LILRB4

Summary

LILRB4 (leukocyte immunoglobulin like receptor B4, HGNC:6608) is a protein-coding gene on chromosome 19q13.42, encoding Leukocyte immunoglobulin-like receptor subfamily B member 4 (Q8NHJ6). Inhibitory receptor involved in the down-regulation of the immune response and the development of immune tolerance.

This gene is a member of the leukocyte immunoglobulin-like receptor (LIR) family, which is found in a gene cluster at chromosomal region 19q13.4. The encoded protein belongs to the subfamily B class of LIR receptors which contain two or four extracellular immunoglobulin domains, a transmembrane domain, and two to four cytoplasmic immunoreceptor tyrosine-based inhibitory motifs (ITIMs). The receptor is expressed on immune cells where it binds to MHC class I molecules on antigen-presenting cells and transduces a negative signal that inhibits stimulation of an immune response. The receptor can also function in antigen capture and presentation. It is thought to control inflammatory responses and cytotoxicity to help focus the immune response and limit autoreactivity. Multiple transcript variants encoding different isoforms have been found for this gene.

Source: NCBI Gene 11006 — RefSeq curated summary.

At a glance

• GWAS associations: 3
• Clinical variants (ClinVar): 38 total
• MANE Select transcript: NM_001278426

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:6608
Approved symbol	LILRB4
Name	leukocyte immunoglobulin like receptor B4
Location	19q13.42
Locus type	gene with protein product
Status	Approved
Aliases	LIR-5, ILT3, HM18, LIR5, CD85k
Ensembl gene	ENSG00000186818
Ensembl biotype	protein_coding
OMIM	604821
Entrez	11006

Gene structure

Transcript identifiers

Ensembl transcripts: 21 — 17 protein_coding, 2 protein_coding_CDS_not_defined, 1 retained_intron, 1 nonsense_mediated_decay

ENST00000270452, ENST00000391733, ENST00000391734, ENST00000391736, ENST00000430952, ENST00000434286, ENST00000461262, ENST00000461839, ENST00000470943, ENST00000494796, ENST00000695418, ENST00000857356, ENST00000857357, ENST00000857358, ENST00000969963, ENST00000969964, ENST00000969965, ENST00000969966, ENST00000969967, ENST00000969968, ENST00000969969

RefSeq mRNA: 11 — MANE Select: NM_001278426 NM_001278426, NM_001278427, NM_001278428, NM_001278429, NM_001394933, NM_001394934, NM_001394935, NM_001394936, NM_001394937, NM_001394938, NM_001394939

CCDS: CCDS12902, CCDS42618, CCDS92687, CCDS92688

Canonical transcript exons

ENST00000612454 — 0 exons

Expression profiles

Bgee: expression breadth ubiquitous, 132 present calls, max score 94.54.

FANTOM5 (CAGE): breadth broad, TPM avg 39.4697 / max 1241.5538, expressed in 446 samples.

FANTOM5 promoters (4 alternative TSS)

Promoter ID	TPM avg	Samples expressed
177541	39.0059	445
177543	0.2337	108
177540	0.1154	56
177539	0.1147	47

Top tissues by expression

132 total, by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
vermiform appendix	UBERON:0001154	94.54	gold quality
monocyte	CL:0000576	93.82	gold quality
leukocyte	CL:0000738	93.63	gold quality
granulocyte	CL:0000094	92.68	gold quality
lymph node	UBERON:0000029	92.42	gold quality
blood	UBERON:0000178	91.89	gold quality
spleen	UBERON:0002106	87.52	gold quality
C1 segment of cervical spinal cord	UBERON:0006469	85.79	gold quality
gall bladder	UBERON:0002110	85.70	gold quality
placenta	UBERON:0001987	82.99	gold quality
bone marrow	UBERON:0002371	82.48	gold quality
substantia nigra	UBERON:0002038	81.72	gold quality
upper lobe of left lung	UBERON:0008952	81.66	gold quality
bone marrow cell	CL:0002092	80.55	gold quality
right coronary artery	UBERON:0001625	80.53	gold quality
smooth muscle tissue	UBERON:0001135	79.35	gold quality
omental fat pad	UBERON:0010414	78.95	gold quality
right lung	UBERON:0002167	77.67	gold quality
duodenum	UBERON:0002114	77.58	gold quality
lung	UBERON:0002048	77.39	gold quality
rectum	UBERON:0001052	77.07	gold quality
tonsil	UBERON:0002372	76.64	gold quality
adipose tissue	UBERON:0001013	76.63	gold quality
descending thoracic aorta	UBERON:0002345	76.43	gold quality
thoracic aorta	UBERON:0001515	76.41	gold quality
right adrenal gland cortex	UBERON:0035827	76.39	gold quality
left adrenal gland	UBERON:0001234	76.30	gold quality
left adrenal gland cortex	UBERON:0035825	76.25	gold quality
left coronary artery	UBERON:0001626	76.24	gold quality
ascending aorta	UBERON:0001496	76.19	gold quality

Single-cell (SCXA)

Detected in 4 experiment(s), a significant marker in 4.

