Ndfip1 restricts mTORC1 signalling and glycolysis in regulatory T cells to prevent autoinflammatory disease

Awo Akosua Kesewa Layman, Guoping Deng, Claire E. O’Leary, Samuel Tadros, Rajan M. Thomas, Joseph M. Dybas, Emily K. Moser, Andrew D. Wells, Nicolai M. Doliba and Paula M. Oliver ()
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Awo Akosua Kesewa Layman: Medical Scientist Training Program, Perelman School of Medicine at the University of Pennsylvania
Guoping Deng: The Children’s Hospital of Philadelphia
Claire E. O’Leary: The Children’s Hospital of Philadelphia
Samuel Tadros: The Children’s Hospital of Philadelphia
Rajan M. Thomas: The Children’s Hospital of Philadelphia
Joseph M. Dybas: The Children’s Hospital of Philadelphia
Emily K. Moser: The Children’s Hospital of Philadelphia
Andrew D. Wells: The Children’s Hospital of Philadelphia
Nicolai M. Doliba: Institute for Diabetes, Obesity, and Metabolism, University of Pennsylvania School of Medicine
Paula M. Oliver: The Children’s Hospital of Philadelphia

Nature Communications, 2017, vol. 8, issue 1, 1-16

Abstract: Abstract Foxp3+ T regulatory (Treg) cells suppress immune cell activation and establish normal immune homeostasis. How Treg cells maintain their identity is not completely understood. Here we show that Ndfip1, a coactivator of Nedd4-family E3 ubiquitin ligases, is required for Treg cell stability and function. Ndfip1 deletion in Treg cells results in autoinflammatory disease. Ndfip1-deficient Treg cells are highly proliferative and are more likely to lose Foxp3 expression to become IL-4-producing TH2 effector cells. Proteomic analyses indicate altered metabolic signature of Ndfip1-deficient Treg cells and metabolic profiling reveals elevated glycolysis and increased mTORC1 signalling. Ndfip1 restricts Treg cell metabolism and IL-4 production via distinct mechanisms, as IL-4 deficiency does not prevent hyperproliferation or elevated mTORC1 signalling in Ndfip1-deficient Treg cells. Thus, Ndfip1 preserves Treg lineage stability and immune homeostasis by preventing the expansion of highly proliferative and metabolically active Treg cells and by preventing pathological secretion of IL-4 from Treg cells.

Date: 2017
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DOI: 10.1038/ncomms15677

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