title: RGMb is a novel binding partner for PD-L2 and its engagement with PD-L2 promotes respiratory tolerance.
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.
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute; 2 Division of Immunology and Department of Pediatrics, Boston Children's Hospital; 3 Department of Microbiology and Immunobiology and 4 Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115.
authors.forename: Yanping
authors.initials: Y
authors.lastname: Xiao
authors.forename: Sanhong
authors.initials: S
authors.lastname: Yu
authors.forename: Baogong
authors.initials: B
authors.lastname: Zhu
authors.forename: Denis
authors.initials: D
authors.lastname: Bedoret
authors.forename: Xia
authors.initials: X
authors.lastname: Bu
authors.forename: Loise M
authors.initials: LM
authors.lastname: Francisco
authors.forename: Ping
authors.initials: P
authors.lastname: Hua
authors.forename: Jonathan S
authors.initials: JS
authors.lastname: Duke-Cohan
authors.forename: Dale T
authors.initials: DT
authors.lastname: Umetsu
authors.forename: Arlene H
authors.initials: AH
authors.lastname: Sharpe
authors.forename: Rosemarie H
authors.initials: RH
authors.lastname: DeKruyff
authors.forename: Gordon J
authors.initials: GJ
authors.lastname: Freeman
mesh_terms: D000818:Animals; D055396:Bone Morphogenetic Protein 2 / Q000378:metabolism; D015816:Cell Adhesion Molecules, Neuronal; D045744:Cell Line, Tumor; D004847:Epithelial Cells / Q000378:metabolism; D058851:GPI-Linked Proteins; D006801:Humans; D007108:Immune Tolerance / Q000276:immunology*; D008168:Lung / Q000276:immunology* / Q000378:metabolism; D016676:Macrophages, Alveolar / Q000378:metabolism; D051379:Mice; D009419:Nerve Tissue Proteins / Q000276:immunology / Q000378:metabolism*; D061027:Programmed Cell Death 1 Ligand 2 Protein / Q000276:immunology / Q000378:metabolism*; D011485:Protein Binding
chemical_list: C525719:Bmp2 protein, mouse; D055396:Bone Morphogenetic Protein 2; D015816:Cell Adhesion Molecules, Neuronal; D058851:GPI-Linked Proteins; D009419:Nerve Tissue Proteins; C556978:Pdcd1lg2 protein, mouse; D061027:Programmed Cell Death 1 Ligand 2 Protein; C483497:Rgmb protein, mouse
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