ICOSLG

Summary

ICOSLG (inducible T cell costimulator ligand, HGNC:17087) is a protein-coding gene on chromosome 21q22.3, encoding ICOS ligand (O75144). Ligand for the T-cell-specific cell surface receptor ICOS.

Enables identical protein binding activity and receptor ligand activity. Involved in T follicular helper cell differentiation. Located in intracellular membrane-bounded organelle. Is active in plasma membrane.

Source: NCBI Gene 23308 — RefSeq curated summary.

At a glance

• Gene–disease (curated): combined immunodeficiency (Moderate, ClinGen) — +1 more curated relationship
• GWAS associations: 21
• Clinical variants (ClinVar): 322 total — 3 likely-pathogenic
• Phenotypes (HPO): 17
• Druggable target: yes
• MANE Select transcript: NM_015259

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:17087
Approved symbol	ICOSLG
Name	inducible T cell costimulator ligand
Location	21q22.3
Locus type	gene with protein product
Status	Approved
Aliases	KIAA0653, GL50, B7-H2, B7RP-1, B7H2, B7RP1, ICOS-L, CD275, B7h
Ensembl gene	ENSG00000160223
Ensembl biotype	protein_coding
OMIM	605717
Entrez	23308

Gene structure

Transcript identifiers

Ensembl transcripts: 19 — 12 protein_coding, 4 nonsense_mediated_decay, 3 retained_intron

ENST00000344330, ENST00000400377, ENST00000400379, ENST00000407780, ENST00000643466, ENST00000700350, ENST00000700351, ENST00000700352, ENST00000700353, ENST00000700354, ENST00000700355, ENST00000700356, ENST00000700357, ENST00000700358, ENST00000700359, ENST00000700360, ENST00000700361, ENST00000867614, ENST00000867615

RefSeq mRNA: 6 — MANE Select: NM_015259 NM_001283050, NM_001283051, NM_001283052, NM_001365759, NM_001395918, NM_015259

CCDS: CCDS42952, CCDS63377, CCDS63379, CCDS93102, CCDS93104

Canonical transcript exons

ENST00000407780 — 7 exons

Exon	Start	End
ENSE00001110032	44230054	44230089
ENSE00001881360	44222991	44229044
ENSE00003979594	44231280	44231444
ENSE00003979602	44240804	44240943
ENSE00003979611	44238448	44238488
ENSE00003979622	44236867	44237217
ENSE00003979624	44235272	44235562

Expression profiles

Bgee: expression breadth ubiquitous, 166 present calls, max score 81.51.

FANTOM5 (CAGE): breadth tissue_specific, TPM avg 0.0028 / max 2.2146, expressed in 2 samples.

FANTOM5 promoters (1 alternative TSS)

Promoter ID	TPM avg	Samples expressed
190735	0.0028	2

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
cartilage tissue	UBERON:0002418	81.51	gold quality
upper arm skin	UBERON:0004263	81.09	gold quality
apex of heart	UBERON:0002098	80.97	gold quality
C1 segment of cervical spinal cord	UBERON:0006469	80.47	gold quality
spinal cord	UBERON:0002240	78.62	gold quality
lower esophagus mucosa	UBERON:0035834	78.45	gold quality
corpus callosum	UBERON:0002336	75.81	gold quality
putamen	UBERON:0001874	75.64	gold quality
cardiac muscle of right atrium	UBERON:0003379	75.38	gold quality
left ventricle myocardium	UBERON:0006566	75.02	gold quality
bone marrow cell	CL:0002092	74.98	gold quality
substantia nigra	UBERON:0002038	74.88	gold quality
skin of leg	UBERON:0001511	74.54	gold quality
skin of abdomen	UBERON:0001416	74.51	gold quality
prefrontal cortex	UBERON:0000451	73.83	gold quality
amygdala	UBERON:0001876	73.77	gold quality
lymph node	UBERON:0000029	73.58	gold quality
Ammon’s horn	UBERON:0001954	73.50	gold quality
zone of skin	UBERON:0000014	73.44	gold quality
midbrain	UBERON:0001891	73.40	gold quality
granulocyte	CL:0000094	73.13	gold quality
vermiform appendix	UBERON:0001154	72.95	gold quality
adult mammalian kidney	UBERON:0000082	72.91	gold quality
esophagus mucosa	UBERON:0002469	72.75	gold quality
metanephros cortex	UBERON:0010533	72.39	gold quality
Brodmann (1909) area 9	UBERON:0013540	71.79	gold quality
gall bladder	UBERON:0002110	71.71	gold quality
caudate nucleus	UBERON:0001873	71.32	gold quality
hypothalamus	UBERON:0001898	71.22	gold quality
endocervix	UBERON:0000458	70.86	gold quality