Experiment	Marker?	Max mean expression
E-MTAB-10287	yes	23.55
E-MTAB-9467	yes	12.13
E-ANND-3	yes	9.53
E-MTAB-9801	yes	6.71

Regulation

Is transcription factor: yes

Downstream targets (CollecTRI)

1 targets.

Target	Regulation
VMP1	Repression

Upstream regulators (CollecTRI, top): TRERF1

miRNA regulators (miRDB)

97 targeting LILRB4, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-6867-5P	100.00	82.21	3464
HSA-LET-7A-3P	100.00	74.03	3932
HSA-LET-7B-3P	100.00	74.08	3913
HSA-LET-7F-1-3P	100.00	74.02	3928
HSA-MIR-98-3P	100.00	74.08	3907
HSA-MIR-4747-5P	100.00	67.90	2681
HSA-MIR-5196-5P	100.00	67.98	2761
HSA-MIR-8485	100.00	77.57	4731
HSA-MIR-3924	100.00	72.09	2394
HSA-MIR-548AW	99.99	72.57	3559
HSA-MIR-3185	99.99	68.12	1959
HSA-MIR-511-3P	99.99	68.85	1467
HSA-MIR-3692-3P	99.98	70.27	2139
HSA-MIR-548P	99.98	72.25	3784
HSA-MIR-3065-5P	99.97	71.56	3281
HSA-MIR-5688	99.96	73.23	4504
HSA-MIR-9718	99.94	68.91	918
HSA-MIR-335-3P	99.93	73.36	4958
HSA-MIR-6753-3P	99.93	66.57	637
HSA-MIR-7107-3P	99.93	66.73	627
HSA-MIR-3143	99.93	71.96	3104
HSA-MIR-7-2-3P	99.91	71.40	4394
HSA-MIR-153-5P	99.89	73.86	6317
HSA-MIR-6783-3P	99.89	67.92	2059
HSA-MIR-1343-3P	99.89	66.78	1815
HSA-MIR-4496	99.88	68.89	2236
HSA-MIR-4492	99.87	68.25	3611
HSA-MIR-4728-5P	99.85	69.39	4718
HSA-MIR-5010-3P	99.83	70.60	2357
HSA-MIR-6785-5P	99.82	68.68	4428

Literature-anchored findings (GeneRIF, showing 40)

