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LKB1-PTEN axis controls Th1 and Th17 cell differentiation via regulating mTORC1

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Abstract

Immuno-environmental change triggers CD4+ T cell differentiation. T cell specialization activates metabolic signal pathways to meet energy requirements. Defective T cell-intrinsic metabolism can aggravate immunopathology in chronic diseases. Liver kinase B1 (LKB1) deletion in T cell or Treg cell results in systemic inflammatory symptoms, indicating a crucial role of LKB1 in T cells. However, the mechanism underlying the development of inflammation is unclear. In our study, LKB1-deficient T cells were differentiated preferentially into Th1 and Th17 cells in the absence of inflammation. Mechanistically, LKB1 directly binds and phosphorylates phosphatase and tensin homolog (PTEN), an upstream regulator of mammalian target of rapamycin complex 1 (mTORC1), which is independent of AMP-activated protein kinase (AMPK). As a result, LKB1 deficiency was associated with increased mTORC1 activity and hypoxia-inducible factor (HIF)1α-mediated glycolysis. Inhibition of glycolysis or biallelic disruption of LKB1 and HIF1α abrogated this phenotype, suggesting Th1- and Th17-biased differentiation in LKB1-deficient T cells was mediated by glycolysis. Our study indicates that LKB1 controls mTORC1 signaling through PTEN activation, not AMPK, which controls effector T cell differentiation in a T cell-intrinsic manner.

Key messages

• LKB1 maintains T cell homeostasis in a cell intrinsic manner.

• Glycolysis is involved in the LKB1-mediated T cell differentiation.

• LKB1 phosphorylates PTEN, not AMPK, to regulate mTORC1.

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Data availability

The data that support the findings of this study are available from the corresponding author upon reasonable request.

References

  1. Blagih J, Krawczyk CM, Jones RG (2012) LKB1 and AMPK: central regulators of lymphocyte metabolism and function. Immunol Rev 249:59–71

    Article  CAS  PubMed  Google Scholar 

  2. Pearce EL, Pearce EJ (2013) Metabolic pathways in immune cell activation and quiescence. Immunity 38:633–643

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Laplante M, Sabatini DM (2012) mTOR signaling. Cold Spring Harb Perspect Biol 4. https://doi.org/10.1101/cshperspect.a011593

  4. Delgoffe GM, Kole TP, Zheng Y, Zarek PE, Matthews KL, Xiao B, Worley PF, Kozma SC, Powell JD (2009) The mTOR kinase differentially regulates effector and regulatory T cell lineage commitment. Immunity 30:832–844

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Chi H (2012) Regulation and function of mTOR signalling in T cell fate decisions. Nat Rev Immunol 12:325–338

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Delgoffe GM, Pollizzi KN, Waickman AT, Heikamp E, Meyers DJ, Horton MR, Xiao B, Worley PF, Powell JD (2011) The kinase mTOR regulates the differentiation of helper T cells through the selective activation of signaling by mTORC1 and mTORC2. Nat Immunol 12:295–303

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Hirahara K, Nakayama T (2016) CD4+ T-cell subsets in inflammatory diseases: beyond the Th1/Th2 paradigm. Int Immunol 28:163–171

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Shackelford DB, Shaw RJ (2009) The LKB1–AMPK pathway: metabolism and growth control in tumour suppression. Nat Rev Cancer 9:563–575

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Poffenberger M, Metcalfe-Roach A, Aguilar E, Chen J, Hsu B, Wong A, Johnson R, Flynn B, Samborska B, Ma E (2018) LKB1 deficiency in T cells promotes the development of gastrointestinal polyposis. Science 361:406–411

    Article  CAS  PubMed  Google Scholar 

  10. Zhou W, Marcus AI, Vertino PM (2013) Dysregulation of mTOR activity through LKB1 inactivation. Chin J Cancer 32:427–433

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Timilshina M, You Z, Lacher SM, Acharya S, Jiang L, Kang Y, Kim J-A, Chang HW, Kim K-J, Park B et al (2019) Activation of mevalonate pathway via LKB1 is essential for stability of Treg cells. Cell Rep 27:2948–2961.e2947

    Article  CAS  PubMed  Google Scholar 

  12. Yang K, Blanco DB, Neale G, Vogel P, Avila J, Clish CB, Wu C, Shrestha S, Rankin S, Long L (2017) Homeostatic control of metabolic and functional fitness of T reg cells by LKB1 signalling. Nature 548:602–606

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Jung SH, Hwang HJ, Kang D, Park HA, Lee HC, Jeong D, Lee K, Park HJ, Ko Y-G, Lee J-S (2019) mTOR kinase leads to PTEN-loss-induced cellular senescence by phosphorylating p53. Oncogene 38:1639–1650

    Article  CAS  PubMed  Google Scholar 

  14. Suzuki A, Yamaguchi MT, Ohteki T, Sasaki T, Kaisho T, Kimura Y, Yoshida R, Wakeham A, Higuchi T, Fukumoto M (2001) T cell-specific loss of Pten leads to defects in central and peripheral tolerance. Immunity 14:523–534

