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The Liver Kinase B1 Is a Central Regulator of T Cell Development, Activation, and Metabolism
Open accessAbstract
T cell activation leads to engagement of cellular metabolic pathways necessary to support cell proliferation and function. However, our understanding of the signal transduction pathways that regulate metabolism and their impact on T cell function remains limited. The liver kinase B1 (LKB1) is a serine/threonine kinase that links cellular metabolism with cell growth and proliferation. In this study, we demonstrate that LKB1 is a critical regulator of T cell development, viability, activation, and metabolism. T cell-specific ablation of the gene that encodes LKB1 resulted in blocked thymocyte development and a reduction in peripheral T cells. LKB1-deficient T cells exhibited defects in cell proliferation and viability and altered glycolytic and lipid metabolism. Interestingly, loss of LKB1 promoted increased T cell activation and inflammatory cytokine production by both CD4(+) and CD8(+) T cells. Activation of the AMP-activated protein kinase (AMPK) was decreased in LKB1-deficient T cells. AMPK was found to mediate a subset of LKB1 functions in T lymphocytes, as mice lacking the α1 subunit of AMPK displayed similar defects in T cell activation, metabolism, and inflammatory cytokine production, but normal T cell development and peripheral T cell homeostasis. LKB1- and AMPKα1-deficient T cells each displayed elevated mammalian target of rapamycin complex 1 signaling and IFN-γ production that could be reversed by rapamycin treatment. Our data highlight a central role for LKB1 in T cell activation, viability, and metabolism and suggest that LKB1-AMPK signaling negatively regulates T cell effector function through regulation of mammalian target of rapamycin activity.
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“This increased mitochondrial metabolism in Tregs was found to be due to increased AMPK-dependent fatty acid oxidation (MacIver et al., 2011; Michalek et al., 2011).”
From Mitochondria in the Regulation of Innate and Adaptive Immunity (2015) · cites this paper as MacIver et al., 2011
In the citing paper
“The importance of fatty acid oxidation for Tm cells is bolstered by the observations that diminishing or enhancing AMPK, a positive regulator of fatty acid oxidation, decreases or increases formation of memory T cells (MacIver et al., 2011; Pearce et al., 2009; Rolf et al., 2013; Tamás et al., 2010).”
From Mitochondria in the Regulation of Innate and Adaptive Immunity (2015) · cites this paper as MacIver et al., 2011
In the citing paper
“Lymphocytes exclusively express the a1 catalytic subunit of AMPK (87), and TCR stimulation promotes LKB1-dependent AMPK activation in lymphocytes (87, 88).”
From Fueling Immunity: Insights into Metabolism and Lymphocyte Function (2013) · cites this paper as [88]
In the citing paper
“Loss of LKB1-AMPK signaling promotes increased mTORC1 activity in both naïve and TEFF cells (88, 90), which in turn facilitates production of the TH1 cytokine interferon-γ (IFN-γ) by TEFF cells (88).”
From Fueling Immunity: Insights into Metabolism and Lymphocyte Function (2013) · cites this paper as [88]
In the citing paper
“Glycolysis is enhanced in resting AMPKα-deficient T cells (88), consistent with observations that silencing AMPK in tumor cells promotes the Warburg effect (89).”
From Fueling Immunity: Insights into Metabolism and Lymphocyte Function (2013) · cites this paper as [88]
In the citing paper
“Perhaps not surprisingly, deletion of either LKB1 or AMPKα1 disrupts normal lymphocyte homeostasis, resulting in an accumulation of activated (CD44hi CD62Llo) CD8+ T cells in animals (88).”
From Fueling Immunity: Insights into Metabolism and Lymphocyte Function (2013) · cites this paper as [88]
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Metadata
- Authors
- MacIver, N. J., Blagih, J., Saucillo, D. C., Tonelli, L., Griss, T., Rathmell, J. C., & Jones, R. G.
- Affiliations
- Duke Medical Center (US)
- McGill University (CA)
- Duke University (US)
- Corresponding author
- Rathmell, Jeffrey C
- Jones, Russell G
- Venue
- The Journal of Immunology
- Publisher
- Oxford University Press (OUP)
- Published
- 2011-10
- Volume
- 187
- Issue
- 8
- Pages
- 4187-4198
- ISSN
- 0022-1767 (ISSN-L)
- 1550-6606
- PMC
- PMC3206094
- OpenAlex
- W2105344440
- Cited by
- 235
- References
- 66
- Citations by year
- 2026: 4 · 2025: 8 · 2024: 9 · 2023: 11 · 2022: 17 · 2021: 19 · 2020: 17 · 2019: 20 · 2018: 14 · 2017: 24 · 2016: 19 · 2015: 23 · 2014: 16 · 2013: 19 · 2012: 15
- FWCI
- 7.09
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- The Journal of Immunology (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- DukeSpace (Duke University) (submittedVersion, cc-by-nc-nd)
- Funders
- Canadian Institutes of Health Research (MOP-93 799)
- National Heart, Lung, and Blood Institute (HL108006, R01HL108006)
- National Institute of Allergy and Infectious Diseases (R01S AI063345, R01AI063345)
- National Institute of Diabetes and Digestive and Kidney Diseases (K08DK087944)
- Eunice Kennedy Shriver National Institute of Child Health and Human Development (K12HD043494)
- Topics
- Life Sciences › Immunology and Microbiology › Immunology › T-cell and B-cell Immunology
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolism, Diabetes, and Cancer
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › PI3K/AKT/mTOR signaling in cancer
- Keywords
- LKB1, T cell development, T cell activation, T cell metabolism, AMPK, mTORC1 signaling, glycolysis, lipid metabolism, inflammatory cytokine production, interferon-gamma, T cell proliferation, T cell viability, rapamycin
- MeSH terms
- Animals, Cell Differentiation, Cell Separation, Cell Survival, Flow Cytometry, Homeostasis, Lymphocyte Activation, T-Lymphocytes, Immunoblotting, Signal Transduction, Protein Serine-Threonine Kinases, Mice, Knockout, Reverse Transcriptase Polymerase Chain Reaction, Cell Proliferation, Mice, AMP-Activated Protein Kinases
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