Homeostatic control of metabolic and functional fitness of T reg cells by LKB1 signalling

• Published in: Nature (London) Vol. 548; no. 7669; p. 602
• Main Authors: Yang, Kai, Blanco, Daniel Bastardo, Neale, Geoffrey, Vogel, Peter, Avila, Julian, Clish, Clary B, Wu, Chuan, Shrestha, Sharad, Rankin, Sherri, Long, Lingyun, Kc, Anil, Chi, Hongbo
• Format: Journal Article
• Language: English
• Published: England 31.08.2017
• Subjects: Animals; Apoptosis; beta Catenin - metabolism; Cell Survival - genetics; Cytokines - metabolism; Dendritic Cells - immunology; Forkhead Transcription Factors - genetics; Forkhead Transcription Factors - metabolism; Glucocorticoid-Induced TNFR-Related Protein - metabolism; Homeostasis; Immune Tolerance; Mice; Mitochondria - metabolism; Mitochondria - pathology; Programmed Cell Death 1 Receptor - antagonists & inhibitors; Programmed Cell Death 1 Receptor - biosynthesis; Programmed Cell Death 1 Receptor - metabolism; Protein-Serine-Threonine Kinases - deficiency; Protein-Serine-Threonine Kinases - genetics; Protein-Serine-Threonine Kinases - metabolism; Receptors, OX40 - metabolism; Receptors, Tumor Necrosis Factor - metabolism; Signal Transduction; T-Lymphocytes, Regulatory - cytology; T-Lymphocytes, Regulatory - immunology; T-Lymphocytes, Regulatory - metabolism; Th2 Cells - immunology
• ISSN: 1476-4687
• DOI: 10.1038/nature23665

Regulatory T cells (T cells) have a pivotal role in the establishment and maintenance of immunological self-tolerance and homeostasis. Transcriptional programming of regulatory mechanisms facilitates the functional activation of T cells in the prevention of diverse types of inflammatory responses. It remains unclear how T cells orchestrate their homeostasis and interplay with environmental signals. Here we show that liver kinase B1 (LKB1) programs the metabolic and functional fitness of T cells in the control of immune tolerance and homeostasis. Mice with a T -specific deletion of LKB1 developed a fatal inflammatory disease characterized by excessive T 2-type-dominant responses. LKB1 deficiency disrupted T cell survival and mitochondrial fitness and metabolism, but also induced aberrant expression of immune regulatory molecules including the negative co-receptor PD-1 and the TNF receptor superfamily proteins GITR and OX40. Unexpectedly, LKB1 function in T cells was independent of conventional AMPK signalling or the mTORC1-HIF-1α axis, but contributed to the activation of β-catenin signalling for the control of PD-1 and TNF receptor proteins. Blockade of PD-1 activity reinvigorated the ability of LKB1-deficient T cells to suppress T 2 responses and the interplay with dendritic cells primed by thymic stromal lymphopoietin. Thus, T cells use LKB1 signalling to coordinate their metabolic and immunological homeostasis and to prevent apoptotic and functional exhaustion, thereby orchestrating the balance between immunity and tolerance.