State Key Laboratory of Experimental Hematology, Institute of Hematology and Hospital of Blood Disease, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin, 300020, China.
Department of Respiration, The Second Affiliated Hospital of Nanchang University, Nanchang, 330006, China.
Nat Commun. 2018 Dec 13;9(1):5298. doi: 10.1038/s41467-018-07545-8.
To balance immunity and tolerance, the endogenous pool of Foxp3 regulatory T (T) cells is tightly controlled, but the underlying mechanisms of this control remain poorly understood. Here we show that the number of T cells is negatively regulated by the kinase Lkb1 in dendritic cells (DCs). Conditional knockout of the Lkb1 gene in DCs leads to excessive T 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 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 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 cell homeostasis, immune response and tolerance.
为了平衡免疫和耐受，Foxp3 调节性 T (T) 细胞的内源性池受到严格控制，但这种控制的潜在机制仍知之甚少。本文中，我们发现激酶 Lkb1 在树突状细胞 (DC) 中负调控 T 细胞的数量。条件敲除 DC 中的 Lkb1 基因会导致多个器官中 T 细胞过度扩增，并抑制抗原特异性 T 细胞免疫。与野生型 DC 相比，Lkb1 缺陷型 DC 能够通过细胞间接触增强 T 细胞增殖，涉及 IKK/IKBα 非依赖性 NF-κB/OX40L 通路的激活。有趣的是，用脂多糖处理野生型小鼠可选择性地耗尽 DC 中的 Lkb1 蛋白，导致 T 细胞扩增，并在随后的挑战中抑制炎症损伤。Lkb1 的缺失并没有明显上调 DC 上促炎分子的表达。因此，我们确定 Lkb1 是 DC 中控制 T 细胞动态平衡、免疫反应和耐受的调节开关。