• report that ILT2 receptor, ILT3 receptor, ILT4 receptor, and KIR2DL4 receptor expression is up-regulated by HLA-G histocompatibility antigen in antigen-presenting cells, natural killer cells, and T cells (PMID:15670976)
• ILT3 precursor RNA is expressed and retained in nuclei of resting endothelial cells. (PMID:16433759)
• Our findings indicate that expression of ILT3 and ILT4 on CLL B cells represents a phenotypic abnormality that may play a role in tolerization of tumor-specific T cells. (PMID:17266150)
• The inhibitory effect of serum and membrane ILT3 in a humanized SCID mouse model describes an immune-escape mechanism that could contribute to impaired T cell responses in patients with cancer. (PMID:17513794)
• Both membrane and soluble ILT3 are proteins with potent immunosuppressive activity which are of importance for treatment of rejection, autoimmunity and cancer. (PMID:17923119)
• describe an immune-escape mechanism mediated by the inhibitory receptor immunoglobulin-like transcript 3 (ILT3) which may be responsible for failure of pancreatic cancer therapy (PMID:17993722)
• Progenitor mast cells expressed cell surface inhibitory LILRB4. Mature cord-blood-derived mast cells had detectable mRNA encoding multiple LILRs, none were expressed on the cell surface. (PMID:17998301)
• ILT3-Fc is a potent immunoregulatory agent that suppresses islet allograft rejection in humanized NOD/SCID mice. (PMID:18420485)
• 15 single nucleotide polymorphisms are identified in the extracellular domain of immunoglobulin-like transcript 3 gene from healthy individuals. (PMID:18486764)
• Expressed on cultured osteoclast precursor cells derived from peripheral blood monocytes; could be inhibitory for osteoclast development in presence of receptor activator of NF-kappaB ligand (RANKL) and macrophage colony stimulating factor (M-CSF). (PMID:18802077)
• A significant association is observed between ILT3 dendritic cells in kidney transplants and donor age. (PMID:19010139)
• ILT3 may play a critical role in the control of inflammation. (PMID:19380766)
• A tryptophan-deprived environment generates monocyte-derived dendritic cells with a marked up-regulation of inhibitory receptors ILT3 and ILT4 and enhanced capacity to induce CD4+CD25+Foxp3+ regulatory T cells in an ILT3-dependent manner. (PMID:19535644)
• Data show that LILRB4 is a potent inhibitor of monocyte activation via FcgammaRI. (PMID:19833736)
• upregulated on antigen-presenting cells in response to Salmonella infection (PMID:19860908)
• Crystal structure of leukocyte Ig-like receptor LILRB4 (ILT3/LIR-5/CD85k): a myeloid inhibitory receptor involved in immune tolerance. (PMID:21454581)
• ILT3Fc inhibits T cell activation and induces the generation of suppressor T cells targeting multiple inflammatory miRNA pathways. (PMID:22387553)
• Cyclosporine up-regulated the expression of ILT3 and ILT4 on natural killer cells, which influenced their cytotoxicity against tumor cells. (PMID:22664025)
• involvement of ILT3 and ILT4 in the modulation of immune responsiveness in multiple sclerosis by both interferon and vitamin D (PMID:25551576)
• Identification of ILT4 as a cellular receptor for CSP C4d (PMID:26678451)
• These results suggest that tyrosine phosphorylation may be critical in FcgammaRI-dependent endocytosis/phagocytosis that may be regulated by LILRB4 by triggering dephosphorylation of key signalling proteins. (PMID:27725776)
• The ILT3 PBs/PCs were suggested to be developmentally equivalent based on the simultaneous generation of these populations upon activation of memory B cells in vitro ILT3 expression was found to be induced efficiently by IL-2, while IFN-alpha effectively induced ILT3 PBs/PCs in vitro Utilizing the elevated ILT3 will support opening a new avenue for molecular markers for, pathogenic cells. (PMID:27742834)
• LILRB4 expression is significantly upregulated in human masticatory mucosa during wound healing (PMID:28005267)
• this study shows that LILRB4 might have dual inhibitory and activating functions, depending on the position of the functional tyrosine residues in its immunoreceptor tyrosine-based inhibitory motifs and/or the nature of the stimuli (PMID:28409541)
• ILT3 may functionally contribute to a regulatory network controlling tumor progression by suppressing the Akt pathway. (PMID:28931525)
• Results suggest that ILT3 played an important role in tumor progression in colorectal cancer by possible influence on CD45RO+ T cells in the tumor microenvironment. (PMID:30126665)
• Our data demonstrate that anti-LILRB4 CAR-T cells specifically target monocytic acute myeloid leukemia cells with no toxicity to normal hematopoietic progenitors. (PMID:30131301)
• LILRB4 orchestrates tumour invasion pathways in monocytic leukaemia cells by creating an immunosuppressive microenvironment; LILRB4 represents a compelling target for the treatment of monocytic AML (PMID:30333625)
• LILRB4 expression is decreased in hypertrophic hearts. (PMID:30581005)
• The observed inflammation was mainly due to BMDM-induced NF-kappaB signaling. In conclusion, our study demonstrates that LILRB4 deficiency plays a detrimental role in ALI-associated BMDM activation by prompting the NF-kappaB signal pathway. (PMID:31138763)
• LILRB4 ITIMs mediate the T cell suppression and infiltration of acute myeloid leukemia cells. (PMID:31700117)
• LILRB4 expression in chronic myelomonocytic leukemia and myelodysplastic syndrome based on response to hypomethylating agents. (PMID:32036728)
• Leukocyte immunoglobulin-like receptor B1 and B4 (LILRB1 and LILRB4): Highly sensitive and specific markers of acute myeloid leukemia with monocytic differentiation. (PMID:32918786)
• ILT3 promotes tumor cell motility and angiogenesis in non-small cell lung cancer. (PMID:33152402)
• ILT3 (LILRB4) Promotes the Immunosuppressive Function of Tumor-Educated Human Monocytic Myeloid-Derived Suppressor Cells. (PMID:33372059)
• LILRB4 suppresses immunity in solid tumors and is a potential target for immunotherapy. (PMID:33974041)
• Blockade of checkpoint ILT3/LILRB4/gp49B binding to fibronectin ameliorates autoimmune disease in BXSB/Yaa mice. (PMID:34089617)
• Upregulation of leukocyte immunoglobulin-like receptor B4 on interstitial macrophages in COPD; their possible protective role against emphysema formation. (PMID:34425800)
• LILRB4 regulates the function of decidual MDSCs via the SHP-2/STAT6 pathway during Toxoplasma gondii infection. (PMID:37461040)
• Downregulation of LILRB4 Promotes Human Aortic Smooth Muscle Cell Contractile Phenotypic Switch and Apoptosis in Aortic Dissection. (PMID:38324114)

