LKB1 expressed in dendritic cells governs the development and expansion of thymus-derived regulatory T cells

Leonard R Pelgrom; Thiago A Patente; Alexey Sergushichev; Ekaterina Esaulova; Frank Otto; Arifa Ozir-Fazalalikhan; Hendrik J P van der Zande; Alwin J van der Ham; Stefan van der Stel; Maxim N Artyomov; Bart Everts

doi:10.1038/s41422-019-0161-8

LKB1 expressed in dendritic cells governs the development and expansion of thymus-derived regulatory T cells

Cell Res. 2019 May;29(5):406-419. doi: 10.1038/s41422-019-0161-8. Epub 2019 Apr 2.

Affiliations

¹ Department of Parasitology, Leiden University Medical Center, Leiden, The Netherlands.
² Computer Technologies Department, ITMO University, Saint Petersburg, Russia.
³ Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, USA.
⁴ Department of Parasitology, Leiden University Medical Center, Leiden, The Netherlands. [email protected].

Abstract

Liver Kinase B1 (LKB1) plays a key role in cellular metabolism by controlling AMPK activation. However, its function in dendritic cell (DC) biology has not been addressed. Here, we find that LKB1 functions as a critical brake on DC immunogenicity, and when lost, leads to reduced mitochondrial fitness and increased maturation, migration, and T cell priming of peripheral DCs. Concurrently, loss of LKB1 in DCs enhances their capacity to promote output of regulatory T cells (Tregs) from the thymus, which dominates the outcome of peripheral immune responses, as suggested by increased resistance to asthma and higher susceptibility to cancer in CD11c^ΔLKB1 mice. Mechanistically, we find that loss of LKB1 specifically primes thymic CD11b⁺ DCs to facilitate thymic Treg development and expansion, which is independent from AMPK signalling, but dependent on mTOR and enhanced phospholipase C β1-driven CD86 expression. Together, our results identify LKB1 as a critical regulator of DC-driven effector T cell and Treg responses both in the periphery and the thymus.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

AMP-Activated Protein Kinases
Animals
Asthma / immunology
Asthma / pathology
B7-2 Antigen / metabolism
CD11b Antigen / metabolism
CD11c Antigen / deficiency
CD11c Antigen / genetics
Cell Line, Tumor
Dendritic Cells / cytology
Dendritic Cells / metabolism*
Disease Models, Animal
Melanoma / metabolism
Melanoma / pathology
Membrane Proteins / metabolism
Mice
Mice, Inbred C57BL
Mitochondria / metabolism
Phospholipase C beta / metabolism
Protein Serine-Threonine Kinases / deficiency
Protein Serine-Threonine Kinases / genetics
Protein Serine-Threonine Kinases / metabolism*
Signal Transduction
T-Lymphocytes, Regulatory / cytology
T-Lymphocytes, Regulatory / metabolism*
TOR Serine-Threonine Kinases / metabolism
Thymus Gland / cytology
Thymus Gland / immunology

Substances

B7-2 Antigen
CD11b Antigen
CD11c Antigen
Cd86 protein, mouse
Membrane Proteins
flt3 ligand protein
mTOR protein, mouse
Protein Serine-Threonine Kinases
Stk11 protein, mouse
TOR Serine-Threonine Kinases
AMP-Activated Protein Kinases
Phospholipase C beta