Mechanistic dissection of the PD-L1:B7-1 co-inhibitory immune complex
Open Access
- 4 June 2020
- journal article
- research article
- Published by Public Library of Science (PLoS) in PLOS ONE
- Vol. 15 (6), e0233578
- https://doi.org/10.1371/journal.pone.0233578
Abstract
The B7 family represents one of the best-studied subgroups within the Ig superfamily, yet new interactions continue to be discovered. However, this binding promiscuity represents a major challenge for defining the biological contribution of each specific interaction. We developed a strategy for addressing these challenges by combining cell microarray and high-throughput FACS methods to screen for promiscuous binding events, map binding interfaces, and generate functionally selective reagents. Applying this approach to the interactions of mPD-L1 with its receptor mPD-1 and its ligand mB7-1, we identified the binding interface of mB7-1 on mPD-L1 and as a result generated mPD-L1 mutants with binding selectivity for mB7-1 or mPD-1. Next, using a panel of mB7-1 mutants, we mapped the binding sites of mCTLA-4, mCD28 and mPD-L1. Surprisingly, the mPD-L1 binding site mapped to the dimer interface surface of mB7-1, placing it distal from the CTLA-4/CD28 recognition surface. Using two independent approaches, we demonstrated that mPD-L1 and mB7-1 bind in cis, consistent with recent reports from Chaudhri A et al. and Sugiura D et al. We further provide evidence that while CTLA-4 and CD28 do not directly compete with PD-L1 for binding to B7-1, they can disrupt the cis PD-L1:B7-1 complex by reorganizing B7-1 on the cell surface. These observations offer new functional insights into the regulatory mechanisms associated with this group of B7 family proteins and provide new tools to elucidate their function in vitro and in vivo.Funding Information
- National Human Genome Research Institute (HG008325)
This publication has 46 references indexed in Scilit:
- PD-L1 Binds to B7-1 Only In Cis on the Same Cell SurfaceCancer Immunology Research, 2018
- PD-L1 interacts with CD80 to regulate graft-versus-leukemia activity of donor CD8+ T cellsJCI Insight, 2017
- A Soluble Form of CD80 Enhances Antitumor Immunity by Neutralizing Programmed Death Ligand-1 and Simultaneously Providing CostimulationCancer Immunology Research, 2014
- Sequence, structure, function, immunity: structural genomics of costimulationImmunological Reviews, 2009
- Therapeutic efficacy of ipilimumab, an anti-CTLA-4 monoclonal antibody, in patients with metastatic melanoma unresponsive to prior systemic treatments: clinical and immunological evidence from three patient casesCancer Immunology, Immunotherapy, 2009
- Programmed Death-1 Ligand 1 Interacts Specifically with the B7-1 Costimulatory Molecule to Inhibit T Cell ResponsesImmunity, 2007
- Review: Anti–CTLA-4 Antibody Ipilimumab: Case Studies of Clinical Response and Immune-Related Adverse EventsThe Oncologist, 2007
- Crystal structure of a soluble CD28-Fab complexNature Immunology, 2005
- T lymphocyte co-signaling pathways of the B7-CD28 family.2004
- Crystal structure of the B7-1/CTLA-4 complex that inhibits human immune responsesNature, 2001