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

• Published in: Nature communications Vol. 9; no. 1; pp. 1 - 16
• Main Authors: Chen, Song, Fang, Lijun, Guo, Wei, Zhou, Yushan, Yu, Gang, Li, Wenwen, Dong, Kui, Liu, Jingru, Luo, Yuechen, Wang, Bing, Li, Zhonglong, Zhao, Chunxiao, Sun, Zhina, Shen, Yue, Leng, Qibing, Zhou, Dongming, Han, Zhongchao, Huang, Huifang, Ren, He, Xu, Guogang, Feng, Xiaoming
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 13.12.2018; Nature Publishing Group; Nature Portfolio
• Subjects: 13/31; 38/15; 38/61; 38/88; 631/250/1619/554/1898/1271; 631/250/2499; 631/250/2504/133; 631/250/516/1909; 64/110; Cell adhesion; Cell proliferation; Dendritic cells; Foxp3 protein; Homeostasis; Humanities and Social Sciences; Immune response; Immune system; Immunity; Immunological tolerance; Inflammation; Kinases; Lipopolysaccharides; LKB1 protein; Lymphocytes; Lymphocytes T; multidisciplinary; NF-κB protein; Organs; Ox40L protein; Proteins; Science; Science (multidisciplinary)
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-018-07545-8

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. Regulatory T (Treg) cells are important for maintaining immune homeostasis by suppressing immune cell activation, but how the Treg cell pool is maintained is still unclear. Here the authors show that a kinase, Lkb1, operates in dendritic cells (DC) to inhibit Treg cell expansion and immunosuppression via mechanisms involving NF-kB/OX40L signalling.