CDB15:0000749 HLA-A — LILRB2
Experimentally validated in Human; Orthology-inferred in Frog, Chicken, Macaque, Chimp, Horse
Title
Journal:; Year Published:
Abstract
Human inhibitory receptors Ig-like transcript 2 (ILT2) and ILT4 compete with CD8 for MHC class I binding and bind preferentially to HLA-G.
Proceedings of the National Academy of Sciences of the United States of America, 2003; PubMed, Homo sapiens HLA-A — Homo sapiens LILRB2
ABSTRACT: Ig-like transcript 4 (ILT4) (also known as leukocyte Ig-like receptor 2, CD85d, and LILRB2) is a cell surface receptor expressed mainly on myelomonocytic cells, whereas ILT2 (also known as leukocyte Ig-like receptor 1, CD85j, and LILRB1) is expressed on a wider range of immune cells including subsets of natural killer and T cells. Both ILTs contain immunoreceptor tyrosine-based inhibitory receptor motifs in their cytoplasmic tails that inhibit cellular responses by recruiting phosphatases such as SHP-1 (Src homology 2 domain containing tyrosine phosphatase 1). Although these ILTs have been shown to recognize a broad range of classical and nonclassical human MHC class I molecules (MHCIs), their precise binding properties remain controversial. We have used surface plasmon resonance to analyze the interaction of soluble forms of ILT4 and ILT2 with several MHCIs. Although the range of affinities measured was quite broad (Kd = 2-45 microM), some interesting differences were observed. ILT2 generally bound with a 2- to 3-fold higher affinity than ILT4 to the same MHCI. Furthermore, ILT2 and ILT4 bound to HLA-G with a 3- to 4-fold higher affinity than to classical MHCIs, suggesting that ILT/HLA-G recognition may play a dominant role in the regulation of natural killer, T, and myelomonocytic cell activation. Finally, we show that ILT2 and ILT4 effectively compete with CD8 for MHCI binding, raising the possibility that ILT2 modulates CD8+ T cell activation by blocking the CD8 binding as well as by recruiting inhibitory molecules through its immunoreceptor tyrosine-based inhibitory receptor motif.
HLA class I allelic sequence and conformation regulate leukocyte Ig-like receptor binding.
Journal of immunology, 2011; PubMed, Homo sapiens HLA-A — Homo sapiens LILRB2
ABSTRACT: Leukocyte Ig-like receptors (LILRs) are a family of innate immune receptors predominantly expressed by myeloid cells that can alter the Ag presentation properties of macrophages and dendritic cells. Several LILRs bind HLA class I. Altered LILR recognition due to HLA allelic variation could be a contributing factor in disease. We comprehensively assessed LILR binding to >90 HLA class I alleles. The inhibitory receptors LILRB1 and LILRB2 varied in their level of binding to different HLA alleles, correlating in some cases with specific amino acid motifs. LILRB2 displayed the weakest binding to HLA-B*2705, an allele genetically associated with several autoimmune conditions and delayed progression of HIV infection. We also assessed the effect of HLA class I conformation on LILR binding. LILRB1 exclusively bound folded β(2)-microglobulin-associated class I, whereas LILRB2 bound both folded and free H chain forms. In contrast, the activating receptor LILRA1 and the soluble LILRA3 protein displayed a preference for binding to HLA-C free H chain. To our knowledge, this is the first study to identify the ligand of LILRA3. These findings support the hypothesis that LILR-mediated detection of unfolded versus folded MHC modulates immune responses during infection or inflammation.
LILRA3 binds both classical and non-classical HLA class I molecules but with reduced affinities compared to LILRB1/LILRB2: structural evidence.
PloS one, 2011; PubMed, Homo sapiens HLA-A — Homo sapiens LILRB2
ABSTRACT: Structurally, Group 1 LILR (Leukocyte Immunoglobulin (Ig)-Like Receptor, also known as Ig-like transcripts, ILT; Leukocyte Ig-like receptor, LIR; and CD85) members are very similar in terms of the HLAIs (human leukocyte antigen class I molecules) binding region and were hypothesized that they all bind to HLAIs. As one of the Group 1 LILRs, LILRA3 is the only secretory LILR and may greatly control the inhibitory immune response induced by LILRB1, LILRB2, and other HLA-binding LILR molecules like LILRA1. Nevertheless, little was known about the binding of LILRA3 to HLAIs. In this report, we present the crystal structure of the LILRA3 domain 1 (D1) and evaluate the D1 and D1D2 (domain 1 and domain 2) binding to classical and non-classical HLAIs using BIAcore® surface plasmon resonance analysis (SPR). We found that LILRA3 binds both classical HLA-A*0201 and non-classical HLA-G1 but with reduced affinities compared to either LILRB1 or LILRB2. The polymorphic amino acids and the LILRA3 D1 structure support this notion.
Human myelomonocytic cells express an inhibitory receptor for classical and nonclassical MHC class I molecules.
Journal of immunology, 1998; PubMed, Homo sapiens HLA-A — Homo sapiens LILRB2
ABSTRACT: Leukocyte activation can be negatively regulated by inhibitory receptors specific for MHC class I molecules. While one inhibitory receptor, Ig-like transcript 2 (ILT2), is expressed by all lymphoid and myelomonocytic cell types, other receptors display a more selective tissue distribution. Here we characterize an inhibitory receptor, termed ILT4, which is selectively expressed in monocytes, macrophages, and dendritic cells (DCs), binds classical class I molecules and the nonclassical class I molecules HLA-G, and transduces negative signals that can inhibit early signaling events triggered by stimulatory receptors. ILT4 may control inflammatory responses and cytotoxicity mediated by myelomonocytic cells and may modulate their Ag-presenting functions, focusing immune responses to microbial challenges and avoiding autoreactivity.