    Article  CAS  PubMed  Google Scholar 

  15. Delgoffe GM, Woo S-R, Turnis ME, Gravano DM, Guy C, Overacre AE, Bettini ML, Vogel P, Finkelstein D, Bonnevier J (2013) Stability and function of regulatory T cells is maintained by a neuropilin-1–semaphorin-4a axis. Nature 501:252–256

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Pandit M, Acharya S, Gu Y, Seo S-U, Kweon M-N, Kang B, Chang J-H (2021) Geranylgeranyl pyrophosphate amplifies Treg differentiation via increased IL-2 expression to ameliorate DSS-induced colitis. Eur J Immunol n/a. https://doi.org/10.1002/eji.202048991

  17. Snapper C, McIntyre T, Mandler R, Pecanha L, Finkelman F, Lees A, Mond J (1992) Induction of IgG3 secretion by interferon gamma: a model for T cell-independent class switching in response to T cell-independent type 2 antigens. J Exp Med 175:1367–1371

    Article  CAS  PubMed  Google Scholar 

  18. Bossie A, Vitetta ES (1991) IFN-γ enhances secretion of IgG2a from IgG2a-committed LPS-stimulated murine B cells: implications for the role of IFN-γ in class switching. Cell Immunol 135:95–104

    Article  CAS  PubMed  Google Scholar 

  19. MacIver NJ, Blagih J, Saucillo DC, Tonelli L, Griss T, Rathmell JC, Jones RG (2011) The liver kinase B1 is a central regulator of T cell development, activation, and metabolism. J Immunol 187:4187–4198

    Article  CAS  PubMed  Google Scholar 

  20. van Veelen W, Korsse SE, van de Laar L, Peppelenbosch MP (2011) The long and winding road to rational treatment of cancer associated with LKB1/AMPK/TSC/mTORC1 signaling. Oncogene 30:2289–2303

    Article  PubMed  CAS  Google Scholar 

  21. Pelgrom LR, Patente TA, Sergushichev A, Esaulova E, Otto F, Ozir-Fazalalikhan A, van der Zande HJP, van der Ham AJ, van der Stel S, Artyomov MN et al (2019) LKB1 expressed in dendritic cells governs the development and expansion of thymus-derived regulatory T cells. Cell Res 29:406–419

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Wang Y, Du X, Wei J, Long L, Tan H, Guy C, Dhungana Y, Qian C, Neale G, Fu YX et al (2019) LKB1 orchestrates dendritic cell metabolic quiescence and anti-tumor immunity. Cell Res 29:391–405

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Xu Z, You W, Wang F, Wang Y, Shan T (2019) Elucidating the role of Lkb1 and mTOR in adipose tissue. Adipocyte 8:26–30

    Article  CAS  PubMed  Google Scholar 

  24. Chang CH, Curtis JD, Maggi LB Jr, Faubert B, Villarino AV, O'Sullivan D, Huang SC, van der Windt GJ, Blagih J, Qiu J et al (2013) Posttranscriptional control of T cell effector function by aerobic glycolysis. Cell 153:1239–1251

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Finlay DK, Rosenzweig E, Sinclair LV, Feijoo-Carnero C, Hukelmann JL, Rolf J, Panteleyev AA, Okkenhaug K, Cantrell DA (2012) PDK1 regulation of mTOR and hypoxia-inducible factor 1 integrate metabolism and migration of CD8+ T cells. J Exp Med 209:2441–2453

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Shi LZ, Wang R, Huang G, Vogel P, Neale G, Green DR, Chi H (2011) HIF1alpha-dependent glycolytic pathway orchestrates a metabolic checkpoint for the differentiation of TH17 and Treg cells. J Exp Med 208:1367–1376

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Wang R, Dillon CP, Shi LZ, Milasta S, Carter R, Finkelstein D, McCormick LL, Fitzgerald P, Chi H, Munger J et al (2011) The transcription factor Myc controls metabolic reprogramming upon T lymphocyte activation. Immunity 35:871–882

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Dang EV, Barbi J, Yang HY, Jinasena D, Yu H, Zheng Y, Bordman Z, Fu J, Kim Y, Yen HR et al (2011) Control of T(H)17/T(reg) balance by hypoxia-inducible factor 1. Cell 146:772–784

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Pollizzi KN, Patel CH, Sun IH, Oh MH, Waickman AT, Wen J, Delgoffe GM, Powell JD (2015) mTORC1 and mTORC2 selectively regulate CD8(+) T cell differentiation. J Clin Invest 125:2090–2108

    Article  PubMed  PubMed Central  Google Scholar 

  30. Zeng H, Cohen S, Guy C, Shrestha S, Neale G, Brown SA, Cloer C, Kishton RJ, Gao X, Youngblood B et al (2016) mTORC1 and mTORC2 kinase signaling and glucose metabolism drive follicular helper T cell differentiation. Immunity 45:540–554

