To elucidate the role of Liver Kinase B1 (LKB1), a key regulator of T cell lipid metabolism, on Treg function, Timilshina and You et al. generated genetic mouse models of LKB1-deficient Tregs. LKB1-deficient Tregs produced Th1 and Th17 cytokines, were unable to suppress inflammation in a colitis model, and had defects in oxidative metabolism and mitochondrial function. Treatment of LKB1-deficient Treg mice with mevalonate or its metabolite GGPP resulted in significantly prolonged survival and increased numbers of splenic Foxp3+ T cells with restored suppressive activity, linking LKB1 and the mevalonate pathway to Treg stability and function.
Contributed by Katherine Turner
The function of regulatory T (Treg) cells depends on lipid oxidation. However, the molecular mechanism by which Treg 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 Treg 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 Treg cell functional competency and stability by inducing Treg 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 Treg cells and enhanced survival of LKB1-deficient Treg mice. Thus, LKB1 is a key regulator of lipid metabolism in Treg cells, involved in optimal programming of suppressive activity, immune homeostasis, and tolerance.
Author Info: (1) College of Pharmacy, Yeungnam University, Gyeongsan 38541, Republic of Korea. (2) College of Pharmacy, Yeungnam University, Gyeongsan 38541, Republic of Korea. (3) Institute fo
Author Info: (1) College of Pharmacy, Yeungnam University, Gyeongsan 38541, Republic of Korea. (2) College of Pharmacy, Yeungnam University, Gyeongsan 38541, Republic of Korea. (3) Institute for Molecular Medicine, University Medical Center of the Johannes Gutenberg-University Mainz, Obere Zahlbacher Str. 67, Mainz 55131, Germany. (4) College of Pharmacy, Yeungnam University, Gyeongsan 38541, Republic of Korea. (5) College of Pharmacy, Yeungnam University, Gyeongsan 38541, Republic of Korea. (6) College of Pharmacy, Yeungnam University, Gyeongsan 38541, Republic of Korea. (7) College of Pharmacy, Yeungnam University, Gyeongsan 38541, Republic of Korea. (8) College of Pharmacy, Yeungnam University, Gyeongsan 38541, Republic of Korea. (9) Department of Biomedical Laboratory Science, Daekyeung College, Gyeongsan 38547, Republic of Korea. (10) College of Pharmacy, Keimyung University, Daegu 42601, Republic of Korea. (11) Laboratory of Microbiology and Immunology, College of Pharmacy, Kangwon National University, Chuncheon 24341, Republic of Korea. (12) Laboratory of Microbiology and Immunology, College of Pharmacy, Kangwon National University, Chuncheon 24341, Republic of Korea. (13) Asan Institute for Life Sciences, Asan Medical Center, Seoul 05505, Republic of Korea. (14) New Drug Development Center, Daegu-Gyeongbuk Medical Innovation Foundation, Daegu 41061, Republic of Korea. (15) College of Pharmacy, Yeungnam University, Gyeongsan 38541, Republic of Korea. (16) College of Pharmacy, Yeungnam University, Gyeongsan 38541, Republic of Korea. (17) Research Institute of Pharmaceutical Science, College of Pharmacy, Seoul National University, Seoul 08826, Republic of Korea. (18) Institute for Molecular Medicine, University Medical Center of the Johannes Gutenberg-University Mainz, Obere Zahlbacher Str. 67, Mainz 55131, Germany. Electronic address: waisman@uni-mainz.de. (19) College of Pharmacy, Yeungnam University, Gyeongsan 38541, Republic of Korea. Electronic address: jchang@yu.ac.kr.