Single-cell (SCXA)

Detected in 1 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-ANND-3	yes	3.16

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): NFKB

miRNA regulators (miRDB)

62 targeting ICOSLG, 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-4283	100.00	66.42	2097
HSA-MIR-4713-3P	100.00	65.92	505
HSA-MIR-34A-5P	99.99	71.21	1784
HSA-MIR-449A	99.99	71.05	1776
HSA-MIR-9983-3P	99.94	71.48	3631
HSA-MIR-129-5P	99.88	70.26	3273
HSA-MIR-4492	99.87	68.25	3611
HSA-MIR-6764-5P	99.75	67.89	2304
HSA-MIR-6752-3P	99.72	66.71	1587
HSA-MIR-4530	99.69	66.47	1509
HSA-MIR-1915-3P	99.58	66.79	1988
HSA-MIR-762	99.58	66.61	1994
HSA-MIR-516B-5P	99.56	66.33	1495
HSA-MIR-3147	99.52	66.34	388
HSA-MIR-4498	99.47	67.42	2360
HSA-MIR-578	99.46	68.36	1787
HSA-MIR-584-3P	99.35	67.69	1082
HSA-MIR-6852-5P	99.17	66.69	2073
HSA-MIR-4292	99.16	65.57	1767
HSA-MIR-6791-5P	99.16	65.92	1844
HSA-MIR-7160-5P	99.11	67.17	2207
HSA-MIR-6749-3P	99.00	65.73	1443
HSA-MIR-3619-5P	99.00	68.87	2308
HSA-MIR-6760-5P	98.87	66.73	1515
HSA-MIR-6829-5P	98.86	65.12	1480
HSA-MIR-6846-5P	98.81	65.86	1121
HSA-MIR-6848-5P	98.81	65.49	1126
HSA-MIR-4656	98.79	66.22	1306
HSA-MIR-331-3P	98.76	64.91	793
HSA-MIR-7113-3P	98.75	65.71	1120

Literature-anchored findings (GeneRIF, showing 40)

