Dectin-1-activated dendritic cells trigger potent antitumour immunity through the induction of Th9 cells.

Yinghua Zhao,Siqing Wang,Ying Wang,Yong Lu,Wenjie Zhao,Guangyun Tan,Honglin Xu,Xingzhe Ma,Jintong Chen,Xiao Chu,Xiaoqing Zhu,Huanfa Yi,Sujun Gao,Qing Yi,Yuxue Jiang

doi:10.1038/ncomms12368

Abstract

Dectin-1 signalling in dendritic cells (DCs) has an important role in triggering protective antifungal Th17 responses. However, whether dectin-1 directs DCs to prime antitumour Th9 cells remains unclear. Here, we show that DCs activated by dectin-1 agonists potently promote naive CD4+ T cells to differentiate into Th9 cells. Abrogation of dectin-1 in DCs completely abolishes their Th9-polarizing capability in response to dectin-1 agonist curdlan. Notably, dectin-1 stimulation of DCs upregulates TNFSF15 and OX40L, which are essential for dectin-1-activated DC-induced Th9 cell priming. Mechanistically, dectin-1 activates Syk, Raf1 and NF-κB signalling pathways, resulting in increased p50 and RelB nuclear translocation and TNFSF15 and OX40L expression. Furthermore, immunization of tumour-bearing mice with dectin-1-activated DCs induces potent antitumour response that depends on Th9 cells and IL-9 induced by dectin-1-activated DCs in vivo. Our results identify dectin-1-activated DCs as a powerful inducer of Th9 cells and antitumour immunity and may have important clinical implications.

Highlights

Dectin-1 signalling in dendritic cells (DCs) has an important role in triggering protective antifungal Th17 responses
We show that dectin-1 signalling stimulates DCs to overexpress TNFSF15 and OX40L, which are responsible for promoting Th9 cell differentiation primed by dectin-1-activated-DCs in vitro
To address whether dectin-1-activated DCs affected the differentiation of Th9 cells, we matured mouse bone marrow (BM)-derived DCs with TNF-a plus IL-1b (BMDCs) or a selective dectin-1 agonist Curdlan (CurDCs) and stimulated naive CD4 þ T cells under Th9-polarizing conditions with BMDCs or CurDCs

Summary

Introduction

Dectin-1 signalling in dendritic cells (DCs) has an important role in triggering protective antifungal Th17 responses. We show that DCs activated by dectin-1 agonists potently promote naive CD4 þ T cells to differentiate into Th9 cells. Our results identify dectin-1-activated DCs as a powerful inducer of Th9 cells and antitumour immunity and may have important clinical implications. IL-9 has the potential to enhance the survival and proliferation of antitumour effector T cells[10] These seminal findings provide an impetus for further investigation of efficient strategies to induce and expand Th9 cells for tumour immunotherapy. Dectin-1 activation in DCs stimulates the secretion of IL-6, TNF-a and IL-12p40, which polarize naive CD4 þ T cells into Th17 and Th1 cells, the key effector cells for antifungal immunity[27,28]. Whether dectin-1 activation in DCs favours the induction of antitumour Th9 cells remains unclear

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Conclusion