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

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/IKB?-independent activation of the NF-?B/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.

SUBMITTER: Chen S

PROVIDER: S-EPMC6294005 | biostudies-literature | 2018 Dec

REPOSITORIES: biostudies-literature

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

Chen Song S Fang Lijun L Guo Wei W Zhou Yushan Y Yu Gang G Li Wenwen W Dong Kui K Liu Jingru J Luo Yuechen Y Wang Bing B Li Zhonglong Z Zhao Chunxiao C Sun Zhina Z Shen Yue Y Leng Qibing Q Zhou Dongming D Han Zhongchao Z Huang Huifang H Ren He H Xu Guogang G Feng Xiaoming X

Nature communications 20181213 1

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-defi ...[more]

PMID: 30546010

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Project description:Background Regulatory T cells (Tregs) induce immune responses and may contribute to immune escape in tumors. Accumulation of Tregs in tumors represents a critical barrier to anti-tumor immunity and immunotherapy. However, conflicting results describing the role of Tregs in lymphoma warrant further investigation. The precise features and mechanisms underlying the alteration in Tregs in diffuse large B-cell lymphoma (DLBCL) are not well understood yet. In this study, we analyzed the mechanism underlying the observed alterations in Tregs in DLBCL and examined the effect of Lkb1 expression on the immunosuppressive function of human Tregs. Methods Flow cytometry and immunofluorescence were used to analyze the proportion of Tregs and effector Tregs in the peripheral blood and lymph nodes of patients with DLBCL and control group. In vitro culture assays were used to analyze the immunosuppressive function of Tregs in the two groups. Transcriptome sequencing was performed to analyze the differentially expressed genes in the two groups, and the transcription level and protein expression of Lkb1 in the two groups were detected using RT-PCR and WES microprotein technology. Lentiviral vectors were constructed to explore the functional changes of Tregs with stable upregulation and downregulation of Lkb1. Finally, a humanized murine lymphoma model was established to study the function of Lkb1 in Tregs in the pathogenesis of DLBCL. Results The number of Tregs was found to be dramatically increased in peripheral blood and tumor tissue in DLBCL patients compared with that in healthy controls, and decreased after treatment. Tregs from DLBCL patients exhibited multiple enhanced functions, including increased inhibition of CD8+cytotoxic T cells (CTL) against tumor cells, enhanced suppression of CD8+CTL secretion of granular enzyme, and suppression of CD8+CTL degranulation. Lkb1 was found to be upregulated in Tregs of DLBCL patients. Furthermore, Lkb1 contributes to Treg immunosuppressive function in DLBCL by regulating the mevalonate pathway. Finally, deletion of Lkb1 in Tregs suppressed tumor growth and promoted anti-tumor immunity in a DLBCL murine model. Conclusions These findings confirmed that Lkb1-regulated Tregs are critical for immune escape in DLBCL, which emphasizes that Lkb1 is a potential target for the immunotherapy of DLBCL. Supplementary Information The online version contains supplementary material available at 10.1186/s12967-022-03588-0.

Project description:Both interleukin (IL)-7 and human periodontal ligament cells (hPDLCs) have immunomodulatory properties. However, their combined effect on CD4+T cells has never been studied. In this study, we aimed to investigate the effect of conditioned medium of hPDLCs treated with rhIL-7 on the differentiation of CD4+T cells into regulatory T cells/T helper 17 cells (Treg/Th17 cells) and observe the effect of IL-7 on the immunomodulatory properties of PDLCs. After hPDLCs were treated with different concentrations of rhIL-7 for 24 h, the collected supernatants were used to incubate CD4+T cells for 3 days. A gamma-secretase inhibitor (DAPT) was used to suppress the activation of the Notch1 signaling pathway. Cell proliferation, apoptosis, and necrosis were determined using the cell counting kit-8 (CCK-8) and flow cytometry (FCM). The expressions of forkhead box P3 (Foxp3) in CD4+T cells and transforming growth factor (TGF-β) and IL-6 in the supernatants were determined by ELISA. Reverse transcription-quantitative PCR (RT-qPCR), and the Western blot (WB) determined the mRNA levels and protein expression of various target factors. FCM was used to detect the mean fluorescence intensity of PD-L1 in hPDLCs and to analyze the differentiation of Treg/Th17 cells. Our results showed that IL-7 promoted proliferation and inhibited apoptosis in hPDLCs, promoted the expression of TGF-β, PD-L1, Notch1, Jagged1, and Hes1, and inhibited the levels of hypoxia-inducible factor (HIF)-1α and TCF7, whereas the addition of DAPT effectively reversed these effects. Importantly, we found that the conditioned medium of hPDLCs treated with rhIL-7 promoted the polarization of CD4+T cells into Treg cells but had no significant effect on the differentiation of Th17 cells. Our study indicated that treatment of PDLCs with IL-7 can promote the polarization of CD4+T cells into Treg cells by modulating the expression of inflammatory factors and signaling molecules through activating the Notch1 signaling pathway, thus participating in the regulation of immune homeostasis in the periodontal microenvironment.

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

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Control of T<sub>reg</sub> cell homeostasis and immune equilibrium by Lkb1 in dendritic cells.

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