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

  1. Ronald M. Evansa,d,1
  1. aGene Expression Laboratory, The Salk Institute for Biological Studies, La Jolla, CA 92037;
  2. bStorr Liver Centre, Westmead Institute for Medical Research and Sydney Medical School, Westmead Hospital, University of Sydney, Westmead, NSW 2145, Australia;
  3. cNomis Laboratories for Immunobiology and Microbial Pathogenesis, The Salk Institute for Biological Studies, La Jolla, CA 92037;
  4. dHoward Hughes Medical Institute, The Salk Institute for Biological Studies, La Jolla, CA 92037
  1. Contributed by Ronald M. Evans, October 5, 2017 (sent for review August 31, 2017; reviewed by Chih-Hao Lee and Ming O. Li)

Significance

Regulatory T cells (Tregs) play a critical role in maintaining immune tolerance to self-antigens and in suppressing excessive immune responses that may cause collateral damage to the host. Unlike other CD4+ T cells, Tregs have a distinct, yet-to-be-established metabolic machinery to produce energy for survival and function. Here we show that the metabolic sensor LKB1 is critical for the survival and function of Tregs through regulation of their cellular metabolism. Interestingly, AMP-activated protein kinase, the best-studied downstream kinase of LKB1, is largely dispensable for LKB1 function in Tregs; the MAP/microtubule affinity-regulating kinases and salt-inducible kinases may mediate its functions. We highlight LKB1 as metabolic regulator that links cellular metabolism to immune cell functions.

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.

Footnotes

  • ?1To whom correspondence may be addressed. Email: downes{at}salk.edu or evans{at}salk.edu.
  • Author contributions: N.H., Y.Z., M.D., and R.M.E. designed research; N.H., W.F., and B.H. performed research; N.H., R.T.Y., A.R.A., C.L., Y.Z., M.D., and R.M.E. analyzed data; and N.H., R.T.Y., A.R.A., M.D., and R.M.E. wrote the paper.

  • Reviewers: C.-H.L., Harvard School of Public Health; and M.O.L., Memorial Sloan Kettering Cancer Center.

  • The authors declare no conflict of interest.

  • Data deposition: The sequence reported in this paper has been deposited in the GenBank database (accession no. SRP098763).

  • This article contains supporting information online at www.danielhellerman.com/lookup/suppl/doi:10.1073/pnas.1715363114/-/DCSupplemental.

Online Impact

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