The Function of Leukocyte Immunoglobulin-Like Receptors in Self-Tolerance, Viral Recognition, and Regulation of Adaptive Responses

Abstract

To achieve self-tolerance, many inhibitory receptors recognize major histocompatibility complex class I (MHC-I) molecules, which are normally expressed on healthy cells. In humans, inhibitory MHC-I receptors include the killer cell immunoglobulin (Ig)-like receptors (KIRs), the leukocyte Ig-like receptors (LILRs), and the CD94/NKG2A heterodimer. This chapter focuses on LILRs and, in particular, on their function during cytomegalovirus (CMV) infection and their ability to regulate adaptive responses during bacterial infection and following organ transplantation. The members of the LILR family--also known as immunoglobulin-like transcript (ILT), leukocyte Ig-like receptor (LIR), monocyte and macrophage Ig-like receptor (MIR), or CD85--include at least 11 distinct molecules, which have either two or four homologous extracellular Ig-like domains of the C2 type. Inhibitory LILRs (LILRB1, LILRB2, LILRB3, LILRB4, and LILRB5) contain long cytoplasmic domains with two to four immunoreceptor tyrosine-based inhibitory motifs (ITIMs). Another group of LILRs (LILRA1, LILRA2, ILT7, ILT8, and ILT11) have short cytoplasmic domains that lack ITIMs or recognizable docking motifs for signaling mediators. If LILRs have evolved under the selective pressure of UL18, one would also expect that UL18 mutates to neutralize this strategy of the host immune system. A recent study suggests that the ability of inhibitory LILRs to regulate the function of antigen-presenting cells (APCs) may be an important mechanism utilized by suppressor T (Ts) cells to induce immunological tolerance.