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Metabolic reprogramming in memory CD4 T cell responses of old adults.

ABSTRACT: To determine whether aging affects the ability of T cells to undergo metabolic reprogramming upon activation, we compared CD4 T cell responses after polyclonal in vitro stimulation. Compared to younger adults, CD4 memory T cells from healthy older individuals exhibited a higher upregulation of oxidative phosphorylation with increased production of reactive oxygen species and intracellular and secreted ATP. Increased ATP secretion led to increased purinergic signaling and P2X7-dependent increases in cytoplasmic calcium. The increased mitochondrial activity was not due to a difference in activation-induced mitochondrial biogenesis. Expression of carnitine palmitoyl transferase 1 was higher, conversely that of fatty acid synthase was reduced in older T cells, resulting in increased fatty acid oxidation, while depleting intracellular lipid stores. The aged CD4 memory T cells therefore maintain a more catabolic state in lipid metabolism, while their ability to upregulate glycolysis upon activation is preserved.

SUBMITTER: Yanes RE

PROVIDER: S-EPMC6827883 | biostudies-literature | 2019 Oct

REPOSITORIES: biostudies-literature

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Metabolic reprogramming in memory CD4 T cell responses of old adults.

Yanes Rolando E RE Zhang Huimin H Shen Yi Y Weyand Cornelia M CM Goronzy Jorg J JJ

Clinical immunology (Orlando, Fla.) 20190704

To determine whether aging affects the ability of T cells to undergo metabolic reprogramming upon activation, we compared CD4 T cell responses after polyclonal in vitro stimulation. Compared to younger adults, CD4 memory T cells from healthy older individuals exhibited a higher upregulation of oxidative phosphorylation with increased production of reactive oxygen species and intracellular and secreted ATP. Increased ATP secretion led to increased purinergic signaling and P2X7-dependent increases ...[more]

PMID: 31279855

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Project description:BackgroundLittle is known on how metabolic reprogramming potentially prompts transition of activated and resting CD4+ memory T cells infiltration in tumor microenvironment of gastric cancer (GC). The study aimed to evaluate their interactions and develop a risk model for predicting prognosis in GC.MethodsExpression profiles were obtained from TCGA and GEO databases. An immunotherapeutic IMvigor210 cohort was also enrolled. CIBERSORT algorithm was used to evaluate the infiltration of immune cells. The ssGSEA method was performed to assess levels of 114 metabolism pathways. Prognosis and correlation analysis were conducted to identify metabolism pathways and genes correlated with activated CD4+ memory T cells ratio (AR) and prognosis. An AR-related metabolism gene (ARMG) risk model was constructed and validated in different cohorts. Flow cytometry was applied to validate the effect of all-trans retinoic acid (ATRA) on CD4+ memory T cells.ResultsSince significantly inverse prognostic value and negative correlation of resting and activated CD4+ memory T cells, high AR level was associated with favorable overall survival (OS) in GC. Meanwhile, 15 metabolism pathways including retinoic acid metabolism pathway were significantly correlated with AR and prognosis. The ARMG risk model could classify GC patients with different outcomes, treatment responses, genomic and immune landscape. The prognostic value of the model was also confirmed in the additional validation, immunotherapy and pan-cancer cohorts. Functional analyses revealed that the ARMG model was positively correlated with pro-tumorigenic pathways. In vitro experiments showed that ATRA could inhibit levels of activated CD4+ memory T cells and AR.ConclusionOur study showed that metabolic reprogramming including retinoic acid metabolism could contribute to transition of activated and resting CD4+ memory T cells, and affect prognosis of GC patients. The ARMG risk model could serve as a new tool for GC patients by accurately predicting prognosis and response to treatment.

Dataset Information

Metabolic reprogramming in memory CD4 T cell responses of old adults.

Publications

Metabolic reprogramming in memory CD4 T cell responses of old adults.

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