Abstract
Abstract HVEM is a TNF (tumor necrosis factor) receptor contributing to a broad range of immune functions involving diverse cell types. It interacts with a TNF ligand, LIGHT, and immunoglobulin (Ig) superfamily members BTLA and CD160. Assessing the functional impact of HVEM binding to specific ligands in different settings has been complicated by the multiple interactions of HVEM and HVEM binding partners. To dissect the molecular basis for multiple functions, we determined crystal structures that reveal the distinct HVEM surfaces that engage LIGHT or BTLA/CD160, including the human HVEM–LIGHT–CD160 ternary complex, with HVEM interacting simultaneously with both binding partners. Based on these structures, we generated mouse HVEM mutants that selectively recognized either the TNF or Ig ligands in vitro. Knockin mice expressing these muteins maintain expression of all the proteins in the HVEM network, yet they demonstrate selective functions for LIGHT in the clearance of bacteria in the intestine and for the Ig ligands in the amelioration of liver inflammation. Supported grants from NIH (S10 OD020068, P30CA023100, P30 DK120515, S10RR027366, U01 AI125955, P01 DK46763), U.S. Department of Energy (DE-AC02-98CH10886, DE-AC02-06CH11357), National Center for Research Resources (P41RR012408), National Institute of General Medical Sciences (P41GM103473), Albert Einstein Cancer Center (P30CA013330), Eli Lilly Company, Albert Einstein Macromolecular Therapeutics Development Facility, Price Family Foundation, Albert Einstein Center for Experimental Therapeutics, Pamela and Edward S. Pantzer, and Academia Sinica, Taiwan.
Published Version
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
