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ILC3-derived OX40L is essential for homeostasis of intestinal Tregs in immunodeficient mice

Cellular & Molecular Immunology volume 17, pages 163–177 (2020)Cite this article

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Abstract

OX40L is one of the co-stimulatory molecules that can be expressed by splenic lymphoid tissue inducer (Lti) cells, a subset of group 3 innate lymphoid cells (ILC3s). OX40L expression in subsets of intestinal ILC3s and the molecular regulation of OX40L expression in ILC3s are unknown. Here, we showed intestinal ILC3s marked as an OX40Lhigh population among all the intestinal leukocytes and were the dominant source of OX40L in Rag1–/– mice. All ILC3 subsets expressed OX40L, and NCR–ILC3s were the most abundant source of OX40L. The expression of OX40L in ILC3s could be upregulated during inflammation. In addition to tumor necrosis factor (TNF)-like cytokine 1A (TL1A), which has been known as a trigger for OX40L, we found that Poly (I:C) representing viral stimulus promoted OX40L expression in ILC3s via a cell-autonomous manner. Furthermore, we demonstrated that IL-7-STAT5 signaling sustained OX40L expression by ILC3s. Intestinal regulatory T cells (Tregs), most of which expressed OX40, had defective expansion in chimeric mice, in which ILC3s were specifically deficient for OX40L expression. Consistently, co-localization of Tregs and ILC3s was found in the cryptopatches of the intestine, which suggests the close interaction between ILC3s and Tregs. Our study has unveiled the crosstalk between Tregs and ILC3s in mucosal tissues through OX40–OX40L signaling, which is crucial for the homeostasis of intestinal Tregs.

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Acknowledgements

The authors would like to thank Dr. Dechun Feng for experimental support. We thank the entire Q.J. laboratory team for their help and suggestions. This study was supported by grants 2015CB943400 and 2014CB943300 from the Ministry of Science and Technology of China, grant XDB19000000 from the “Strategic priority research program of the Chinese Academy of Sciences”, grants 91542102 and 31570887 from the National Natural Science Foundation of China, and China's Youth 1000 Talent Program to Q.J.

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  1. CAS Key Laboratory of Tissue Microenvironment and Tumor, Shanghai Jiao Tong University School of Medicine (SJTUSM) & Shanghai Institutes for Biological Sciences (SIBS), Chinese Academy of Sciences (CAS), Shanghai, 200031, China

    Tian Deng

  2. CAS Key Laboratory of Tissue Microenvironment and Tumor, Shanghai Institutes for Biological Sciences, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, 200031, China

    Caixia Suo, Jiali Chang, Rui Yang, Jingyu Li, Ting Cai & Ju Qiu

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Q.J. and D.T. designed the research. D.T. and S.C. conducted the experiments and analyzed the data. Q.J. and D.T. wrote the manuscript. Y.R., C.J, L.J. and C.T. helped with the experiments and writing of the manuscript.

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Correspondence to Ju Qiu.

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Deng, T., Suo, C., Chang, J. et al. ILC3-derived OX40L is essential for homeostasis of intestinal Tregs in immunodeficient mice. Cell Mol Immunol 17, 163–177 (2020). https://doi.org/10.1038/s41423-019-0200-x

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