Cross-species orthologs

15 orthologs

Organism	Symbol	Gene ID
mus_musculus	Lilra6	ENSMUSG00000030427
mus_musculus	Pirb	ENSMUSG00000058818
mus_musculus	Lilra5	ENSMUSG00000070873
mus_musculus	Pira12	ENSMUSG00000074417
mus_musculus	Pira13	ENSMUSG00000074419
mus_musculus	Pira1	ENSMUSG00000081665
mus_musculus	Pira2	ENSMUSG00000089942
rattus_norvegicus	Lilra5	ENSRNOG00000027808
rattus_norvegicus	Lilrb3	ENSRNOG00000046683
rattus_norvegicus	Lilrb2	ENSRNOG00000054954
rattus_norvegicus	Lilrc2	ENSRNOG00000058087
rattus_norvegicus	Pirb	ENSRNOG00000058422
rattus_norvegicus	LOC134485274	ENSRNOG00000062907
rattus_norvegicus		ENSRNOG00000067708
rattus_norvegicus		ENSRNOG00000069029

Paralogs (25): GP6 (ENSG00000088053), LILRB1 (ENSG00000104972), LILRA1 (ENSG00000104974), LILRB5 (ENSG00000105609), A1BG (ENSG00000121410), KIR2DL1 (ENSG00000125498), LILRB2 (ENSG00000131042), IGSF1 (ENSG00000147255), LAIR2 (ENSG00000167618), KIR3DL1 (ENSG00000167633), OSCAR (ENSG00000170909), FCAR (ENSG00000186431), LILRA5 (ENSG00000187116), KIR2DL4 (ENSG00000189013), VSTM1 (ENSG00000189068), NCR1 (ENSG00000189430), LILRB3 (ENSG00000204577), KIR2DS4 (ENSG00000221957), LILRA4 (ENSG00000239961), LILRA2 (ENSG00000239998), KIR3DL2 (ENSG00000240403), KIR3DL3 (ENSG00000242019), KIR2DL3 (ENSG00000243772), LILRA6 (ENSG00000244482), TARM1 (ENSG00000248385)

Protein

Protein identifiers

Leukocyte immunoglobulin-like receptor subfamily B member 4 — Q8NHJ6 (reviewed: Q8NHJ6)

Alternative names: CD85 antigen-like family member K, Immunoglobulin-like transcript 3, Leukocyte immunoglobulin-like receptor 5, Monocyte inhibitory receptor HM18

All UniProt accessions (8): A0A087X0F8, A0A0A0MQW7, A0A0A0MS20, A0A0A0MSZ8, A0A8Q3SHR1, A8MUE1, C9JST2, Q8NHJ6

UniProt curated annotations — full annotation on UniProt →

Function. Inhibitory receptor involved in the down-regulation of the immune response and the development of immune tolerance. Receptor for FN1. Receptor for apolipoprotein APOE. Receptor for ALCAM/CD166. Inhibits receptor-mediated phosphorylation of cellular proteins and mobilization of intracellular calcium ions. Inhibits FCGR1A/CD64-mediated monocyte activation by inducing phosphatase-mediated down-regulation of the phosphorylation of multiple proteins including LCK, SYK, LAT and ERK, leading to a reduction in TNF production. This inhibition of monocyte activation occurs at least in part via binding to FN1. Inhibits T cell proliferation, inducing anergy, suppressing the differentiation of IFNG-producing CD8+ cytotoxic T cells and enhancing the generation of CD8+ T suppressor cells. Induces up-regulation of CD86 on dendritic cells. Interferes with TNFRSF5-signaling and NF-kappa-B up-regulation.

Subunit / interactions. Interacts with PTPN6.

Subcellular location. Cell membrane.

Tissue specificity. Detected on monocytes, macrophages, dendritic cells, natural killer cells and B-cells (at protein level). Expressed in the lung.

