Cutting edge: distinct glycolytic and lipid oxidative metabolic programs are essential for effector and regulatory CD4+ T cell subsets.

Abstract

Stimulated CD4(+) T lymphocytes can differentiate into effector T cell (Teff) or inducible regulatory T cell (Treg) subsets with specific immunological roles. We show that Teff and Treg require distinct metabolic programs to support these functions. Th1, Th2, and Th17 cells expressed high surface levels of the glucose transporter Glut1 and were highly glycolytic. Treg, in contrast, expressed low levels of Glut1 and had high lipid oxidation rates. Consistent with glycolysis and lipid oxidation promoting Teff and Treg, respectively, Teff were selectively increased in Glut1 transgenic mice and reliant on glucose metabolism, whereas Treg had activated AMP-activated protein kinase and were dependent on lipid oxidation. Importantly, AMP-activated protein kinase stimulation was sufficient to decrease Glut1 and increase Treg generation in an asthma model. These data demonstrate that CD4(+) T cell subsets require distinct metabolic programs that can be manipulated in vivo to control Treg and Teff development in inflammatory diseases.

Department

Description

Provenance

Citation

Published Version (Please cite this version)

10.4049/jimmunol.1003613

Publication Info

Michalek, Ryan D, Valerie A Gerriets, Sarah R Jacobs, Andrew N Macintyre, Nancie J MacIver, Emily F Mason, Sarah A Sullivan, Amanda G Nichols, et al. (2011). Cutting edge: distinct glycolytic and lipid oxidative metabolic programs are essential for effector and regulatory CD4+ T cell subsets. J Immunol, 186(6). pp. 3299–3303. 10.4049/jimmunol.1003613 Retrieved from https://hdl.handle.net/10161/10317.

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Scholars@Duke

Macintyre

Andrew Neil Macintyre

Associate Professor in Medicine

Andrew Macintyre, PhD, directs the Immunology Unit within the Duke Regional Biocontainment Laboratory. The Macintyre lab team designs and performs assays to quantify immune reconstitution and immune responses. The lab specializes in multiplex cytokine arrays, flow cytometry, high-throughput ELISAs, qRT-PCR, and other molecular tests. 

The assays his team develops and runs support research into biodefense and critical public health challenges. Long-running collaborative projects include the evaluation of radiation countermeasures and the development of vaccines for influenza, gonorrhea, SARS-CoV2, and other pathogens.

MacIver

Nancie Jo MacIver

Adjunct Associate Professor in the Department of Pediatrics

My laboratory is broadly interested in how large changes in nutritional status (e.g. malnutrition or obesity) influence T cell immunity.  Malnutrition can lead to immunodeficiency and increased risk of infection, whereas obesity is associated with inflammation that promotes multiple diseases including autoimmunity, type 2 diabetes, and cardiovascular disease.  We have identified the adipocyte-secreted hormone leptin as a critical link between nutrition and immunity.  Leptin is secreted from adipocytes in proportion to adipocyte mass and is therefore decreased in malnutrition and increased in obesity.  We have found that leptin is a critical regulator of effector T cell glucose metabolism and thereby drives effector T cell activation.  From these initial findings, we have established further lines of investigation, as summarized here.

(1) Determining molecular mechanisms of T cell dysfunction in malnutrition – Our goal is to identify metabolic and epigenetic mechanisms by which malnutrition and decreased leptin alter T cell function leading to increased susceptibility to infection and protection against autoimmune diseases.  We study this using a mouse model of autoimmunity, experimental autoimmune encephalomyelitis (EAE).

(2) Elucidating mechanisms of T cell inflammation in obesity-induced type 2 diabetes – Our goal is to identify molecular and metabolic mechanisms by which obesity alters the Teff/Treg balance, resulting in inflammation and subsequent insulin resistance leading to type 2 diabetes.  With our collaborators from UNC Chapel Hill, we are also identifying immunometabolic changes in obese animals and humans that correlate with increased susceptibility to influenza.

(3) Determining the role of insulin and IGF-1 in regulating T cell function and metabolism – Our goal is to identify how insulin influences both T cell glucose uptake and T cell differentiation/cytokine production and determine the role of insulin signaling in T cells in the setting of obesity-associated diabetes.  We hypothesize that insulin has a direct role in T cell function through its abiltiy to alter T cell glucose metabolism, influence T cell cytokine production, and impact the pathophysiology of obesity-associated type 2 diabetes. 


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