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Leptin metabolically licenses T cells for activation to link nutrition and immunity.

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Date
2014-01-01
Authors
Saucillo, Donte C
Gerriets, Valerie A
Sheng, John
Rathmell, Jeffrey C
Maciver, Nancie J
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Abstract
Immune responses are highly energy-dependent processes. Activated T cells increase glucose uptake and aerobic glycolysis to survive and function. Malnutrition and starvation limit nutrients and are associated with immune deficiency and increased susceptibility to infection. Although it is clear that immunity is suppressed in times of nutrient stress, mechanisms that link systemic nutrition to T cell function are poorly understood. We show in this study that fasting leads to persistent defects in T cell activation and metabolism, as T cells from fasted animals had low glucose uptake and decreased ability to produce inflammatory cytokines, even when stimulated in nutrient-rich media. To explore the mechanism of this long-lasting T cell metabolic defect, we examined leptin, an adipokine reduced in fasting that regulates systemic metabolism and promotes effector T cell function. We show that leptin is essential for activated T cells to upregulate glucose uptake and metabolism. This effect was cell intrinsic and specific to activated effector T cells, as naive T cells and regulatory T cells did not require leptin for metabolic regulation. Importantly, either leptin addition to cultured T cells from fasted animals or leptin injections to fasting animals was sufficient to rescue both T cell metabolic and functional defects. Leptin-mediated metabolic regulation was critical, as transgenic expression of the glucose transporter Glut1 rescued cytokine production of T cells from fasted mice. Together, these data demonstrate that induction of T cell metabolism upon activation is dependent on systemic nutritional status, and leptin links adipocytes to metabolically license activated T cells in states of nutritional sufficiency.
Type
Journal article
Subject
Animals
Cytokines
Fasting
Glucose
Glucose Transporter Type 1
Glycolysis
Inflammation Mediators
Leptin
Lymphocyte Activation
Mice
Mice, Knockout
Mitochondria
Receptors, Leptin
T-Lymphocyte Subsets
Permalink
https://hdl.handle.net/10161/10314
Published Version (Please cite this version)
10.4049/jimmunol.1301158
Publication Info
Saucillo, Donte C; Gerriets, Valerie A; Sheng, John; Rathmell, Jeffrey C; & Maciver, Nancie J (2014). Leptin metabolically licenses T cells for activation to link nutrition and immunity. J Immunol, 192(1). pp. 136-144. 10.4049/jimmunol.1301158. Retrieved from https://hdl.handle.net/10161/10314.
This is constructed from limited available data and may be imprecise. To cite this article, please review & use the official citation provided by the journal.
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Scholars@Duke

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
Rathmell

Jeffrey Charles Rathmell

Adjunct Associate Professor in the Department of Pharmacology and Cancer Biology
My laboratory studies the mechanisms and role of glucose metabolism in lymphocyte survival and activation. We have found that dramatic increases in glucose metabolism are necessary for lymphocytes to survive and mount immune responses. Excessive glucose metabolism, however, can lead to T cell hyperactivation and autoimmunity. A key mechanism for control of lymphocyte glucose metabolism is regulation of glucose uptake by the glucose transporter, Glut1. Interestingly, upregulation of Glut1
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