Domain organisation. Contains 3 copies of a cytoplasmic motif that is referred to as the immunoreceptor tyrosine-based inhibitor motif (ITIM). This motif is involved in modulation of cellular responses. The phosphorylated ITIM motif can bind the SH2 domain of several SH2-containing phosphatases.

Induction. Induced on monocyte-derived macrophages by S.typhimurium infection. Induced on monocytes and dendritic cells upon contact with CD8(+)CD28(-) alloantigen-specific T suppressor (Ts) cells.

Miscellaneous. Activated by APOE on acute myeloid leukemia (AML) cells which leads to suppression of T cell proliferation and promotion of AML cell migration and infiltration. LILRB4 signaling on AML cells is mediated by PTPN11/SHP-2. Alternative use of an acceptor site.

Isoforms (3)

UniProt ID	Names	Canonical?
Q8NHJ6-1	1	yes
Q8NHJ6-2	2
Q8NHJ6-3	3

RefSeq proteins (11): NP_001265355, NP_001265356, NP_001265357, NP_001265358, NP_001381862, NP_001381863, NP_001381864, NP_001381865, NP_001381866, NP_001381867, NP_001381868 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR007110	Ig-like_dom	Domain
IPR013151	Immunoglobulin_dom	Domain
IPR013783	Ig-like_fold	Homologous_superfamily
IPR036179	Ig-like_dom_sf	Homologous_superfamily
IPR050412	Ig-like_Receptors_ImmuneReg	Family

Pfam: PF00047, PF13895

UniProt features (85 total): mutagenesis site 35, strand 15, sequence variant 9, helix 4, short sequence motif 3, site 3, compositionally biased region 2, disulfide bond 2, topological domain 2, splice variant 2, domain 2, region of interest 2, signal peptide 1, chain 1, modified residue 1, transmembrane region 1

Structure

Experimental structures (PDB)

2 structures.

PDB	Method	Resolution (Å)
3P2T	X-RAY DIFFRACTION	1.7
6K7O	X-RAY DIFFRACTION	3

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q8NHJ6-F1	66.41	0.34

Antibody-complex structures (SAbDab): 1 — 6K7O

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Catalytic / active sites (3): 35 (required for apoe-mediated activation of lilrb4); 106 (required for apoe-mediated activation of lilrb4); 121 (required for apoe-mediated activation of lilrb4)

Post-translational modifications (1): 319

Disulfide bonds (2): 49–98, 144–195

Mutagenesis-validated functional residues (35):

Position	Phenotype
30	no significant change in apoe-mediated activation of lilrb4.
35	significant reduction in apoe-mediated activation of lilrb4.
41	no significant change in apoe-mediated activation of lilrb4.
59	no significant change in apoe-mediated activation of lilrb4.
63	no significant change in apoe-mediated activation of lilrb4.
64	no significant change in apoe-mediated activation of lilrb4.
65	no significant change in apoe-mediated activation of lilrb4.
66	no significant change in apoe-mediated activation of lilrb4.
68	no significant change in apoe-mediated activation of lilrb4.
91	no significant change in apoe-mediated activation of lilrb4.
95	no significant change in apoe-mediated activation of lilrb4.
97	no significant change in apoe-mediated activation of lilrb4.
103	no significant change in apoe-mediated activation of lilrb4.
106	significant reduction in apoe-mediated activation of lilrb4.
109	no significant change in apoe-mediated activation of lilrb4.
111	no significant change in apoe-mediated activation of lilrb4.
112	no significant change in apoe-mediated activation of lilrb4.
113	no significant change in apoe-mediated activation of lilrb4.
114	no significant change in apoe-mediated activation of lilrb4.
121	significant reduction in apoe-mediated activation of lilrb4.
122	no significant change in apoe-mediated activation of lilrb4.
147	no significant change in apoe-mediated activation of lilrb4.
149	no significant change in apoe-mediated activation of lilrb4.
162	no significant change in apoe-mediated activation of lilrb4.
164	no significant change in apoe-mediated activation of lilrb4.

