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B7-DC (PD-L2) costimulation of CD4+ T-helper 1 response via RGMb

Cellular & Molecular Immunology volume 15, pages 888–897 (2018)Cite this article

Abstract

The role of B7-DC in T-cell responses remains controversial because both coinhibitory and costimulatory functions have been reported in various experimental systems in vitro and in vivo. In addition to interacting with the coinhibitory receptor PD-1, B7-DC has also been shown to bind repulsive guidance molecule b (RGMb). The functional consequences of the B7-DC/RGMb interaction, however, remain unclear. More than a decade ago, we reported that replacement of a murine B7-DC mutant lysine with serine (K113S) at positive 113 resulted in a loss of binding capacity to PD-1. Nevertheless, K113S remained costimulatory for T cells in vitro, implicating a dual functionality for B7-DC in T-cell responses. Here we show that recombinant K113S protein interacts with RGMb with a similar affinity to wild-type B7-DC. More importantly, K113S costimulates CD4+ T-cell responses via RGMb and promotes Th1 polarization. RGMb is expressed on the surface of naive mouse T cells, macrophages, neutrophils and dendritic cells. Finally, K113S/RGMb costimulation suppresses Th2-mediated asthma and ameliorates small airway inflammation and lung pathology in an experimental mouse model. Our findings indicate that RGMb is a costimulatory receptor for B7-DC. These findings from the K113S variant provide not only a possible explanation for the B7-DC-triggered contradictory effects on T-cell responses, but also a novel approach to investigate the B7-DC/PD-1/RGMb axis. Recombinant K113S or its derivatives could potentially be developed as an agonist for RGMb to costimulate the Th1 response without triggering PD-1-mediated T-cell inhibition.

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Acknowledgements

We thank Jingjing Song for support of the lung function assays and Beth Cadugan for editing the manuscript. This study is partially supported by grants from Guangdong Province Innovative Research Program Project (No. 2011Y035), 863 Project grants to Sun Yat-sen University and the United Technologies Corporation endowed chair from Yale University.

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Authors and Affiliations

  1. Laboratory of Immunotherapy, Sun Yat-sen University, Guangzhou, Guangdong, China

    Xinxin Nie, Wenni Chen, Ying Zhu, Baozhu Huang, Weiwei Yu, Zhanshuai Wu, Sizheng Guo, Yiping Zhu, Liqun Luo & Lieping Chen

  2. Institute of Biophysics, Chinese Academy of Sciences, Beijing, China

    Shengdian Wang

  3. >Department of Immunobiology, Yale University, New Haven, CT, USA

    Lieping Chen

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Contributions

LC and XN developed the concept and designed the experiments. WC, YZ, BH, WY, ZW, SG, YZ, LL and SW performed and/or advised the experiments.

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Correspondence to Lieping Chen.

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Conflict of interest

LC is an advisor/board member for Pfizer, AstraZeneca, NextCure, GenomiCare and Vcanbio and received research support from Boehringer Ingelheim, Pfizer and NextCure. LC is also an uncompensated adjunct faculty member of Sun Yat-sen University. The other authors declare no competing financial interests.

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Nie, X., Chen, W., Zhu, Y. et al. B7-DC (PD-L2) costimulation of CD4+ T-helper 1 response via RGMb. Cell Mol Immunol 15, 888–897 (2018). https://doi.org/10.1038/cmi.2017.17

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