Disease relevance of LILRB1

• Leukocyte immunoglobulin-like receptor subfamily B member 1 (LILRB1/LIR1/ILT2) is an inhibitory receptor broadly expressed on leukocytes and recognizes HLA-class I and human cytomegalovirus UL18 [1].
• Primary cutaneous CD8+ and CD56+ T-cell lymphomas express HLA-G and killer-cell inhibitory ligand, ILT2 [2].
• Engagement of ILT2/CD85j in Sézary syndrome cells inhibits their CD3/TCR signaling [3].
• The presence of ILT2 (Ig-like transcript 2) killing inhibitory receptors known to interact with HLA-G was also demonstrated in host immune cells that infiltrate breast cancer lesions [4].
• The MICs of cefotaxime were higher for E. coli ILT-1 and K. pneumoniae ILT-2 than for K. pneumoniae ILT-3, while the opposite was found for the MICs of ceftazidime [5].
• CD85j is expressed in PM and sporadic IBM at the sites of partial invasion and in DM in perivascular inflammation, paving the way for dissecting the role of CD85j in the pathogenesis of inflammatory myopathies [6].

High impact information on LILRB1

• Upon tyrosine phosphorylation, LIR-1 associates with the tyrosine phosphatase SHP-1 [7].
• The cytoplasmic domain of LIR-1 contains four putative immunoreceptor tyrosine-based inhibitory motifs [7].
• In contrast to KIRs, LIR-1 is expressed predominantly on monocytic and B lymphoid cell types, suggesting a distinct biological function [7].
• Crystal structure of HLA-A2 bound to LIR-1, a host and viral major histocompatibility complex receptor [8].
• The LIR-1 binding site comprises residues at the interdomain hinge, and a patch at the D1 tip [8].

Biological context of LILRB1

• In the 5' portion of LILRB1, three haplotypes containing four non-synonymous substitutions within the ligand-binding domains and two single nucleotide polymorphisms within the promoter region were identified and designated as PE01-03 [1].
• LILRB1 binds to a wide range of major histocompatibility complex class I molecules (MHCIs) and transduces negative signals that can, for example, prevent killing of MHCI-expressing cells [9].
• In monocytes, phosphorylation of LIR-1 and LIR-2 results in the binding of the tyrosine phosphatase SHP-1 [10].
• The leukocyte immunoglobulin-like receptors (LIRs, also known as ILTs, CD85, and LILRs) comprise a family of related immunoregulatory receptors encoded within the leukocyte receptor cluster (LRC) on human chromosome 19 [11].
• Analysis of mRNA from first trimester and term macrophages, as well as the monocyte cell line U937, resulted in amplicons of similar size to those expected for ILT2 and ILT4 [12].

Anatomical context of LILRB1

• LILRB1 is encoded within the leukocyte receptor complex on 19q13.4, previously implicated to be a susceptibility region to systemic lupus erythematosus (SLE) [1].
• Gross difference was not observed in the crystal structures, thermostabilities and binding affinities to HLA-class I ligands among LILRB1.PE01-03 haplotype products; however, surface expression of LILRB1 was significantly decreased in lymphocytes and monocytes from the carriers of PE01 haplotype [1].
• 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 [13].
• The MHC class I binding proteins LIR-1 and LIR-2 inhibit Fc receptor-mediated signaling in monocytes [10].
• The MHC class I binding proteins leukocyte immunoglobulin-like receptor (LIR)-1 and -2 recognize a similar broad spectrum of HLA-A, -B and -C alleles but are differentially expressed in lymphocytes, monocytes, and dendritic cells [10].

Associations of LILRB1 with chemical compounds

• In order to identify other molecules to which CD85j might interact with in a phosphotyrosine-dependent manner, a cDNA B-cell library was screened in a three-hybrid system in yeast using the CD85j cytoplasmic tail as bait in the presence of the Src-kinase c-fyn420, 531Y-F, 176R-Q mutant [14].
• Mutational analyses and phospho-peptide mapping suggested that the SH2 domain of Csk may preferentially bind to ITIM Y562 of CD85j; yet, mutation to phenylalanine of Y533, Y614, and Y644 also significantly reduced Csk recruitment by CD85j [14].
• Accordingly, the mutated HLA-G transfectants were less effective in the inhibition of NK killing and RBL/LIR-1 induced serotonin release [15].
• Mutating these cysteine residues resulted in a dramatic decrease in LIR-1 Ig binding [15].

Physical interactions of LILRB1

• ILT2 generally bound with a 2- to 3-fold higher affinity than ILT4 to the same MHCI [13].
• These results suggest that subtle structural differences between LILRB family members cause the distinct binding specificities to various forms of HLA-G and other MHCIs, which may in turn regulate immune suppression [16].
• HLA-F tetramer binding could be conferred on non-binding cells by transfection with the inhibitory receptors ILT2 and ILT4 [17].
• Both biochemical and functional analyses revealed tyrosines 644 (SIYATL) and 614 (VTYAQL) as the SHP-1 docking sites required for ILT2 inhibitory function [18].

Regulatory relationships of LILRB1

• CD85j (leukocyte Ig-like receptor-1/Ig-like transcript 2) inhibits human osteoclast-associated receptor-mediated activation of human dendritic cells [19].
• The formation of these complexes on the cell surface might represent a novel mechanism developed specifically by the HLA-G protein aimed to control the efficiency of the CD85J/LIR-1-mediated inhibition [20].
• A significantly increased proportion of CD8 CTL still expressed LIR1/ILT2, a receptor with broad HLA-class I specificity [21].

Other interactions of LILRB1

• We have used surface plasmon resonance to analyze the interaction of soluble forms of ILT4 and ILT2 with several MHCIs [13].
• LILRB2 exhibits an overlapping but distinct MHCI recognition mode compared with LILRB1 and dominantly recognizes the hydrophobic site of the HLA-G alpha3 domain [16].
• Several members of the immunoglobulin-like transcript (ILT), also called leukocyte immunoglobulin-like receptor (LIR), family of transmembrane proteins have been identified as receptors for class I HLA molecules and transduce inhibitory signals to leukocytes upon binding of these ligands [12].
• The 3' untranslated region of the gene for LIR-6 contains a 37-base pair repeat not present in the LIR-1 or LIR-5 genes [22].
• These findings demonstrated that LILRB1 is highly polymorphic and is associated with susceptibility to RA in HLA-DRB1 SE negative subjects, possibly by insufficient inhibitory signaling in leukocytes [1].

Analytical, diagnostic and therapeutic context of LILRB1

• Sequence analysis of the amplicons revealed that the messages from decidual macrophages corresponded to ILT2 and ILT4 messages [12].
• Phosphorylation-dependent recruitment of Csk to the CD85j cytoplasmic tail was confirmed in CD85j-transfected mammalian cells by immunoprecipitation and Western blot analysis [14].
• In some patients functional impairment due to LIR1/ILT2 expression may persist even after 24 months of successful HAART [21].
• The percentage of cells expressing LIR-1 increased in the patients who developed cytomegalovirus disease several weeks before viral DNA was detectable by PCR [23].
• Expression of mRNA coding for CD85/LIR-1/ILT2 has been assessed by RT-PCR [24].

References