Homeostatic control of metabolic and functional fitness of Treg cells by LKB1 signaling
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Author
Yang, Kai
Blanco, Daniel Bastardo
Neale, Geoffrey
Vogel, Peter
Avila, Julian
Clish, Clary B.
Shrestha, Sharad
Sherri, Rankin
Long, Lingyun
Anil, KC
Chi, Hongbo
Note: Order does not necessarily reflect citation order of authors.
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https://doi.org/10.1038/nature23665Metadata
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Yang, K., D. B. Blanco, G. Neale, P. Vogel, J. Avila, C. B. Clish, C. Wu, et al. 2017. “Homeostatic control of metabolic and functional fitness of Treg cells by LKB1 signaling.” Nature 548 (7669): 602-606. doi:10.1038/nature23665. http://dx.doi.org/10.1038/nature23665.Abstract
Regulatory T cells (Treg cells) play a pivotal role in the establishment and maintenance of immunological self-tolerance and homeostasis1,2. Transcriptional programming of regulatory mechanisms facilitates Treg cell functional activation in the prevention of diverse types of inflammatory responses3,4. How Treg cells orchestrate their homeostasis and interplay with environmental signals remains poorly understood. Here we show that liver kinase B1 (LKB1) programs proper metabolic and functional fitness of Treg cells in the control of immune tolerance and homeostasis. Mice with Treg-specific deletion of LKB1 developed a fatal inflammatory disease characterized by excessive TH2-dominant responses. LKB1 deficiency disrupted Treg cell survival and mitochondrial fitness and metabolism, but also induced aberrant expression of immune regulatory molecules including the negative co-receptor PD-1, and TNF receptor (TNRF) superfamily proteins GITR and OX40. Unexpectedly, LKB1 function in Treg cells was independent of conventional AMPK signaling or the mTORC1-HIF-1α axis, but contributed to the activation of β-catenin signaling for the proper control of PD-1 and TNFR proteins. Blockade of PD-1 activity reinvigorated the suppressive capability of LKB1-deficient Treg cells in the repression of TH2 responses and the interplay with thymic stromal lymphopoietin (TSLP)-primed dendritic cells (DCs). Thus, Treg cells employ LKB1 signaling to coordinate their metabolic and immunological homeostasis and to prevent apoptotic and functional exhaustion, thereby orchestrating the balance between immunity and tolerance.Other Sources
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5804356/pdf/Terms of Use
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