• ICOS-L is a ligand for ICOS and plays an important functional role in the activation of memory T cells by endothelial cells [review] (PMID:12456022)
• These results demonstrate that airway epithelial cells express the costimulatory molecule B7-H2, and suggest the possibility that B7-H2 may participate in antigen presentation by epithelial cells. (PMID:12707012)
• ICOS-B7H costimulatory pathway may be involved in the negative regulation of cell-mediated immune responses. (PMID:12800259)
• A critical role of the B7-like protein-ICOS costimulatory pathway is demonstrated in the pathogenesis of lupus nephritis. (PMID:12960306)
• ICOSL protein and mRNA was expressed in 7 of 12 glioma cell lines and expression is upregulated by the inflammatory cytokine, tumor necrosis factor-alpha (TNF-alpha), whereas interferon-gamma (IFN-gamma) has no such effect (PMID:14603470)
• Expression of B7-H3 by nasal epithelial. Expands range of potential costimulatory signals through which these cells may interact with activated mucosal T lymphocytes. Extent of mucociliary differentiation of cultured cells may influence this capability. (PMID:15047568)
• B7h-ICOS protein costimulatory pathway may be important in intestinal epithelial cell(iec):T-cell interactions. IEC expressed B7h and B7-H1. (PMID:15131796)
• Results indicate the expression of functional B7-H2 molecule may facilitate progression of acute myeloid leukemia. (PMID:16115907)
• Interaction of tubular epithelial cells and kidney infiltrating T cells via ICOS-L and B7-H1 may change the balance of positive and negative signals to the T cells (PMID:16221208)
• ICOSL receptor binding site is mediated solely by the immunoglobulin (Ig) variable domain but requires the Ig constant domain for maintaining structural integrity of the protein. (PMID:16951355)
• ICOS-L may be relevant in inducing an acute immune response and may be critically involved in perpetuating inflammation in chronically immune-mediated disorders of the peripheral nervous system. (PMID:17242332)
• The generated a 3T3 cellular library retrovirally expressing mutants of the murine B7h gene. Screening of this unbiased cellular library identified residues of murine B7h. These residues are located on the same of human B7h by mutagenesis. (PMID:18294651)
• Genetic variation in this protein affects the outcome and failure of kidney tranplantation. (PMID:19202444)
• role of stimulus by B7 in myeloblastic leukemic (PMID:19347721)
• ICOSL:ICOS+ pathway costimulates effector T cells, shaping the Th2 response and regulating humoral immunity. (PMID:19395451)
• B7RP-1 is expressed on the membrane of HCAECs. (PMID:19726311)
• Oxidized low density lipoprotein up-regulates the expression of ICOSL in coronary artery endothelial cells. (PMID:19737469)
• Suppressed ICOSLG gene expression is associated with cigarette smoking. (PMID:20217071)
• Data show that ICOS-L expression by melanoma tumor cells may directly drive Treg activation and expansion in the tumor microenvironment as another mechanism of immune evasion. (PMID:21098714)
• Similar to B7-1 and B7-2, B7-H2 costimulation via CD28 induced survival factor Bcl-xL, downregulated cell cycle inhibitor p27(kip1), and triggered signaling cascade of ERK and AKT kinase-dependent pathways (PMID:21530327)
• A model of positive feedback conferred by ICOS-LICOS interaction between TGN1412-treated T cells and endothelial cells. (PMID:22577174)
• ICOS-ICOSL signaling plays a direct role in proliferation and differentiation of thyroid gland cells and may have important effects on the initiation, maintenance and exaggeration of autoimmune responses in local tissue. (PMID:22706735)
• ICOSL-expressing macrophages and mRNA levels of ICOSL were increased in the lesional skin of patients with early diffuse cutaneous systemic sclerosis. (PMID:23024058)
• Results highlight an important relationship between Treg and pDC in breast tumors, and show that ICOS/ICOS-L interaction is a central event in immunosuppression of tumor-associated memory CD4(+) T cells. (PMID:23026134)
• These data suggest that rs2294020 SNP of FOXP3 gene and rs378299 SNP of ICOSLG gene are associated with alopecia areata and with a reduced expression of the FOXP3 and ICOSLG genes in alopecia patients. (PMID:23196741)
• Findings suggest that the single nucleotide polymorphism (snp) rs4819388 in B7-H2 3’-UTR, through disrupting the regulatory role of miR-24 on B7-H2 expression, contributes to the occurrence of gastric cancer. (PMID:23688438)
• Our data show that mDCs from patients with AR display impaired expression of ICOSL, and this defect licenses mDCs to promote aberrant IL-13- and IL-5-producing Th2 cell responses. (PMID:24661627)
• the B7h-ICOS interaction may modulate the spread of cancer metastases (PMID:24729612)
• a critical role is described for the rs7282490 ICOSLG region polymorphism associated with immune-mediated diseases in amplifying pattern-recognition receptor initiated inflammatory signaling and cytokine secretion (PMID:24837102)
• Loss-of-function mutations in NIK cause impaired ICOSL expression. (PMID:25406581)
• ICOS-ICOS-L interaction promoted cytokine production and survival in type 2 innate lymphoid cells through STAT5 signaling in asthma. (PMID:25769613)
• The ICOS and ICOSL SNPs examined do not have an apparent effect on the disease susceptibility and prognosis of autoimmune thyroid diseases. (PMID:26560438)
• results showed that monocyte-derived osteoclast (OC)-like cells (MDOCs) express B7h during their differentiation, and that B7h triggering reversibly inhibits OC differentiation and function both in vitro and in vivo (PMID:27798154)
• ICOSL-ICOS signaling promoted Treg differentiation from CD4(+) T cells through activation of the phosphoinositide 3-kinase-Akt pathway. MSCs primed with Interleukin-1beta significantly induced Tregs through ICOSL upregulation. We demonstrated that the Treg-inducing activity of MSCs is proportionate to their basal ICOSL expression. (PMID:28290526)
• study confirms the importance of ICOSL shedding in ICOS/ICOSL function and expression and it identifies ADAM10 as the most important sheddase for controlling ICOSL levels (PMID:28814605)
• this study found that B7-H2 expression on CD8(+) T cells in colorectal cancer patients’ tumor tissues was significantly higher than in non-tumor tissues (PMID:29414642)
• The expression of ICOSL of patient acute myeloid leukemia (AML) cells and ICOS+ Tregs were found to be predictors for survival in patients with AML, with ICOS+ Treg cell subset being a stronger predictor than total Tregs. Results suggested that AML cells expressed ICOSL promote the expansion of ICOS+ Tregs in tumor environment, and ICOS+ Tregs further promote the proliferation of AML cells through secreting IL-10. (PMID:30319662)
• study identifies human ICOSLG deficiency as a novel cause of a combined immunodeficiency. (PMID:30498080)
• High glucose and advanced glycation end products cause T cell inflammatory response and vascular endothelial dysfunction by upregulating ICOS/ICOSL activity. (PMID:30575933)
• The ICOSL Expression Predicts Better Prognosis for Nasopharyngeal Carcinoma via Enhancing Oncoimmunity. (PMID:31998801)

