Homeostatic control of metabolic and functional fitness of T cells by LKB1 signalling.
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 T2-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 T2 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.
|Year of Publication
2017 08 31
|PubMed Central ID
NS064599 / NH / NIH HHS / United States
AI101407 / NH / NIH HHS / United States
R01 NS064599 / NS / NINDS NIH HHS / United States
R01 AI105887 / AI / NIAID NIH HHS / United States
AI105887 / NH / NIH HHS / United States
R01 CA176624 / CA / NCI NIH HHS / United States
R01 CA221290 / CA / NCI NIH HHS / United States
CA176624 / NH / NIH HHS / United States
R01 AI101407 / AI / NIAID NIH HHS / United States