Activation of Mevalonate Pathway via LKB1 Is Essential for Stability of Treg Cells

Abstract

Graphical AbstractHighlights d LKB1-deficient T reg cells produce Th1 and Th17 cytokines d The loss of LKB1 compromises the mevalonate pathway in T reg cells d Mevalonate or GGPP treatment restores function and stability in LKB1-deficient T reg cells d LKB1-mediated regulation of T reg cells is independent of AMPK SUMMARY The function of regulatory T (T reg ) cells depends on lipid oxidation. However, the molecular mechanism by which T reg cells maintain lipid metabolism after activation remains elusive. Liver kinase B1 (LKB1) acts as a coordinator by linking cellular metabolism to substrate AMP-activated protein kinase (AMPK). We show that deletion of LKB1 in T reg cells exhibited reduced suppressive activity and developed fatal autoimmune inflammation. Mechanistically, LKB1 induced activation of the mevalonate pathway by upregulating mevalonate genes, which was essential for T reg cell functional competency and stability by inducing T reg cell proliferation and suppressing interferon-gamma and interleukin-17A expression independently of AMPK. Furthermore, LKB1 was found to regulate intracellular cholesterol homeostasis and to promote the mevalonate pathway. In agreement, mevalonate and its metabolite geranylgeranyl pyrophosphate inhibited conversion of T reg cells and enhanced survival of LKB1-deficient T reg mice. Thus, LKB1 is a key regulator of lipid metabolism in T reg cells, involved in optimal programming of suppressive activity, immune homeostasis, and tolerance.

Signaling networks in immunometabolism

“…214 However, LKB1 can also promote mevalonate metabolism to support Treg cell homeostasis in an AMPK-independent manner. 215 Thus, LKB1-AMPK signaling primarily acts to suppress lipid synthesis pathways, but AMPKindependent LKB1 signaling may promote de novo lipogenesis in selective contexts.…”

“…226 LKB1-AMPK signaling may indirectly orchestrate the differentiation of Th17 and Treg cell lineages through HIF-1α-or ACC1-mediated changes in glycolysis and mitochondrial oxidative metabolism. 118,119,146 Additionally, recent work demonstrated that LKB1 promotes stable Foxp3 expression, 215,227 as well as Th2-like Treg cell development independently of AMPK 215,228 and mTORC1-HIF-1α signaling but dependent on β-catenin signaling. 228 LKB1 signaling is required for mitochondrial function and mitochondria-dependent metabolic programs upon TCR-mediated Treg cell activation, 228 including FAO or purine and pyrimidine metabolism.…”

“…However, there is emerging evidence that LKB1 has AMPK-independent roles in T cell biology, including Treg cell-dependent suppression of autoimmunity and T cell-dependent inhibition of intestinal polyp formation. 215,228,237 Thus, the contribution of LKB1 downstream targets in T cell biology and metabolism is an exciting area that requires more exploration.…”

Metabolic Control of Treg Cell Stability, Plasticity, and Tissue-Specific Heterogeneity

“…LKB1 promotes mitochondrial fitness and FAO in Treg cells (113); however, these events appear to be AMPK-independent (113-116), suggesting other downstream LKB1 targets as important regulators of metabolic programming in Treg cells. In addition, recent analysis of LKB1-deficient Treg cells demonstrates that LKB1 enhances Foxp3 expression by preventing CNS2 methylation (114), and by activation of the mevalonate pathway that generates many metabolites, including cholesterol and the isoprenoid geranylgeranylpyrophosphate (GGPP) (115). Specifically, LKB1 prevents STAT4 activation and binding to CNS2, thus maintaining Foxp3 stability in response to STAT4-inducing inflammatory cytokines (114).…”

“…Specifically, LKB1 prevents STAT4 activation and binding to CNS2, thus maintaining Foxp3 stability in response to STAT4-inducing inflammatory cytokines (114). Moreover, mevalonate or GGPP treatment restores the function and stability of LKB1-deficient Treg cells (115). The precise mechanisms that control AMPK and LKB1 activation in Treg cells require further study.…”