Cross-species orthologs

2 orthologs

Organism	Symbol	Gene ID
mus_musculus	Icosl	ENSMUSG00000000732
rattus_norvegicus	Icoslg	ENSRNOG00000023109

Paralogs (15): BTN3A1 (ENSG00000026950), CD276 (ENSG00000103855), BTN3A3 (ENSG00000111801), BTN2A1 (ENSG00000112763), BTNL8 (ENSG00000113303), HHLA2 (ENSG00000114455), BTN2A2 (ENSG00000124508), BTN1A1 (ENSG00000124557), VTCN1 (ENSG00000134258), ERMAP (ENSG00000164010), BTNL9 (ENSG00000165810), BTNL3 (ENSG00000168903), BTN3A2 (ENSG00000186470), BTNL2 (ENSG00000204290), MOG (ENSG00000204655)

Protein

Protein identifiers

ICOS ligand — O75144 (reviewed: O75144)

Alternative names: B7 homolog 2, B7-like protein Gl50, B7-related protein 1

All UniProt accessions (11): O75144, A0A096LPE5, A0A2R8Y5W7, A0A8V8TQ42, A0A8V8TQ73, A0A8V8TQV9, A0A8V8TQW2, A0A8V8TR62, A0N0L8, B7Z1W8, K4DIA0

UniProt curated annotations — full annotation on UniProt →

Function. Ligand for the T-cell-specific cell surface receptor ICOS. Acts as a costimulatory signal for T-cell proliferation and cytokine secretion. Also induces B-cell proliferation and differentiation into plasma cells. Could play an important role in mediating local tissue responses to inflammatory conditions, as well as in modulating the secondary immune response by co-stimulating memory T-cell function. In endothelial cells, required for proper neutrophil transmigration in response to chemoattractants, such as CXCL8/IL8 or N-formyl-methionyl peptides (fMLP).

Subunit / interactions. Interacts with CTLA4 (in vitro).

Subcellular location. Cell membrane Cell membrane.

Tissue specificity. Expressed on peripheral blood B-cells and monocytes, as well as on monocyte-derived dendritic cells (at protein level). Widely expressed (brain, heart, kidney, liver, lung, pancreas, placenta, skeletal muscle, bone marrow, colon, ovary, prostate, testis, lymph nodes, leukocytes, spleen, thymus and tonsil). Detected only in lymph nodes, leukocytes and spleen. Expressed on activated monocytes and dendritic cells.

Disease relevance. Immunodeficiency 119 (IMD119) [MIM:620825] An autosomal recessive immunologic disorder characterized by childhood-onset of recurrent respiratory tract infections, susceptibility to chronic DNA-based viral infections, hypogammaglobulinemia, and panlymphopenia. The disease may be caused by variants affecting the gene represented in this entry.

Induction. Constitutive expression is up-regulated by treatment with TNF in peripheral blood B-cells and monocytes, while it is decreased in dendritic cells. In monocytes, up-regulated by CCL3/macrophage inflammatory protein 1-alpha and IFNG.

Similarity. Belongs to the immunoglobulin superfamily. BTN/MOG family.

