Foxp3 drives oxidative phosphorylation and protection from lipotoxicity

Howie, Duncan; Cobbold, Stephen; Adams, Elizabeth; Bokum, Annemieke Ten; Necula, Andra; Zhang, Wei; Huang, Honglei; Roberts, David J.; Thomas, Benjamin; Hester, Svenja; Vaux, David J.; Betz, Alexander G.; Waldmann, Herman

doi:10.1172/jci.insight.89160

Cited by 161 publications

(158 citation statements)

References 64 publications

Supporting

Mentioning

155

Contrasting

Unclassified

Order By: Relevance

“…Rasheed et al showed that HIV replication upregulates lipid metabolism pathways and production of free fatty acids in infected human CD4 T cells, and consistent with this study, Angela et al showed that fatty acid metabolism through mTOR and PPARγ activation is critical for maximal activation of human CD4 T cells [121, 122]. CD4 T regulatory cells, important regulators of adipose tissue homeostasis as well representing a cellular reservoir for latent HIV, preferentially utilize oxphos and recent studies have demonstrated that Foxp3 promotes activation of oxphos and fatty acid oxidation pathways [123–126]. The importance of metabolism for HIV pathogenesis is further highlighted by an earlier report by Mansfield et al demonstrating increased disease progression and death of SIV-infected rhesus macaques fed a high-fat diet of cholesterol and saturated fatty acids [127].…”

Section: Immunometabolism Metabolic Reprogramming and Relevance Forsupporting

confidence: 77%

HIV Persistence in Adipose Tissue Reservoirs

Couturier

Lewis

2018

Curr HIV/AIDS Rep

View full text Add to dashboard Cite

Memory CD4 T cells and macrophages, the major host cells for HIV, accumulate in adipose tissue during HIV/SIV infection of humans and rhesus macaques. Whereas HIV and SIV proviral DNA is detectable in CD4 T cells of multiple fat depots in virtually all infected humans and monkeys examined, viral RNA is less frequently detected, and infected macrophages may be less prevalent in adipose tissue. However, based on viral outgrowth assays, adipose-resident CD4 T cells are latently infected with virus that is replication-competent and infectious. Additionally, adipocytes interact with CD4 T cells and macrophages to promote immune cell activation and inflammation which may be supportive for HIV persistence. Antiviral effector cells, such as CD8 T cells and NK/NKT cells, are abundant in adipose tissue during HIV/SIV infection and typically exceed CD4 T cells, whereas B cells are largely absent from adipose tissue of humans and monkeys. Additionally, CD8 T cells in adipose tissue of HIV patients are activated and have a late differentiated phenotype, with unique TCR clonotypes of less diversity relative to blood CD8 T cells. With respect to the distribution of antiretroviral drugs in adipose tissue, data is limited, but there may be class-specific penetration of fat depots. The trafficking of infected immune cells within adipose tissues is a common event during HIV/SIV infection of humans and monkeys, but the virus may be mostly transcriptionally dormant. Viral replication may occur less in adipose tissue compared to other major reservoirs, such as lymphoid tissue, but replication competence and infectiousness of adipose latent virus are comparable to other tissues. Due to the ubiquitous nature of adipose tissue, inflammatory interactions among adipocytes and CD4 T cells and macrophages, and selective distribution of antiretroviral drugs, the sequestration of infected immune cells within fat depots likely represents a major challenge for cure efforts.

show abstract

Section: Immunometabolism Metabolic Reprogramming and Relevance Forsupporting

confidence: 77%

HIV Persistence in Adipose Tissue Reservoirs

Couturier

Lewis

2018

Curr HIV/AIDS Rep

View full text Add to dashboard Cite

show abstract

“…These exert a network effect as they in turn regulate gene networks influencing biochemical responses including glycolysis. The balance of oxidative phosphorylation is linked to FOXP3 expression and regulatory phenotype, 75,76 and this in part enables Treg to function in environments that are under oxidative stress. 77 Metabolites which can alter transcriptional programming have also been identified.…”