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Nardella C, Chen Z, Salmena L, Carracedo A, Alimonti A, Egia A, Carver B, Gerald W, Cordon-Cardo C, Pandolfi PP (2008) Aberrant Rheb-mediated mTORC1 activation and Pten haploinsufficiency are cooperative oncogenic events. Genes Dev 22:2172–2177

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Corradetti MN, Inoki K, Bardeesy N, DePinho RA, Guan KL (2004) Regulation of the TSC pathway by LKB1: evidence of a molecular link between tuberous sclerosis complex and Peutz-Jeghers syndrome. Genes Dev 18:1533–1538

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Mehenni H, Lin-Marq N, Buchet-Poyau K, Reymond A, Collart MA, Picard D, Antonarakis SE (2005) LKB1 interacts with and phosphorylates PTEN: a functional link between two proteins involved in cancer predisposing syndromes. Hum Mol Genet 14:2209–2219

    Article  CAS  PubMed  Google Scholar 

  34. Cham CM, Gajewski TF (2005) Glucose availability regulates IFN-gamma production and p70S6 kinase activation in CD8+ effector T cells. J Immunol 174:4670–4677

    Article  CAS  PubMed  Google Scholar 

  35. Zarrouk M, Rolf J, Cantrell DA (2013) LKB1 mediates the development of conventional and innate T cells via AMP-dependent kinase autonomous pathways. PLoS One 8:e60217

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Tamás P, Macintyre A, Finlay D, Clarke R, Feijoo-Carnero C, Ashworth A, Cantrell D (2010) LKB1 is essential for the proliferation of T-cell progenitors and mature peripheral T cells. Eur J Immunol 40:242–253

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  37. Su GH, Hruban RH, Bansal RK, Bova GS, Tang DJ, Shekher MC, Westerman AM, Entius MM, Goggins M, Yeo CJ (1999) Germline and somatic mutations of the STK11/LKB1 Peutz-Jeghers gene in pancreatic and biliary cancers. Am J Pathol 154:1835–1840

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Figer A, Kaplan A, Frydman M, Lev D, Paswell J, Papa M, Goldman B, Friedman E (2002) Germline mutations in the PTEN gene in Israeli patients with Bannayan–Riley–Ruvalcaba syndrome and women with familial breast cancer. Clin Genet 62:298–302

    Article  CAS  PubMed  Google Scholar 

  39. Huynh A, DuPage M, Priyadharshini B, Sage PT, Quiros J, Borges CM, Townamchai N, Gerriets VA, Rathmell JC, Sharpe AH (2015) Control of PI (3) kinase in T reg cells maintains homeostasis and lineage stability. Nat Immunol 16:188–196

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Siska PJ, Rathmell JC (2016) Metabolic signaling drives IFN-γ. Cell Metab 24:651–652

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Palmer CS, Ostrowski M, Balderson B, Christian N, Crowe SM (2015) Glucose metabolism regulates T cell activation, differentiation, and functions. Front Immunol 6:1

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  42. Lacher SM, Bruttger J, Kalt B, Berthelet J, Rajalingam K, Wörtge S, Waisman A (2017) HMG-CoA reductase promotes protein prenylation and therefore is indispensible for T-cell survival. Cell Death Dis 8:e2824–e2824

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Halford NG, Hey SJ (2009) Snf1-related protein kinases (SnRKs) act within an intricate network that links metabolic and stress signalling in plants. Biochem J 419:247–259

    Article  CAS  PubMed  Google Scholar 

  44. Jaleel M, McBride A, Lizcano JM, Deak M, Toth R, Morrice NA, Alessi DR (2005) Identification of the sucrose non-fermenting related kinase SNRK, as a novel LKB1 substrate. FEBS Lett 579:1417–1423

    Article  CAS  PubMed  Google Scholar 

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Funding

This work was supported by Yeungnam University Research Grant 220A380067 (http://www.yu.ac.kr/index.php). The funders had no role in the study design, data collection and analysis, decision to publish, or manuscript preparation.

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  1. College of Pharmacy, Yeungnam University, Gyeongsan, 38541, Republic of Korea

    Mahesh Pandit, Maheshwor Timilshina & Jae-Hoon Chang

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  1. Mahesh Pandit
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  2. Maheshwor Timilshina
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Contributions

M.P. and M.T. collected, analyzed, and interpreted the data, and arranged the figure. J.H.C. and M.P. wrote the manuscript. J.H.C. conceptualized, designed, and supervised the study and obtained funding.

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Correspondence to Jae-Hoon Chang.

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All animal studies were reviewed and approved by the Institutional Animal Care and Use Committee of Yeungnam University (Approval numbers 2017-030, 2017-003, 2017-031, and 2014-018), and National Institute of Health Guidelines were followed to care for the animals and perform the experiments.

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The authors declare no competing interests.

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Pandit, M., Timilshina, M. & Chang, JH. LKB1-PTEN axis controls Th1 and Th17 cell differentiation via regulating mTORC1. J Mol Med 99, 1139–1150 (2021). https://doi.org/10.1007/s00109-021-02090-2

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  • DOI: https://doi.org/10.1007/s00109-021-02090-2

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