Isoforms (3)

UniProt ID	Names	Canonical?
O75144-1	1	yes
O75144-2	2
O75144-3	3

RefSeq proteins (7): NP_001269979, NP_001269980, NP_001269981, NP_001350699, NP_001352688, NP_001382847, NP_056074* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR003599	Ig_sub	Domain
IPR007110	Ig-like_dom	Domain
IPR013106	Ig_V-set	Domain
IPR013783	Ig-like_fold	Homologous_superfamily
IPR036179	Ig-like_dom_sf	Homologous_superfamily
IPR050504	IgSF_BTN/MOG-like	Family
IPR053896	BTN3A2-like_Ig-C	Domain

Pfam: PF07686, PF22705

UniProt features (42 total): strand 15, glycosylation site 5, turn 5, helix 4, disulfide bond 2, splice variant 2, sequence variant 2, topological domain 2, domain 2, signal peptide 1, chain 1, transmembrane region 1

Structure

Experimental structures (PDB)

2 structures.

PDB	Method	Resolution (Å)
6X4T	X-RAY DIFFRACTION	3.15
6X4G	X-RAY DIFFRACTION	3.5

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-O75144-F1	82.99	0.63

Antibody-complex structures (SAbDab): 2 — 6X4G, 6X4T

Functional residue map

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

Disulfide bonds (2): 37–113, 158–216

Glycosylation sites (5): 186, 225, 70, 137, 173

Function

Pathways and Gene Ontology

Reactome pathways

1 pathways

ID	Pathway
R-HSA-9927354	Co-stimulation by ICOS

MSigDB gene sets: 260 (showing top): GOBP_REGULATION_OF_CELL_ACTIVATION, GOBP_REGULATION_OF_LEUKOCYTE_PROLIFERATION, REACTOME_ADAPTIVE_IMMUNE_SYSTEM, GOBP_B_CELL_ACTIVATION, GOBP_T_CELL_ACTIVATION_INVOLVED_IN_IMMUNE_RESPONSE, GOBP_ALPHA_BETA_T_CELL_DIFFERENTIATION, GOBP_ANTIGEN_RECEPTOR_MEDIATED_SIGNALING_PATHWAY, GOCC_CELL_SURFACE, GOBP_HYPEROSMOTIC_RESPONSE, GOBP_POSITIVE_REGULATION_OF_CELL_ADHESION, GOBP_POSITIVE_REGULATION_OF_LEUKOCYTE_PROLIFERATION, GOBP_CELL_ACTIVATION_INVOLVED_IN_IMMUNE_RESPONSE, GOBP_CELL_CELL_ADHESION, GOBP_REGULATION_OF_IMMUNE_RESPONSE, GOBP_CD4_POSITIVE_ALPHA_BETA_T_CELL_ACTIVATION

GO Biological Process (11): regulation of cytokine production (GO:0001817), adaptive immune response (GO:0002250), defense response (GO:0006952), hyperosmotic response (GO:0006972), signal transduction (GO:0007165), positive regulation of activated T cell proliferation (GO:0042104), T cell activation (GO:0042110), B cell activation (GO:0042113), T cell receptor signaling pathway (GO:0050852), T follicular helper cell differentiation (GO:0061470), immune system process (GO:0002376)

GO Molecular Function (4): signaling receptor binding (GO:0005102), identical protein binding (GO:0042802), receptor ligand activity (GO:0048018), protein binding (GO:0005515)

GO Cellular Component (4): plasma membrane (GO:0005886), external side of plasma membrane (GO:0009897), membrane (GO:0016020), extracellular exosome (GO:0070062)

Reactome top-level categories

Rollup of top-1 pathways:

Category	Pathways
Regulation of T cell activation by CD28 family	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
lymphocyte activation	2
protein binding	2
cytokine production	1
regulation of gene expression	1
regulation of multicellular organismal process	1
immune response	1
response to stress	1
response to osmotic stress	1
cell communication	1
cellular process	1
signaling	1
regulation of cellular process	1
cellular response to stimulus	1
positive regulation of T cell proliferation	1
regulation of activated T cell proliferation	1
activated T cell proliferation	1
antigen receptor-mediated signaling pathway	1
T-helper cell differentiation	1
biological_process	1
signaling receptor binding	1
signal transduction	1
signaling receptor activator activity	1
binding	1
membrane	1
cell periphery	1
plasma membrane	1
cell surface	1
side of membrane	1
cellular anatomical structure	1
extracellular vesicle	1