Function

Pathways and Gene Ontology

Reactome pathways

3 pathways

ID	Pathway
R-HSA-198933	Immunoregulatory interactions between a Lymphoid and a non-Lymphoid cell
R-HSA-1280218	Adaptive Immune System
R-HSA-168256	Immune System

MSigDB gene sets: 348 (showing top): GOBP_MYELOID_CELL_DIFFERENTIATION, GOBP_REGULATION_OF_T_CELL_RECEPTOR_SIGNALING_PATHWAY, GOBP_REGULATION_OF_CELL_ACTIVATION, GOBP_REGULATION_OF_ANTIGEN_RECEPTOR_MEDIATED_SIGNALING_PATHWAY, GOBP_REGULATION_OF_LEUKOCYTE_PROLIFERATION, GOBP_NEGATIVE_REGULATION_OF_CELL_DEVELOPMENT, GOBP_REGULATION_OF_OSTEOCLAST_DIFFERENTIATION, GOBP_NEGATIVE_REGULATION_OF_ADAPTIVE_IMMUNE_RESPONSE, GOBP_REGULATION_OF_ALPHA_BETA_T_CELL_ACTIVATION, GOBP_POSITIVE_REGULATION_OF_HEMOPOIESIS, GOBP_TOLERANCE_INDUCTION, GOBP_NEGATIVE_REGULATION_OF_INTERLEUKIN_1_PRODUCTION, REACTOME_ADAPTIVE_IMMUNE_SYSTEM, GOBP_INFLAMMATORY_RESPONSE, GOBP_RESPONSE_TO_PEPTIDE

GO Biological Process (35): adaptive immune response (GO:0002250), tolerance induction (GO:0002507), positive regulation of T cell anergy (GO:0002669), negative regulation of T cell cytokine production (GO:0002725), immune response-regulating signaling pathway (GO:0002764), Fc receptor mediated inhibitory signaling pathway (GO:0002774), cytokine-mediated signaling pathway (GO:0019221), receptor internalization (GO:0031623), negative regulation of chemokine production (GO:0032682), negative regulation of type II interferon production (GO:0032689), negative regulation of interleukin-1 beta production (GO:0032691), negative regulation of interleukin-10 production (GO:0032693), negative regulation of interleukin-2 production (GO:0032703), negative regulation of interleukin-5 production (GO:0032714), negative regulation of interleukin-6 production (GO:0032715), negative regulation of tumor necrosis factor production (GO:0032720), negative regulation of T cell proliferation (GO:0042130), negative regulation of canonical NF-kappaB signal transduction (GO:0043124), positive regulation of CD8-positive, alpha-beta T cell differentiation (GO:0043378), negative regulation of MAPK cascade (GO:0043409), negative regulation of cytotoxic T cell differentiation (GO:0045584), positive regulation of regulatory T cell differentiation (GO:0045591), negative regulation of osteoclast differentiation (GO:0045671), negative regulation of activated T cell proliferation (GO:0046007), negative regulation of T cell receptor signaling pathway (GO:0050860), negative regulation of IP-10 production (GO:0071659), interleukin-10-mediated signaling pathway (GO:0140105), negative regulation of monocyte activation (GO:0150102), negative regulation of cytokine production involved in inflammatory response (GO:1900016), negative regulation of protein localization to nucleus (GO:1900181), negative regulation of intracellular signal transduction (GO:1902532), negative regulation of miRNA transcription (GO:1902894), negative regulation of T cell costimulation (GO:2000524), immune system process (GO:0002376), cell surface receptor signaling pathway (GO:0007166)

GO Molecular Function (8): fibronectin binding (GO:0001968), protein phosphatase binding (GO:0019903), protein tyrosine kinase inhibitor activity (GO:0030292), transmembrane receptor protein tyrosine kinase inhibitor activity (GO:0030293), signaling receptor inhibitor activity (GO:0030547), inhibitory MHC class I receptor activity (GO:0032396), apolipoprotein binding (GO:0034185), protein binding (GO:0005515)

GO Cellular Component (5): plasma membrane (GO:0005886), cytoplasmic side of plasma membrane (GO:0009898), cell surface (GO:0009986), extracellular exosome (GO:0070062), membrane (GO:0016020)

Reactome top-level categories

Rollup of top-2 pathways:

Category	Pathways
Adaptive Immune System	1
Immune System	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
negative regulation of cytokine production	6
negative regulation of intracellular signal transduction	2
protein binding	2
cellular anatomical structure	2
immune response	1
immune system process	1
immune system development	1
positive regulation of T cell tolerance induction	1
regulation of T cell anergy	1
T cell anergy	1
positive regulation of lymphocyte anergy	1
T cell cytokine production	1
negative regulation of T cell mediated immunity	1
negative regulation of cytokine production involved in immune response	1
regulation of T cell cytokine production	1
signal transduction	1
regulation of immune response	1
immune response-inhibiting cell surface receptor signaling pathway	1
cell surface receptor signaling pathway	1
cellular response to cytokine stimulus	1
receptor-mediated endocytosis	1
chemokine production	1
regulation of chemokine production	1
type II interferon production	1
regulation of type II interferon production	1
interleukin-1 beta production	1
regulation of interleukin-1 beta production	1
negative regulation of interleukin-1 production	1
interleukin-10 production	1
regulation of interleukin-10 production	1
interleukin-2 production	1
regulation of interleukin-2 production	1
interleukin-5 production	1
regulation of interleukin-5 production	1
interleukin-6 production	1
regulation of interleukin-6 production	1
tumor necrosis factor production	1
regulation of tumor necrosis factor production	1
negative regulation of tumor necrosis factor superfamily cytokine production	1
T cell proliferation	1

