Leptin directly promotes T-cell glycolytic metabolism to drive effector T-cell differentiation in a mouse model of autoimmunity.
Abstract
Upon activation, T cells require energy for growth, proliferation, and function. Effector
T (Teff) cells, such as Th1 and Th17 cells, utilize high levels of glycolytic metabolism
to fuel proliferation and function. In contrast, Treg cells require oxidative metabolism
to fuel suppressive function. It remains unknown how Teff/Treg-cell metabolism is
altered when nutrients are limited and leptin levels are low. We therefore examined
the role of malnutrition and associated hypoleptinemia on Teff versus Treg cells.
We found that both malnutrition-associated hypoleptinemia and T cell-specific leptin
receptor knockout suppressed Teff-cell number, function, and glucose metabolism, but
did not alter Treg-cell metabolism or suppressive function. Using the autoimmune mouse
model EAE, we confirmed that fasting-induced hypoleptinemia altered Teff-cell, but
not Treg-cell, glucose metabolism, and function in vivo, leading to decreased disease
severity. To explore potential mechanisms, we examined HIF-1α, a key regulator of
Th17 differentiation and Teff-cell glucose metabolism, and found HIF-1α expression
was decreased in T cell-specific leptin receptor knockout Th17 cells, and in Teff
cells from fasted EAE mice, but was unchanged in Treg cells. Altogether, these data
demonstrate a selective, cell-intrinsic requirement for leptin to upregulate glucose
metabolism and maintain function in Teff, but not Treg cells.
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https://hdl.handle.net/10161/12472Published Version (Please cite this version)
10.1002/eji.201545861Publication Info
Gerriets, Valerie A; Danzaki, Keiko; Kishton, Rigel J; Eisner, William; Nichols, Amanda
G; Saucillo, Donte C; ... MacIver, Nancie J (2016). Leptin directly promotes T-cell glycolytic metabolism to drive effector T-cell differentiation
in a mouse model of autoimmunity. Eur J Immunol, 46(8). pp. 1970-1983. 10.1002/eji.201545861. Retrieved from https://hdl.handle.net/10161/12472.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
Mari L. Shinohara
Professor of Integrative Immunobiology
Shinohara Lab WebsiteImmune responses against pathogens are essential for host protection,
but excessive and uncontrolled immune reactions can lead to autoimmunity. How does
our immune system keep the balance fine-tuned? This is a central question being asked
in my laboratory.
The immune system needs to detect pathogens quickly and effectively. This is performed
by the innate immune system, which includes cells such as mac
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