Protein interactions and networks

STRING

1364 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
ICOSLG	ICOS	Q9Y6W8	999
ICOSLG	CD28	P10747	997
ICOSLG	TNFRSF4	P43489	993
ICOSLG	CTLA4	P16410	993
ICOSLG	CD40LG	P29965	989
ICOSLG	CD40	P25942	977
ICOSLG	CD27	P26842	964
ICOSLG	TNFRSF9	Q07011	926
ICOSLG	TNFSF4	P23510	904
ICOSLG	PDCD1	Q15116	883
ICOSLG	TNFSF13B	Q9Y275	874
ICOSLG	TNFSF9	P41273	873
ICOSLG	CD276	Q5ZPR3	871
ICOSLG	IL10	P22301	843
ICOSLG	VTCN1	Q7Z7D3	825

IntAct

23 interactions, top by confidence:

A	B	Type	Score
ICOS	ICOSLG	psi-mi:“MI:0915”(physical association)	0.850
ICOS	ICOSLG	psi-mi:“MI:0407”(direct interaction)	0.850
ICOSLG	ICOS	psi-mi:“MI:0915”(physical association)	0.850
ICOSLG	ICOS	psi-mi:“MI:0407”(direct interaction)	0.850
ICOSLG	ICOSLG	psi-mi:“MI:0407”(direct interaction)	0.670
ICOSLG	ICOSLG	psi-mi:“MI:0915”(physical association)	0.670
ICOSLG	CD28	psi-mi:“MI:0915”(physical association)	0.400
ICOSLG	CTLA4	psi-mi:“MI:0915”(physical association)	0.400
ICOSLG	UPK3BL1	psi-mi:“MI:0914”(association)	0.350
GTF2H3	ICOSLG	psi-mi:“MI:0914”(association)	0.350
ICOSLG	TMEM131L	psi-mi:“MI:0914”(association)	0.350

BioGRID (25): ICOSLG (Affinity Capture-MS), ZDHHC6 (Affinity Capture-MS), PTPRD (Affinity Capture-MS), LGALS1 (Affinity Capture-MS), C2CD2L (Affinity Capture-MS), PREB (Affinity Capture-MS), UPK3BL (Affinity Capture-MS), ICOSLG (Affinity Capture-RNA), ICOS (Reconstituted Complex), C2CD2L (Affinity Capture-MS), LGALS1 (Affinity Capture-MS), PREB (Affinity Capture-MS), UPK3BL (Affinity Capture-MS), PTPRD (Affinity Capture-MS), ICOSLG (Affinity Capture-MS)

ESM2 similar proteins: A0JNA2, A2RRU4, A4FUY1, A5D7V5, A8MVS5, D4A6L0, E1BBQ2, O19131, O54693, O75144, P09564, P15151, P19438, P29590, P31994, P32506, P32507, P50555, P97260, Q14CZ8, Q28110, Q3TEW6, Q53EL9, Q5BJT4, Q5DRQ8, Q5T848, Q61190, Q640R3, Q6AYP5, Q6AYT8, Q6BAA4, Q6GQT6, Q6P6J9, Q6UX15, Q70EL4, Q75VT8, Q7TSK2, Q7Z692, Q8C419, Q8N126

Diamond homologs: O75144, Q5ZPR3, Q62556, Q7TPB4, Q8VE98, Q9JHJ8, P15151, P55803, Q13410, Q16653, Q29ZQ1, Q501W4, Q5R960, Q61885, Q63345, Q68EV1, Q6UX41, Q7TSP5, Q9BGS7, D3YXG0, D3ZB51, P11464, P32506, Q08180, Q16557, Q8NDA2, Q8UVR8, Q8VD31, Q9UM44, Q9UPX0, Q7TST0

SIGNOR signaling

3 interactions.

A	Effect	B	Mechanism
ICOSLG	“up-regulates activity”	ICOS	binding
PRKCB	“up-regulates activity”	ICOSLG	phosphorylation
PRKCA	“up-regulates activity”	ICOSLG	phosphorylation

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	3
Uncertain significance	149
Likely benign	135
Benign	8

Top pathogenic / likely-pathogenic (3)

Variant ID	HGVS	Classification
1339546	NM_015259.6(ICOSLG):c.499C>T (p.Pro167Ser)	Likely pathogenic
522117	NM_015259.6(ICOSLG):c.55+1G>T	Likely pathogenic
816179	GRCh37/hg19 21q22.3(chr21:45490774-48097372)x1	Likely pathogenic

SpliceAI

1508 predictions. Top by Δscore:

