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Leptin metabolically licenses T cells for activation to link nutrition and immunity.
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 articleSubject
AnimalsCytokines
Fasting
Glucose
Glucose Transporter Type 1
Glycolysis
Inflammation Mediators
Leptin
Lymphocyte Activation
Mice
Mice, Knockout
Mitochondria
Receptors, Leptin
T-Lymphocyte Subsets
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https://hdl.handle.net/10161/10314Published Version (Please cite this version)
10.4049/jimmunol.1301158Publication 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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Show full item recordScholars@Duke
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
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 and glu
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