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Proc Natl Acad Sci U S A. 2017 Nov 21;114(47):12542-12547. doi: 10.1073/pnas.1715363114. Epub 2017 Nov 6.

Metabolic control of regulatory T cell (Treg) survival and function by Lkb1.

Author information

1
Gene Expression Laboratory, The Salk Institute for Biological Studies, La Jolla, CA 92037.
2
Storr Liver Centre, Westmead Institute for Medical Research and Sydney Medical School, Westmead Hospital, University of Sydney, Westmead, NSW 2145, Australia.
3
Nomis Laboratories for Immunobiology and Microbial Pathogenesis, The Salk Institute for Biological Studies, La Jolla, CA 92037.
4
Gene Expression Laboratory, The Salk Institute for Biological Studies, La Jolla, CA 92037; downes@salk.edu evans@salk.edu.
5
Howard Hughes Medical Institute, The Salk Institute for Biological Studies, La Jolla, CA 92037.

Abstract

The metabolic programs of functionally distinct T cell subsets are tailored to their immunologic activities. While quiescent T cells use oxidative phosphorylation (OXPHOS) for energy production, and effector T cells (Teffs) rely on glycolysis for proliferation, the distinct metabolic features of regulatory T cells (Tregs) are less well established. Here we show that the metabolic sensor LKB1 is critical to maintain cellular metabolism and energy homeostasis in Tregs. Treg-specific deletion of Lkb1 in mice causes loss of Treg number and function, leading to a fatal, early-onset autoimmune disorder. Tregs lacking Lkb1 have defective mitochondria, compromised OXPHOS, depleted cellular ATP, and altered cellular metabolism pathways that compromise their survival and function. Furthermore, we demonstrate that the function of LKB1 in Tregs is largely independent of the AMP-activated protein kinase, but is mediated by the MAP/microtubule affinity-regulating kinases and salt-inducible kinases. Our results define a metabolic checkpoint in Tregs that couples metabolic regulation to immune homeostasis and tolerance.

KEYWORDS:

Foxp3; Lkb1; Treg; autoimmune disease; cellular metabolism

PMID:
29109251
PMCID:
PMC5703326
DOI:
10.1073/pnas.1715363114
[Indexed for MEDLINE]
Free PMC Article

Conflict of interest statement

The authors declare no conflict of interest.

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