Cell Research | 2019
LKB1 restrains dendritic cell function
Abstract
Three independent recent studies support the notion that liver kinase B1 (LKB1), a key nutrient sensor, controls dendritic cell (DC) function. Selective loss of LKB1 in DCs leads to their increased ability to prime effector T cell responses, but the prevailing effect is the expansion of thymus-derived natural regulatory T cells, creating a dominant immunosuppressive environment. Tight regulation of T cell priming by dendritic cells (DCs) is key to maintain tissue homeostasis and orchestrate immunity. As immune sentinels, DCs control the activation of different flavors of immunity including effector CD8 T cells and CD4 helper T (Th) cells, the latter comprising IFNγ-producing Th1, IL-4-producing Th2, IL-17-producing Th17 cells and follicular helper T cells (Tfh) that promote B cell differentiation in germinal centers. However, DCs also contribute to homeostasis and self-tolerance through the induction of regulatory T cells (Tregs), which can be Helios thymus-derived/natural (tTregs) or generated upon antigen exposure in the periphery (Helios pTregs). DCs integrate environmental cues such as pathogenor dangerassociated molecular patterns and cytokines to activate different intracellular signaling pathways. Those adaptions lead to adjustment of antigen uptake, processing and presentation on MHC molecules (signal 1), expression of co-stimulatory molecules (signal 2) and production of specific cytokines (signal 3) by DCs to modulate induction of effector and regulatory T cell responses. Different DC subsets include plasmacytoid (pDCs), conventional type 1 (cDC1s) and 2 (cDC2s) DCs, and express a varying repertoire of pattern recognition receptors sensing those extracellular cues culminating in diverse functional features. Metabolic alterations in DCs upon sensing the environment have emerged as an essential mechanism for control of DC function in the regulation of adaptive immune responses. Resting or tolerogenic DCs preferentially display an active catabolic energy metabolism via the Krebs cycle and oxidative phosphorylation (OXPHOS) that can be fueled by fatty acid oxidation. Immunogenic activation of DCs generally fosters an anabolic metabolism characterized by enhanced glycolysis, and fatty acid synthesis to drive the extension of the Golgi apparatus and endoplasmic reticulum for cytokine production. The early induction of glycolysis regulates many aspects of immunogenic DC activation, including migration, upregulation of MHC and co-stimulatory molecules, and T cell stimulation. The metabolic adaption of DCs upon stimulation is, at least partially, regulated by a balance of AKT/mTOR/HIF and AMPK signaling pathways. Activation of mTOR can sustain immunogenic DC activation, while active AMPK is associated with resting and tolerized DCs. However, the precise pathways regulating the metabolic state that drive tolerogenic DC function are poorly understood. LKB1 is a serine/threonine kinase that can activate AMPK upon low intracellular ATP to induce catabolic oxidative metabolism. As such, LKB1 is implicated in modulating metabolism, survival, differentiation and functional features of hematopoietic stem cells, effector CD4 and CD8 T cells as well as Tregs in AMPKdependent and -independent fashions. Also, LKB1 is phosphorylated on Ser428 in lipopolysaccharide (LPS)-stimulated macrophages and restricts their pro-inflammatory functions by inhibition of NF-κB signaling, likely via binding to IκB kinase (IKK) β. To dissect the contribution of LKB1 to DC function, three independent studies have analyzed CD11c-Cre LKB1 (CD11cΔLKB1) mice (Fig. 1). 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, while Escherichia coli or LPS stimulation downregulates LKB1 expression in DCs, which associates with expansion of tTregs. 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. Further, Wang et al. 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. Indeed, Pelgrom et al. identify the thymic CD11b cDC2 subset, which is associated with regulation of tTreg responses, 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. Frequencies of cDC2s are also increased in thymi of CD11cΔLKB1 mice, likely further fostering induction of tTregs. Moreover, thymic CD11cΔLKB1 cDC2s express higher levels of CCR7, in line with increased presence and CCR7 expression of migratory DCs in lymph nodes and augmented DC-Treg interaction. Peripheral CD11cΔLKB1 cDC2s, but not cDC1s, also induce additional tTreg proliferation outside the thymus. Chen et al. report an additional contributing mechanism by showing that LKB1 loss in splenic or lymph node DCs induces non-canonical NF-κB (p65) activation and subsequent upregulation of OX40L, which engages OX40 that is highly expressed on Tregs mediating their expansion in the periphery. Interestingly, the increased T cell-priming ability of LKB1deficient DCs is not restricted to tTregs. LPSand ovalbuminstimulated CD11cΔLKB1 DCs (GM-DCs) generated in vitro more