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

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.