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 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.展开更多
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.
文摘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.
