Leukocyte Ig-Like Receptors - A Model for MHC Class I Disease Associations

Abstract

MHC class I (MHC-I) polymorphisms are associated with the outcome of some viral infections and autoimmune diseases. MHC-I proteins present antigenic peptides and are recognized by receptors on natural killer cells and cytotoxic T lymphocytes, thus enabling the immune system to detect self-antigens and eliminate targets lacking self or expressing foreign antigens. Recognition of MHC-I, however, extends beyond receptors on cytotoxic leukocytes. Members of the leukocyte Ig-like receptor (LILR) family are expressed on monocytic cells and can recognize both classical and non-classical MHC-I alleles. Despite their relatively broad specificity when compared to the T cell receptor or killer Ig-like receptors, variations in the strength of LILR binding between different MHC-I alleles have recently been shown to correlate with control of HIV infection. We suggest that LILR recognition may mediate MHC-I disease association in a manner that does not depend on a binary discrimination of self/non-self by cytotoxic cells. Instead, the effects of LILR activity following engagement by MHC-I may represent a "degrees of self" model, whereby strength of binding to different alleles determines the degree of influence exerted by these receptors on immune cell functions. LILRs are expressed by myelomonocytic cells and lymphocytes, extending their influence across antigen-presenting cell subsets including dendritic cells, macrophages, and B cells. They have been identified as important players in the response to infection, inflammatory diseases, and cancer, with recent literature to indicate that MHC-I recognition by these receptors and consequent allelic effects could extend an influence beyond the immune system.

Keywords: HIV; HLA; KIR; LILR; MHC.

Figure 1

LILR expression profile, according to literature. Blue shaded squares indicate expression according to the literature (–40); annotation within boxes indicates expression specifics (for example, observed during HIV infection or for a particular cell phenotype). Green denotes Group 1 LILR and red, Group 2 LILR.

Figure 2

Immunoregulatory receptor mechanisms and functions. (A) T-cell-mediated non-self killing through non-self MHC-I peptide presentation. (B) NK-mediated non-self killing through missing-self, non-self, and stress/damage-induced lysis. (C) LILR-mediated regulation of immune cells. LILR may regulate cell phenotype and functions in a variety of ways, which have yet to be determined in full.