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B7-DC (PD-L2) costimulation of CD4+ T-helper 1 response via RGMb
Xinxin Nie1, Wenni Chen1, Ying Zhu1
1Laboratory of Immunotherapy, Sun Yat-sen University, Guangzhou, Guangdong, China.
Insights
The repulsive guidance molecule b (RGMb) acts as a costimulatory receptor for B7-DC, promoting T-cell responses and suppressing asthma. This discovery clarifies B7-DC
Area of Science:
- Immunology
- Molecular Biology
- Cell Biology
Background:
- The function of B7-DC in T-cell responses is debated, with evidence suggesting both coinhibitory and costimulatory roles.
- B7-DC interacts with both PD-1 and repulsive guidance molecule b (RGMb), but the consequences of the RGMb interaction are not well understood.
- A previously generated B7-DC mutant (K113S) lost PD-1 binding but retained costimulatory function, suggesting dual roles.
Purpose of the Study:
- To investigate the functional consequences of the B7-DC/RGMb interaction.
- To determine if RGMb serves as a costimulatory receptor for B7-DC.
- To explore the therapeutic potential of targeting the B7-DC/RGMb axis.
Main Methods:
- Utilized a recombinant B7-DC mutant (K113S) that does not bind PD-1.
- Assessed the interaction affinity between K113S and RGMb.
- Investigated the costimulatory effects of K113S/RGMb on CD4+ T-cell responses and Th1 polarization.
- Examined RGMb expression on various immune cells.
- Evaluated the impact of K113S/RGMb costimulation on a mouse model of asthma.
Main Results:
- Recombinant K113S protein binds RGMb with similar affinity to wild-type B7-DC.
- K113S costimulates CD4+ T-cell responses via RGMb and promotes Th1 polarization.
- RGMb is expressed on naive T cells, macrophages, neutrophils, and dendritic cells.
- K113S/RGMb costimulation suppressed Th2-mediated asthma, reducing airway inflammation and lung pathology.
Conclusions:
- RGMb functions as a costimulatory receptor for B7-DC.
- The K113S variant explains the dual functionality of B7-DC and offers a new avenue for studying the B7-DC/PD-1/RGMb axis.
- Recombinant K113S or its derivatives may serve as RGMb agonists to enhance Th1 responses without PD-1-mediated inhibition.
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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