Abstract
To balance immunity and tolerance, the endogenous pool of Foxp3+ regulatory T (Treg) cells is tightly controlled, but the underlying mechanisms of this control remain poorly understood. Here we show that the number of Treg cells is negatively regulated by the kinase Lkb1 in dendritic cells (DCs). Conditional knockout of the Lkb1 gene in DCs leads to excessive Treg cell expansion in multiple organs and dampens antigen-specific T cell immunity. Lkb1-deficient DCs are capable of enhancing, compared with wild-type DCs, Treg cell proliferation via cell-cell contact involving the IKK/IKBα-independent activation of the NF-κB/OX40L pathway. Intriguingly, treating wild-type mice with lipopolysaccharide selectively depletes Lkb1 protein in DCs, resulting in Treg cell expansion and suppressed inflammatory injury upon subsequent challenge. Loss of Lkb1 does not obviously upregulate proinflammatory molecules expression on DCs. We thus identify Lkb1 as a regulatory switch in DCs for controlling Treg cell homeostasis, immune response and tolerance.
Highlights
To balance immunity and tolerance, the endogenous pool of Foxp3+ regulatory T (Treg) cells is tightly controlled, but the underlying mechanisms of this control remain poorly understood
We find that after challenging wild-type (WT) mice with Escherichia coli (E. coli)-derived lipopolysaccharide (LPS), Lkb[1] protein is selectively depleted in dendritic cells (DCs) in a negative-feedback manner, resulting in the expansion of Treg cells that is necessary for protecting the host from inflammatory injury responses induced by lethal rechallenge doses
Chromatin immunoprecipitation (ChIP) assays showed more NF-κB p65 binding on the Ox40l promotor in Liver kinase B1 (Lkb1)-deficient DCs than in WT DCs (Fig. 5j), suggesting a direct effect of NF-κB signalling on promoting Ox40l transcription. These results suggest that an unusual form of IKKα/β- and IκBα-independent NF-κB activation drove the upregulation of Ox40l in Lkb1-deficient DCs and that this activated NF-κB signalling promoted Treg cell proliferation at least partially via OX40L
Summary
To balance immunity and tolerance, the endogenous pool of Foxp3+ regulatory T (Treg) cells is tightly controlled, but the underlying mechanisms of this control remain poorly understood. We show that the number of Treg cells is negatively regulated by the kinase Lkb[1] in dendritic cells (DCs). Conditional knockout of the Lkb[1] gene in DCs leads to excessive Treg cell expansion in multiple organs and dampens antigen-specific T cell immunity. The number of Treg cells in each organ is maintained at a constant threshold level to ensure self-tolerance while allowing the efficient initiation of defensive responses[2]. Known as sentinels of the immune system required for initiating defensive responses, DCs critically maintain immune homeostasis through suppressing the activation or inducing the unresponsiveness/apoptosis of self-reactive T cells and by promoting the generation, maintenance and/or expansion of Treg cells[5,6,7]. The specific role played by Lkb[1] in DCs, which are central to immune regulation, has not yet been studied
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