Protein interactions and networks

STRING

1464 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
LILRB4	HLA-G	P17693	859
LILRB4	APOE	P02649	856
LILRB4	ALCAM	Q13740	812
LILRB4	CD86	P42081	753
LILRB4	CD300C	Q08708	743
LILRB4	CD80	P33681	726
LILRB4	CD28	P10747	655
LILRB4	IL10	P22301	645
LILRB4	PTPN6	P29350	638
LILRB4	CD8A	P01732	622
LILRB4	CD40LG	P29965	580
LILRB4	TREM2	Q9NZC2	556
LILRB4	HLA-F	P30511	547
LILRB4	HLA-E	P13747	539
LILRB4	IL2	P01585	534

IntAct

13 interactions, top by confidence:

A	B	Type	Score
PLTP	SEL1L3	psi-mi:“MI:0914”(association)	0.530
LILRB4	LAIR1	psi-mi:“MI:0407”(direct interaction)	0.440
LILRB4	PTPN6	psi-mi:“MI:0915”(physical association)	0.400
PTPN6	LILRB4	psi-mi:“MI:0915”(physical association)	0.400
ECE1	LILRB4	psi-mi:“MI:0915”(physical association)	0.370
LILRB4	CLU	psi-mi:“MI:0914”(association)	0.350
LILRB4	ATP2B1	psi-mi:“MI:0914”(association)	0.350
LILRB4	HIP1R	psi-mi:“MI:0914”(association)	0.350
LILRB4	uup	psi-mi:“MI:0915”(physical association)	0.000

BioGRID (35): ATP2B3 (Affinity Capture-MS), ATP2B4 (Affinity Capture-MS), CD47 (Affinity Capture-MS), ATP2B2 (Affinity Capture-MS), C10orf88 (Affinity Capture-MS), ARMC8 (Affinity Capture-MS), PTPRD (Affinity Capture-MS), MKLN1 (Affinity Capture-MS), GID4 (Affinity Capture-MS), GID8 (Affinity Capture-MS), LILRB2 (Affinity Capture-MS), CD276 (Affinity Capture-MS), PAM (Affinity Capture-MS), MKLN1 (Affinity Capture-MS), PTPRD (Affinity Capture-MS)

ESM2 similar proteins: A0A0K2S4Q6, A2A7V7, A6NI73, A8K4G0, O43699, O75019, O75022, O75023, O75871, O76036, P0C191, P20138, P24071, P40198, P59901, P80943, Q08708, Q13410, Q28110, Q3U497, Q496F6, Q64JA4, Q6GTX8, Q6ISS4, Q6PI73, Q6UXZ3, Q7TSN2, Q863H2, Q8C567, Q8K249, Q8MJZ2, Q8MJZ7, Q8N149, Q8N423, Q8N6C8, Q8NHJ6, Q8NHL6, Q8VBT3, Q8VCH2, Q95JB9

Diamond homologs: A0A0G2KBC9, A6NI73, C0HJX2, C0HJX3, D3ZQX2, O75019, O75022, O75023, O76036, P0C191, P24071, P43626, P43629, P43630, P59901, P83556, P97484, Q14943, Q14954, Q61450, Q64281, Q6GTX8, Q6ISS4, Q6PI73, Q7TQA1, Q863H2, Q8C567, Q8IYS5, Q8MJZ2, Q8MJZ7, Q8N109, Q8N149, Q8N423, Q8N6C8, Q8N743, Q8NHJ6, Q8NHK3, Q8NHL6, Q95JB9, Q9HCN6

SIGNOR signaling

1 interactions.

