Control of Treg cell homeostasis and immune equilibrium by Lkb1 in dendritic cells

Abstract

Abstract To balance immunity and tolerance, the endogenous pool of Foxp3 + regulatory T (T reg ) cells is tightly controlled, but the underlying mechanisms of this control remain poorly understood. Here we show that the number of T reg cells is negatively regulated by the kinase Lkb1 in dendritic cells (DCs). Conditional knockout of the Lkb1 gene in DCs leads to excessive T reg cell expansion in multiple organs and dampens antigen-specific T cell immunity. Lkb1-deficient DCs are capable of enhancing, compared with wild-type DCs, T reg 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 T reg 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 T reg cell homeostasis, immune response and tolerance.