Leptin directly promotes T-cell glycolytic metabolism to drive effector T-cell differentiation in a mouse model of autoimmunity.
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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.
Published Version (Please cite this version)10.1002/eji.201545861
Publication InfoDanzaki, K; Eisner, W; Gerriets, VA; Kishton, RJ; MacIver, Nancie Jo; Nichols, AG; ... Shinohara, Mari L (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 http://hdl.handle.net/10161/12472.
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Associate Professor 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
Associate Professor of Immunology
We need to mount a strong immune response against pathogens during infections, 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.Immune system needs to detect pathogens quickly and effectively. This is performed by the innate immune system, which includes cells such as macrophages and dendritic cells (DCs). Pathogens are recog
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