Phosphofructokinase deficiency impairs ATP generation, autophagy, and redox balance in rheumatoid arthritis T cells

Yang, Zhen; Fujii, Hiroshi; Mohan, Shalini; Goronzy, Jörg J.; Weyand, Cornelia M.

doi:10.1084/jem.20130252

Cited by 272 publications

(280 citation statements)

References 77 publications

(92 reference statements)

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“…During T cell activation, ROS derived from mitochondrial complex III critically underpin IL-2 production and proliferation (29). Furthermore, activated T cells from individuals with rheumatoid arthritis demonstrate reduced abundance of ROS, associated with increased apoptosis, which could be recapitulated in healthy cells by scavenging mROS (30). ROS thus constitute both a survival and differentiation signal for T cells, as also described for stem cells (9).…”

Section: Discussionmentioning

confidence: 91%

The Immune-Metabolic Basis of Effector Memory CD4+ T Cell Function under Hypoxic Conditions

Dimeloe

Mehling

Frick

et al. 2016

The Journal of Immunology

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Effector memory (EM) CD4+ T cells recirculate between normoxic blood and hypoxic tissues to screen for cognate Ag. How mitochondria of these cells, shuttling between normoxia and hypoxia, maintain bioenergetic efficiency and stably uphold antiapoptotic features is unknown. In this study, we found that human EM CD4+ T cells had greater spare respiratory capacity (SRC) than did naive counterparts, which was immediately accessed under hypoxia. Consequently, hypoxic EM cells maintained ATP levels, survived and migrated better than did hypoxic naive cells, and hypoxia did not impair their capacity to produce IFN-γ. EM CD4+ T cells also had more abundant cytosolic GAPDH and increased glycolytic reserve. In contrast to SRC, glycolytic reserve was not tapped under hypoxic conditions, and, under hypoxia, glucose metabolism contributed similarly to ATP production in naive and EM cells. However, both under normoxic and hypoxic conditions, glucose was critical for EM CD4+ T cell survival. Mechanistically, in the absence of glycolysis, mitochondrial membrane potential (ΔΨm) of EM cells declined and intrinsic apoptosis was triggered. Restoring pyruvate levels, the end product of glycolysis, preserved ΔΨm and prevented apoptosis. Furthermore, reconstitution of reactive oxygen species (ROS), whose production depends on ΔΨm, also rescued viability, whereas scavenging mitochondrial ROS exacerbated apoptosis. Rapid access of SRC in hypoxia, linked with built-in, oxygen-resistant glycolytic reserve that functionally insulates ΔΨm and mitochondrial ROS production from oxygen tension changes, provides an immune-metabolic basis supporting survival, migration, and function of EM CD4+ T cells in normoxic and hypoxic conditions.

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Section: Discussionmentioning

confidence: 91%

The Immune-Metabolic Basis of Effector Memory CD4+ T Cell Function under Hypoxic Conditions

Dimeloe

Mehling

Frick

et al. 2016

The Journal of Immunology

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“…Naive CD4 T cells from patients with RA, pre-aged by about 20 years, generate lower amounts of lactate and ATP (40), whereas the accumulation of NADPH is increased (41). The underlying molecular defect has been mapped to the imbalance of two enzymes regulating glucose utilization: 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 3 (PFKFB3) and glucose-6-phosphate dehydrogenase TRANSATLANTIC AIRWAY CONFERENCE S424 (G6PD) (41,42). With decreased activity of PFKFB3 and enhanced activity of G6PD, pyruvate production is disfavored.…”

Section: Metabolic Reprogramming Of Aging T Cellsmentioning

confidence: 99%

Aging of the Immune System. Mechanisms and Therapeutic Targets

2016

Self Cite

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Beginning with the sixth decade of life, the human immune system undergoes dramatic aging-related changes, which continuously progress to a state of immunosenescence. The aging immune system loses the ability to protect against infections and cancer and fails to support appropriate wound healing. Vaccine responses are typically impaired in older individuals. Conversely, inflammatory responses mediated by the innate immune system gain in intensity and duration, rendering older individuals susceptible to tissue-damaging immunity and inflammatory disease. Immune system aging functions as an accelerator for other age-related pathologies. It occurs prematurely in some clinical conditions, most prominently in patients with the autoimmune syndrome rheumatoid arthritis (RA); and such patients serve as an informative model system to study molecular mechanisms of immune aging. T cells from patients with RA are prone to differentiate into proinflammatory effector cells, sustaining chronic-persistent inflammatory lesions in the joints and many other organ systems. RA T cells have several hallmarks of cellular aging; most importantly, they accumulate damaged DNA. Because of deficiency of the DNA repair kinase ataxia telangiectasia mutated, RA T cells carry a higher burden of DNA double-strand breaks, triggering cell-indigenous stress signals that shift the cell's survival potential and differentiation pattern. Immune aging in RA T cells is also associated with metabolic reprogramming; specifically, with reduced glycolytic flux and diminished ATP production. Chronic energy stress affects the longevity and the functional differentiation of older T cells. Altered metabolic patterns provide opportunities to therapeutically target the immune aging process through metabolic interference.

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“…1E-H). Impairment of glycolysis has been linked to autoimmune conditions, such as multiple sclerosis, type 1 diabetes, and rheumatoid arthritis (16,26). This is because engagement of glycolysis in Tconvs generates waves of FOXP3 + inducible Tregs in the most metabolically active fraction of proliferating Tconvs (16).…”

Section: Lymphopenia In Gsd-1b Patients Is Associated With An Impairementioning

confidence: 99%

Cutting Edge: Increased Autoimmunity Risk in Glycogen Storage Disease Type 1b Is Associated with a Reduced Engagement of Glycolysis in T Cells and an Impaired Regulatory T Cell Function

Melis

Carbone

Minopoli

et al. 2017

The Journal of Immunology

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Glycogen storage disease type 1b (GSD-1b) is an autosomal-recessive disease caused by mutation of glucose-6–phosphate transporter and characterized by altered glycogen/glucose homeostasis. A higher frequency of autoimmune diseases has been observed in GSD-1b patients, but the molecular determinants leading to this phenomenon remain unknown. To address this question, we investigated the effect of glucose-6–phosphate transporter mutation on immune cell homeostasis and CD4+ T cell functions. In GSD-1b subjects, we found lymphopenia and a reduced capacity of T cells to engage glycolysis upon TCR stimulation. These phenomena associated with reduced expression of the FOXP3 transcription factor, lower suppressive function in peripheral CD4+CD25+FOXP3+ regulatory T cells, and an impaired capacity of CD4+CD25− conventional T cells to induce expression of FOXP3 after suboptimal TCR stimulation. These data unveil the metabolic determinant leading to an increased autoimmunity risk in GSD-1b patients.

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Phosphofructokinase deficiency impairs ATP generation, autophagy, and redox balance in rheumatoid arthritis T cells

Abstract: T cells from RA patients are hypoglycolytic due to insufficient induction of the glycolytic activator PFKFB3, resulting in impaired autophagy and reduced ROS production.

Cited by 272 publications

References 77 publications

The Immune-Metabolic Basis of Effector Memory CD4+ T Cell Function under Hypoxic Conditions

The Immune-Metabolic Basis of Effector Memory CD4+ T Cell Function under Hypoxic Conditions

Aging of the Immune System. Mechanisms and Therapeutic Targets

Cutting Edge: Increased Autoimmunity Risk in Glycogen Storage Disease Type 1b Is Associated with a Reduced Engagement of Glycolysis in T Cells and an Impaired Regulatory T Cell Function

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