CORRESPONDENCE

(B7-DC, CD273) are key inhibitory molecules in immune regulation (Keir et al., 2008; Pardoll, 2012). This pathway provides particularly prom-ising targets for cancer immunotherapy (Topalian et al., 2012). There is considerable evidence that PD-L2 inhibits immunity by binding to the PD-1 co-inhibitory receptor (Latchman et al., 2001; Zhang et al., 2006). However, several studies have shown that PD-L2 can function to stimulate T cell proliferation and cytokine production, even in PD-1–deficient T cells or with PD-L2 mutants that did not bind to PD-1 (Liu et al., 2003; Shin et al., 2003; Wang et al., 2003). These findings suggest that PD-L2 may function through a receptor other than PD-1. Most stud-ies using blocking mAbs show a dominant role for PD-L1 in inhibiting immune responses; however, PD-L2 plays a dominant role in responses such as airway hypersensitivity, experimental allergic con-junctivitis and nematode infection (Ritprajak et al., 2012). In some situations, PD-L2 domi-nance may be explained by preferential PD-L2 up-regulation by IL-4, but other instances may be explained by the binding of PD-L2 to a re-ceptor other than PD-1. Here, we demonstrate that PD-L2 binds to a second receptor, repulsive guidance molecule b (RGMb). RGMb, also known as DRAGON, is a member of the RGM family which consists of RGMa, RGMb, and RGMc/hemojuvelin (Severyn et al., 2009). RGMs are glycosylphos-phatidylinositol-anchored membrane proteins that bind bone morphogenetic proteins (BMPs) and neogenin (Conrad et al., 2010). RGMs d