Lkb1 maintains Treg cell lineage identity

Di Wu,Huifang Huang,Song Chen,Fei Yang,Fang Liao,Xiaolei Sun,Yong‐Guang Yang ,Yuechen Luo,Wei Guo,Qing Niu,Ting Xue,Yuanyuan Liu,Zhina Sun,Chenjing Zhao ,Jingru Liu,Guogang Xu,Zhongchao Han,Tao Cheng,Dongming Zhou,Xiaoming Feng

doi:10.1038/ncomms15876

Abstract

Regulatory T (Treg) cells are a distinct T-cell lineage characterized by sustained Foxp3 expression and potent suppressor function, but the upstream dominant factors that preserve Treg lineage-specific features are mostly unknown. Here, we show that Lkb1 maintains Treg cell lineage identity by stabilizing Foxp3 expression and enforcing suppressor function. Upon T-cell receptor (TCR) stimulation Lkb1 protein expression is upregulated in Treg cells but not in conventional T cells. Mice with Treg cell-specific deletion of Lkb1 develop a fatal early-onset autoimmune disease, with no Foxp3 expression in most Treg cells. Lkb1 stabilizes Foxp3 expression by preventing STAT4-mediated methylation of the conserved noncoding sequence 2 (CNS2) in the Foxp3 locus. Independent of maintaining Foxp3 expression, Lkb1 programs the expression of a wide spectrum of immunosuppressive genes, through mechanisms involving the augmentation of TGF-β signalling. These findings identify a critical function of Lkb1 in maintaining Treg cell lineage identity.

Highlights

Regulatory T (Treg) cells are a distinct T-cell lineage characterized by sustained Foxp[3] expression and potent suppressor function, but the upstream dominant factors that preserve Treg lineage-specific features are mostly unknown
Foxp3CreLkb1f/f mice had substantial expansion of CD4 þ conventional T cells (Supplementary Fig. 1c), associated with drastically increased percentages of cells that displayed a CD44highCD62Llow effector/memory phenotype (Fig. 2a and Supplementary Fig. 1d). These mice had higher percentages of CD4 þ and CD8 þ conventional T cells that expressed the proliferation marker Ki67 and acute activation markers CD25 and CD69 (Fig. 2b and Supplementary Fig. 1e), and produced the inflammatory cytokines interferon-g, IL-4 and IL-17A (Fig. 2c and Supplementary Fig. 1f). These phenotypes were similar in severity to those observed in mice deficient of Foxp[3] or depleted of Treg cells[23], indicating a severe defect of immune suppression mediated by Treg cells
We examined the methylation of conserved noncoding sequence 2 (CNS2) in Foxp3Cre and Foxp3CreLkb1f/f Treg cells treated with IL-2, IL-2 þ IL-12 or IL-2 þ IL-12 þ 5-aza-deoxycytidine (5-aza-dC, a DNA methyltransferase inhibitor) to investigate the relationship between STAT4 and CNS2 methylation

Summary

Introduction

Regulatory T (Treg) cells are a distinct T-cell lineage characterized by sustained Foxp[3] expression and potent suppressor function, but the upstream dominant factors that preserve Treg lineage-specific features are mostly unknown. We show that Lkb[1] maintains Treg cell lineage identity by stabilizing Foxp[3] expression and enforcing suppressor function. Independent of maintaining Foxp[3] expression, Lkb[1] programs the expression of a wide spectrum of immunosuppressive genes, through mechanisms involving the augmentation of TGF-b signalling. These findings identify a critical function of Lkb[1] in maintaining Treg cell lineage identity. Delineating the molecular mechanisms that maintain the Treg lineage identity is important for understanding and treating Treg cell-related immune diseases. Lkb[1] has been shown to restrain the activation and proinflammatory function of conventional T cells[18,19]

Methods

Results

Conclusion