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

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.Cellular & Molecular Immunology advance online publication, 8 May 2017; doi:10.1038/cmi.2017.17.

PD-L2 expression is correlated with the molecular and clinical features of glioma, and acts as an unfavorable prognostic factor

“…8,13,32 Nevertheless, PD-L2 would be significantly upregulated by a series of cytokines which were stimulated by tumor microenvironment, such as IL-15 and IL-7. 9,13,33,34 In recent years, emerging data has shown that PD-L2 mainly focused on inducing the phase of T cell immunity and response in esophageal squamous cell carcinoma, 35 colorectal cancer, 36 and hepatocellular carcinoma. 37 However, the potential roles of PD-L2 in glioma were relatively less studied than PD-L1.…”

PD-L2 Regulates B-1 Cell Antibody Production against Phosphorylcholine through an IL-5–Dependent Mechanism

“…Further work by Shin and colleagues demonstrated that PD-L2 inhibits Th2 responses induced by the nematode Nippostrongylus brasiliensis in a PD-1–independent manner (110). Thus, there is strong evidence for PD-L2 suppression of Th2 responses through PD-1–independent mechanisms (111). Indeed, the distinct phenotypes of PD-1 −/− mice (moderate increases in PC-specific IgM and total IgM levels) and PD-L2 −/− mice (significant increases in PC-specific IgM, significant decreases in total IgM levels) raise the question of whether PD-L2 regulation of PC-specific Ab secretion is also PD-1–independent.…”

Blockade of RGMb inhibits allergen-induced airways disease

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