Section: Tissue and Metabolic Cues Can Alter Transcriptional Programmmentioning

confidence: 99%

Unravelling the molecular basis for regulatory T‐cell plasticity and loss of function in disease

et al. 2018

View full text Add to dashboard Cite

Regulatory T cells (Treg) are critical for preventing autoimmunity and curtailing responses of conventional effector T cells (Tconv). The reprogramming of T‐cell fate and function to generate Treg requires switching on and off of key gene regulatory networks, which may be initiated by a subtle shift in expression levels of specific genes. This can be achieved by intermediary regulatory processes that include microRNA and long noncoding RNA‐based regulation of gene expression. There are well‐documented microRNA profiles in Treg and Tconv, and these can operate to either reinforce or reduce expression of a specific set of target genes, including FOXP3 itself. This type of feedforward/feedback regulatory loop is normally stable in the steady state, but can alter in response to local cues or genetic risk. This may go some way to explaining T‐cell plasticity. In addition, in chronic inflammation or autoimmunity, altered Treg/Tconv function may be influenced by changes in enhancer–promoter interactions, which are highly cell type‐specific. These interactions are impacted by genetic risk based on genome‐wide association studies and may cause subtle alterations to the gene regulatory networks controlled by or controlling FOXP3 and its target genes. Recent insights into the 3D organisation of chromatin and the mapping of noncoding regulatory regions to the genes they control are shedding new light on the direct impact of genetic risk on T‐cell function and susceptibility to inflammatory and autoimmune conditions.

show abstract

“…We have shown that deletion of HDAC9 increases OXPHOS in Treg (Beier et al, 2015), and found similar patterns in other HDAC deletion models, in which Foxp3 acetylation and Treg function were increased. This led us to hypothesize, that it may not just be a state in cellular metabolism such as OXPHOS that favors Treg differentiation and function (Lee et al, 2015), but also that Foxp3 exercises direct transcriptional control over T cell metabolism (Gerriets et al, 2016; Howie et al, 2017). Such Foxp3-mediated metabolic adaptations could enable Treg to maintain function in metabolically challenging conditions, where they can suppress inflammation as part of limiting injury, e.g.…”

Section: Introductionmentioning

confidence: 99%

Foxp3 Reprograms T Cell Metabolism to Function in Low-Glucose, High-Lactate Environments

et al. 2017

View full text Add to dashboard Cite

Summary Immune cells function in diverse metabolic environments. Tissues with low glucose and high lactate concentrations, such as the intestinal tract or ischemic tissues, frequently require immune responses to be more pro-tolerant avoiding unwanted reactions against self-antigens or commensal bacteria. T-regulatory cells (Treg) maintain peripheral tolerance, but how Treg function in low glucose lactate rich environments is unknown. We report that the Treg transcription factor Foxp3 reprograms T cell metabolism by suppressing Myc and glycolysis, enhancing oxidative phosphorylation, and increasing nicotinamide adenine dinucleotide oxidation. These adaptations allow Treg a metabolic advantage in low glucose, lactate rich environments; resisting lactate mediated suppression of T cell function and proliferation. This metabolic phenotype may explain how Tregs promote peripheral immune tolerance during tissue injury, but also how cancer cells evade immune destruction in the tumor microenvironment. Understanding Treg metabolism may therefore lead to novel approaches for selective immune modulation in cancer and autoimmune diseases.

show abstract

Foxp3 drives oxidative phosphorylation and protection from lipotoxicity

Cited by 161 publications

References 64 publications

HIV Persistence in Adipose Tissue Reservoirs

HIV Persistence in Adipose Tissue Reservoirs

Unravelling the molecular basis for regulatory T‐cell plasticity and loss of function in disease

Foxp3 Reprograms T Cell Metabolism to Function in Low-Glucose, High-Lactate Environments

Contact Info

Product

Resources

About