The liver kinase B1 is a central regulator of T cell development, activation, and metabolism.
Abstract
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.
Type
Journal articleSubject
AnimalsCell Differentiation
Cell Proliferation
Cell Separation
Cell Survival
Flow Cytometry
Homeostasis
Immunoblotting
Lymphocyte Activation
Mice
Mice, Knockout
Protein-Serine-Threonine Kinases
Reverse Transcriptase Polymerase Chain Reaction
Signal Transduction
T-Lymphocytes
Permalink
https://hdl.handle.net/10161/10316Published Version (Please cite this version)
10.4049/jimmunol.1100367Publication Info
MacIver, Nancie J; Blagih, Julianna; Saucillo, Donte C; Tonelli, Luciana; Griss, Takla;
Rathmell, Jeffrey C; & Jones, Russell G (2011). The liver kinase B1 is a central regulator of T cell development, activation, and
metabolism. J Immunol, 187(8). pp. 4187-4198. 10.4049/jimmunol.1100367. Retrieved from https://hdl.handle.net/10161/10316.This is constructed from limited available data and may be imprecise. To cite this
article, please review & use the official citation provided by the journal.
Collections
More Info
Show full item recordScholars@Duke
Nancie Jo MacIver
Adjunct Associate Professor in the Department of Pediatrics
My laboratory is broadly interested in how large changes in nutritional status (e.g.
malnutrition or obesity) influence T cell immunity. Malnutrition can lead to immunodeficiency
and increased risk of infection, whereas obesity is associated with inflammation that
promotes multiple diseases including autoimmunity, type 2 diabetes, and cardiovascular
disease. We have identified the adipocyte-secreted hormone leptin as a critical link
between nutrition and immunity. Leptin is
Jeffrey Charles Rathmell
Adjunct Associate Professor in the Department of Pharmacology and Cancer Biology
My laboratory studies the mechanisms and role of glucose metabolism in lymphocyte
survival and activation. We have found that dramatic increases in glucose metabolism
are necessary for lymphocytes to survive and mount immune responses. Excessive glucose
metabolism, however, can lead to T cell hyperactivation and autoimmunity. A key mechanism
for control of lymphocyte glucose metabolism is regulation of glucose uptake by the
glucose transporter, Glut1. Interestingly, upregulation of Glut1 and glu
Alphabetical list of authors with Scholars@Duke profiles.

Articles written by Duke faculty are made available through the campus open access policy. For more information see: Duke Open Access Policy
Rights for Collection: Scholarly Articles
Works are deposited here by their authors, and represent their research and opinions, not that of Duke University. Some materials and descriptions may include offensive content. More info