@article {542066, title = {RGMb is a novel binding partner for PD-L2 and its engagement with PD-L2 promotes respiratory tolerance.}, journal = {J Exp Med}, volume = {211}, number = {5}, year = {2014}, month = {2014 May 5}, pages = {943-59}, abstract = {We report that programmed death ligand 2 (PD-L2), a known ligand of PD-1, also binds to repulsive guidance molecule b (RGMb), which was originally identified in the nervous system as a co-receptor for bone morphogenetic proteins (BMPs). PD-L2 and BMP-2/4 bind to distinct sites on RGMb. Normal resting lung interstitial macrophages and alveolar epithelial cells express high levels of RGMb mRNA, whereas lung dendritic cells express PD-L2. Blockade of the RGMb-PD-L2 interaction markedly impaired the development of respiratory tolerance by interfering with the initial T cell expansion required for respiratory tolerance. Experiments with PD-L2-deficient mice showed that PD-L2 expression on non-T cells was critical for respiratory tolerance, but expression on T cells was not required. Because PD-L2 binds to both PD-1, which inhibits antitumor immunity, and to RGMb, which regulates respiratory immunity, targeting the PD-L2 pathway has therapeutic potential for asthma, cancer, and other immune-mediated disorders. Understanding this pathway may provide insights into how to optimally modulate the PD-1 pathway in cancer immunotherapy while minimizing adverse events.}, keywords = {Animals, Bone Morphogenetic Protein 2, Cell Line, Tumor, Epithelial Cells, Humans, Immune Tolerance, Lung, Macrophages, Alveolar, Mice, Nerve Tissue Proteins, Programmed Cell Death 1 Ligand 2 Protein, Protein Binding}, issn = {1540-9538}, doi = {10.1084/jem.20130790}, author = {Xiao, Yanping and Yu, Sanhong and Zhu, Baogong and Bedoret, Denis and Bu, Xia and Francisco, Loise M and Hua, Ping and Duke-Cohan, Jonathan S and Umetsu, Dale T and Sharpe, Arlene H and DeKruyff, Rosemarie H and Freeman, Gordon J} }