations that should be taken into consideration to improve the reliability and the interpretation of autophagy biomarkers in human tissue samples.

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“…Au-delà de son rôle protecteur lors de stress énergétiques, l'autophagie est impliquée de manière décisive dans la régulation de l'immunité, en particulier dans le développement, l'éducation et l'homéostasie des lymphocytes [11] ainsi que lors de la présentation antigénique. Divers modèles murins d'invalidation conditionnelle sont venus étayer le rôle primordial de plusieurs gènes liés à l'autophagie dans la fonction des LT, les données générées dans les LB demeurant encore complexes à analyser à ce jour [12][13][14][15][16][17][18]. Différents gènes autophagiques arbitrent en effet la qualité des fonctions des thymocytes.…”

Section: Synthèse Revuesunclassified

Autophagie, auto-immunité et maladies auto-immunes

Muller

2017

Med Sci (Paris)

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Autoimmune diseases such as systemic lupus, are the consequence of immunity directed against the organism itself. The immune system abnormally recognizes self-components as foreign and produces antibodies targeting normal cells and tissues. We and others have discovered a number of failures affecting autophagy pathways in the lymphocytes of model mice and patients with lupus. While the current treatments are mainly based on immunosuppressive drugs that can lead to important side effects, the synthetic phosphopeptide P140/Lupuzor, which targets chaperone-mediated autophagy and displays no side effects, holds a lot of promise as a drug candidate. P140, which is currently evaluated in a phase III clinical trial, targets chaperone-mediated autophagy that is hyperactivated in lupus mice, and reduces antigenic peptides presentation to autoreactive helper T cells. Remarkably, we showed in lupus mice that upon treatment with P140, a number of immunological abnormalities affecting the pool of T and B cells as well as many biological and clinical features no longer occur.

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Key roles of autophagy in regulating T‐cell function

Cited by 68 publications

References 94 publications

Metabolic programming in chronically stimulated T cells: Lessons from cancer and viral infections

Metabolic programming in chronically stimulated T cells: Lessons from cancer and viral infections

Assessing Autophagy in Archived Tissue or How to Capture Autophagic Flux from a Tissue Snapshot

Autophagie, auto-immunité et maladies auto-immunes

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