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

查看全文 作　　者：Xinxin [1]Nie;Wenni [1]Chen;Ying [1]Zhu;Baozhu [1]Huang;Weiwei [1]Yu;Zhanshuai [1]Wu;Sizheng [1]Guo;Yiping [1]Zhu;Liqun [1]Luo;Shengdian [2]Wang;Lieping [1,3]Chen

机构地区：[1]Laboratory of Immunotherapy,Sun Yat-sen University,Guangzhou,Guangdong,China;[2]Institute of Biophysics,Chinese Academy of Sciences,Beijing,China;[3]Department of Immunobiology,Yale University,New Haven,CT,USA

出　　处：《Cellular & Molecular Immunology》索引2018年第15卷第10期,共10页

基　　金：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. 摘　　要：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. 关键词：ASTHMA B7-DC K113S RGMb TH1/TH2

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

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