The Inhibitory Receptor LIR-1 Uses a Common Binding Interaction to Recognize Class I MHC Molecules and the Viral Homolog UL18

LIR-1 is a class I MHC receptor related to natural killer inhibitory receptors (KIRs). Binding of LIR-1 or KIRs to class I molecules results in inhibitory signals. Unlike individual KIRs, LIR-1 recognizes many class I alleles and also binds UL18, a human cytomegalovirus class I MHC homolog. Here, we show that LIR-1 interacts with the relatively nonpolymorphic α3 domain of class I proteins and the analogous region of UL18 using its N-terminal immunoglobulin-like domain. The >1000-fold higher affinity of LIR-1 for UL18 than for class I illustrates how a viral protein competes with host proteins to subvert the host immune response. LIR-1 recognition of class I molecules resembles the CD4–class II MHC interaction more than the KIR–class I interaction, implying a functional distinction between LIR-1 and KIRs.