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

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.

LKB1 restrains dendritic cell function

“…1). [9][10][11] They find an enlarged tTreg pool throughout the body of CD11cΔLKB1 mice, including the thymus, which protects them from experimental allergy or autoimmunity but makes them more susceptible to grafted tumors. LKB1 is phosphorylated in intratumoral DCs, 11 while Escherichia coli or LPS stimulation downregulates LKB1 expression in DCs, which associates with expansion of tTregs.…”

“…9 Two studies show that Tregs of CD11cΔLKB1 mice express higher levels of immune-suppressive molecules and display an enhanced suppressive activity limiting T cell proliferation. 10,11 Further, Wang et al 11 demonstrate that LKB1-deficient DCs express higher levels of Treg-inducing IL-2, indoleamine 2, 3-dioxygenase (IDO) 1, arginase (Arg) 2 and integrin beta (Itgb) 8 than wild-type DCs. These factors contribute to induction of mTOR signaling in tTregs and enhance tTreg proliferation.…”

“…Notably, LKB1-deficient splenic DCs (subsets) display enhanced MHC and co-stimulatory molecule expression, foremost OX40-ligand (OX40L) and CD86, the latter also being elevated on CD11cΔLKB1 DCs in the thymus. [9][10][11] Indeed, Pelgrom et al identify the thymic CD11b + cDC2 subset, which is associated with regulation of tTreg responses, 12 but not thymic cDC1s or pDCs, to be a key player in inducing tTregs upon LKB1 loss. Mechanistically, high CD86 expression, driven by enhanced phospholipase C-β1 (PLC-β1) expression and calcium signaling in thymic CD11cΔLKB1 cDC2s, potentiates tTreg induction.…”

“…Mechanistically, high CD86 expression, driven by enhanced phospholipase C-β1 (PLC-β1) expression and calcium signaling in thymic CD11cΔLKB1 cDC2s, potentiates tTreg induction. 10 Frequencies of cDC2s are also increased in thymi of CD11cΔLKB1 mice, likely further fostering induction of tTregs. 10,11 Moreover, thymic CD11cΔLKB1 cDC2s express higher levels of CCR7, 10 in line with increased presence and CCR7 expression of migratory DCs in lymph nodes and augmented DC-Treg interaction.…”

“…10 Frequencies of cDC2s are also increased in thymi of CD11cΔLKB1 mice, likely further fostering induction of tTregs. 10,11 Moreover, thymic CD11cΔLKB1 cDC2s express higher levels of CCR7, 10 in line with increased presence and CCR7 expression of migratory DCs in lymph nodes and augmented DC-Treg interaction. 10,11 Peripheral CD11cΔLKB1 cDC2s, but not cDC1s, also induce additional tTreg proliferation outside the thymus.…”