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Regulatory T cells (T reg 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 reg cells in the prevention of diverse types of inflammatory responses. It remains unclear how T reg 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 reg cells in the control of immune tolerance and homeostasis. Mice with a T reg -specific deletion of LKB1 developed a fatal inflammatory disease characterized by excessive T H 2-type-dominant responses. LKB1 deficiency disrupted T reg 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 reg 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 reg cells to suppress T H 2 responses and the interplay with dendritic cells primed by thymic stromal lymphopoietin. Thus, T reg 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.

Homeostatic control of metabolic and functional fitness of Treg cells by LKB1 signalling