Homeostatic control of metabolic and functional fitness of T reg 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. I...
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Veröffentlicht in: | Nature (London) 2017-08, Vol.548 (7669), p.602 |
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Sprache: | eng |
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Zusammenfassung: | 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. |
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ISSN: | 1476-4687 |
DOI: | 10.1038/nature23665 |