Variant	Effect	Δscore
21:44231440:ATTTC:A	acceptor_gain	1.0000
21:44231441:TTTC:T	acceptor_gain	1.0000
21:44231442:TTC:T	acceptor_gain	1.0000
21:44231442:TTCCT:T	acceptor_loss	1.0000
21:44231443:TC:T	acceptor_gain	1.0000
21:44231443:TCC:T	acceptor_loss	1.0000
21:44231443:TCCTA:T	acceptor_loss	1.0000
21:44231444:CC:C	acceptor_gain	1.0000
21:44231445:C:CC	acceptor_gain	1.0000
21:44231445:CTA:C	acceptor_loss	1.0000
21:44235266:CCTTA:C	donor_loss	1.0000
21:44235267:CTTA:C	donor_loss	1.0000
21:44235268:TTAC:T	donor_loss	1.0000
21:44235268:TTACC:T	donor_loss	1.0000
21:44235269:TA:T	donor_loss	1.0000
21:44235269:TACCT:T	donor_loss	1.0000
21:44235270:A:AC	donor_gain	1.0000
21:44235270:ACC:A	donor_loss	1.0000
21:44235270:ACCT:A	donor_loss	1.0000
21:44235271:C:CC	donor_gain	1.0000
21:44235271:C:T	donor_loss	1.0000
21:44235271:CCTGT:C	donor_gain	1.0000
21:44235558:GTTTG:G	acceptor_gain	1.0000
21:44235559:TTTG:T	acceptor_gain	1.0000
21:44235560:TTG:T	acceptor_gain	1.0000
21:44235561:TG:T	acceptor_gain	1.0000
21:44235561:TGC:T	acceptor_loss	1.0000
21:44235562:GC:G	acceptor_loss	1.0000
21:44235562:GCT:G	acceptor_loss	1.0000
21:44235563:C:CC	acceptor_gain	1.0000

AlphaMissense

1985 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
21:44235456:C:A	W171C	0.999
21:44235456:C:G	W171C	0.999
21:44237111:C:A	W54C	0.999
21:44237111:C:G	W54C	0.999
21:44235325:C:G	C215S	0.997
21:44235326:A:T	C215S	0.997
21:44235458:A:G	W171R	0.997
21:44235458:A:T	W171R	0.997
21:44235469:G:T	P167H	0.997
21:44235496:C:G	C158S	0.997
21:44235497:A:G	C158R	0.997
21:44235497:A:T	C158S	0.997
21:44236941:A:C	F111C	0.997
21:44235312:G:C	N219K	0.996
21:44235312:G:T	N219K	0.996
21:44235475:G:T	P165H	0.996
21:44235491:A:G	S160P	0.996
21:44235495:A:C	C158W	0.996
21:44235496:C:T	C158Y	0.996
21:44236934:G:C	C113W	0.996
21:44236974:A:G	L100S	0.996
21:44235366:G:C	S201R	0.995
21:44235366:G:T	S201R	0.995
21:44235368:T:G	S201R	0.995
21:44235476:G:A	P165S	0.995
21:44235481:C:T	G163D	0.995
21:44235555:G:C	F138L	0.995
21:44235555:G:T	F138L	0.995
21:44235557:A:G	F138L	0.995
21:44236935:C:G	C113S	0.995

dbSNP variants (sampled 300 via entrez): RS1000401044 (21:44227103 C>G,T), RS1000742298 (21:44231011 C>T), RS1000931828 (21:44241060 C>T), RS1001471630 (21:44233980 G>A), RS1001954835 (21:44230507 C>T), RS1003116223 (21:44232610 G>A,C), RS1003135109 (21:44218704 G>A), RS1003503369 (21:44224818 G>C), RS1004224776 (21:44222589 G>A), RS1004330662 (21:44227586 T>C), RS1004704589 (21:44227303 G>A), RS1004784845 (21:44231577 T>A), RS1004813670 (21:44231842 C>A,T), RS1005859849 (21:44221126 C>T), RS1005876677 (21:44229779 C>T)

Disease associations

OMIM: gene MIM:605717 | disease phenotypes: MIM:620825

GenCC curated gene-disease

Disease	Classification	Inheritance
immunodeficiency 119	Moderate	Autosomal recessive

ClinGen Gene-Disease Validity (1)

Expert-panel classifications — Definitive > Strong > Moderate > Limited > Disputed > Refuted.