A	Effect	B	Mechanism
sirolimus	“down-regulates quantity by repression”	LILRB4

Disease & clinical

Clinical variants and AI predictions

ClinVar

38 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	0
Likely benign	4
Benign	0

Top pathogenic / likely-pathogenic (0)

SpliceAI

1961 predictions. Top by Δscore:

Variant	Effect	Δscore
19:54662901:T:TA	acceptor_gain	1.0000
19:54664185:GGA:G	acceptor_gain	1.0000
19:54664918:GATC:G	donor_gain	1.0000
19:54666313:G:GT	donor_gain	1.0000
19:54666437:G:GG	donor_gain	1.0000
19:54666441:G:GG	donor_gain	1.0000
19:54667634:GCA:G	acceptor_gain	1.0000
19:54667634:GCAGA:G	acceptor_gain	1.0000
19:54662981:C:A	acceptor_gain	0.9900
19:54663749:TCCA:T	acceptor_loss	0.9900
19:54663750:CCA:C	acceptor_loss	0.9900
19:54663751:CAG:C	acceptor_loss	0.9900
19:54663752:A:AC	acceptor_loss	0.9900
19:54663752:A:AG	acceptor_gain	0.9900
19:54663752:AG:A	acceptor_gain	0.9900
19:54663753:G:GG	acceptor_gain	0.9900
19:54663753:GG:G	acceptor_gain	0.9900
19:54663964:G:GT	donor_gain	0.9900
19:54664035:ACAGG:A	donor_loss	0.9900
19:54664037:AG:A	donor_loss	0.9900
19:54664038:GGTGA:G	donor_loss	0.9900
19:54664039:GTGAG:G	donor_loss	0.9900
19:54664040:T:A	donor_loss	0.9900
19:54664183:TAG:T	acceptor_loss	0.9900
19:54664184:A:AG	acceptor_gain	0.9900
19:54664184:A:G	acceptor_loss	0.9900
19:54664184:AG:A	acceptor_gain	0.9900
19:54664185:G:A	acceptor_loss	0.9900
19:54664185:G:GG	acceptor_gain	0.9900
19:54664185:GG:G	acceptor_gain	0.9900

AlphaMissense

0 scored. Top likely-pathogenic:

dbSNP variants (sampled 300 via entrez): RS1000011440 (19:54666038 A>G), RS1000111734 (19:54661699 A>G), RS1000751915 (19:54668592 A>G), RS1001000908 (19:54667335 C>T), RS1001153181 (19:54662222 T>G), RS1001221072 (19:54662294 G>A), RS1001273250 (19:54662411 C>T), RS1003078720 (19:54664219 C>G,T), RS1003432514 (19:54668488 G>A), RS1003465381 (19:54663363 G>A,C), RS1003623243 (19:54664988 G>A), RS1003716886 (19:54667257 G>A), RS1003919644 (19:54668290 T>C), RS1005022404 (19:54668830 A>G), RS1005566866 (19:54667073 T>C)

Disease associations

OMIM: gene MIM:604821 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

0 total (0 of 0 shown, HPO-id order):

GWAS associations

3 associations (top):

Study	Trait	p-value
GCST001204_8	Response to platinum-based chemotherapy (carboplatin)	6.000000e-06
GCST001725_62	Inflammatory bowel disease	7.000000e-11
GCST002595_28	Clozapine-induced agranulocytosis	9.000000e-06

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

PharmGKB: 1 entry (VIP=true, CPIC=false)

CTD chemical–gene interactions

15 total (human), top 15 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Nickel	increases expression	2
sulforaphane	decreases expression	1
tebuconazole	decreases expression	1
Air Pollutants, Occupational	affects expression	1
Atrazine	increases expression	1
Benzo(a)pyrene	affects methylation	1
Cadmium	decreases expression, increases abundance	1
Calcitriol	increases expression	1
Doxorubicin	decreases expression	1
Lead	affects expression	1
Naled	affects expression	1
Phthalic Acids	increases methylation	1
Zidovudine	affects cotreatment, increases expression	1
Antirheumatic Agents	decreases expression	1
Cadmium Chloride	increases abundance, decreases expression	1

Cellosaurus cell lines

3 cell lines: 1 cancer cell line, 1 spontaneously immortalized cell line, 1 transformed cell line

First 10 cell lines (id-ordered, not curated):

Cellosaurus	Name	Category	Sex
CVCL_B2NT	Abcam A-549 LILRB4 KO	Cancer cell line	Male
CVCL_E6R2	Genomeditech CHO-K1 H_LILRB4(ILT3)	Spontaneously immortalized cell line	Female
CVCL_E6UG	Genomeditech HEK-293 H_LILRB4(ILT3)	Transformed cell line	Female

Clinical trials (associated diseases)

0 trials via MONDO — disease-level, not drug-specific.