HVEM structures and mutants reveal distinct functions of binding to LIGHT and BTLA/CD160

HVEM is a TNF (tumor necrosis factor) receptor contributing to a broad range of immune functions involving diverse celltypes. It interacts with a TNF ligand, LIGHT, and immunoglobulin (Ig) superfamily members BTLA and CD160. Assessing thefunctional impact of HVEM binding to specific ligands in different settings has been complicated by the multiple interactionsof HVEM and HVEM binding partners. To dissect the molecular basis for multiple functions, we determined crystal structuresthat reveal the distinct HVEM surfaces that engage LIGHT or BTLA/CD160, including the human HVEM-LIGHT-CD160 ternarycomplex, with HVEM interacting simultaneously with both binding partners. Based on these structures, we generated mouseHVEM mutants that selectively recognized either the TNF or Ig ligands in vitro. Knockin mice expressing these muteinsmaintain expression of all the proteins in the HVEM network, yet they demonstrate selective functions for LIGHT in theclearance of bacteria in the intestine and for the Ig ligands in the amelioration of liver inflammation