Disease	Classification	Inheritance
combined immunodeficiency	Moderate	AR

Mondo (2): combined immunodeficiency (MONDO:0015131), immunodeficiency 119 (MONDO:0970993)

Orphanet (1): Combined T and B cell immunodeficiency (Orphanet:101972)

HPO phenotypes

17 total (17 of 17 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000403	Recurrent otitis media
HP:0001875	Decreased total neutrophil count
HP:0001888	Decreased total lymphocyte count
HP:0002090	Pneumonia
HP:0002837	Recurrent bronchitis
HP:0002863	Myelodysplasia
HP:0003453	Antineutrophil antibody positivity
HP:0004313	Decreased circulating immunoglobulin concentration
HP:0005387	Combined immunodeficiency
HP:0011108	Recurrent sinusitis
HP:0011463	Childhood onset
HP:0030318	Angular cheilitis
HP:0030388	Decreased class-switched memory B cell proportion
HP:0031160	Myelokathexis
HP:0032301	Genital warts
HP:0410028	Recurrent oral herpes

GWAS associations

21 associations (top):

Study	Trait	p-value
GCST000207_26	Crohn’s disease	1.000000e-09
GCST000612_27	Celiac disease	2.000000e-09
GCST000879_34	Crohn’s disease	2.000000e-14
GCST000964_25	Ulcerative colitis	6.000000e-11
GCST001725_107	Inflammatory bowel disease	2.000000e-26
GCST003630_2	Left ventricular QRS voltage	6.000000e-06
GCST004600_119	Eosinophil percentage of white cells	2.000000e-09
GCST004606_95	Eosinophil count	5.000000e-10
GCST004617_43	Eosinophil percentage of granulocytes	7.000000e-09
GCST005523_38	Celiac disease	6.000000e-07
GCST005529_6	Ankylosing spondylitis	6.000000e-09
GCST005529_63	Ankylosing spondylitis	1.000000e-06
GCST005536_24	Type 1 diabetes	1.000000e-07
GCST006585_1052	Blood protein levels	6.000000e-194
GCST006585_868	Blood protein levels	2.000000e-06
GCST006904_6	Cerebral amyloid deposition (PET imaging)	3.000000e-06
GCST006959_104	Rheumatoid arthritis	8.000000e-08
GCST90002381_274	Eosinophil count	1.000000e-28
GCST90002382_548	Eosinophil percentage of white cells	9.000000e-28
GCST90013445_12	Type 1 diabetes	7.000000e-11
GCST90013445_72	Type 1 diabetes	7.000000e-11

EFO canonical traits (6, from GWAS)

EFO ID	Trait name
EFO:0007741	R wave amplitude
EFO:0007742	QRS amplitude
EFO:0007991	eosinophil percentage of leukocytes
EFO:0004842	eosinophil count
EFO:0007996	eosinophil percentage of granulocytes
EFO:0007707	cerebral amyloid deposition measurement

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (2): CHEMBL3712949 (SINGLE PROTEIN), CHEMBL5482971 (PROTEIN-PROTEIN INTERACTION)

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

ChEMBL bioactivities

5 potent at pChembl≥5 of 17 total, top 5 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
5.73	IC50	1870	nM	CHEMBL5591374
5.43	IC50	3680	nM	CHEMBL5592269
5.35	IC50	4480	nM	CHEMBL5591374
5.33	IC50	4680	nM	CHEMBL2171562
5.25	IC50	5650	nM	CHEMBL5429501

PubChem BioAssay actives

5 with measured affinity, of 26 total; 4 most potent distinct compounds. Largely complementary to BindingDB; screening values are coarse (µM, 4 dp), so sub-nM hits tie at the floor.

Compound	Assay	Type	Value	Unit
(2S)-4-amino-2-[[(2S)-2-[[(2S)-2-[[(3S,9S,12S,18S,21S,27S,30R,35R,38S,41S,44S,47S)-30-[[(2S)-2-amino-3-(4-hydroxyphenyl)propanoyl]amino]-41,44-dibenzyl-9,27-bis[(4-hydroxyphenyl)methyl]-38-(2-methylpropyl)-2,8,11,17,20,26,29,37,40,43,46-undecaoxo-18-propan-2-yl-32,33-dithia-1,7,10,16,19,25,28,36,39,42,45-undecazapentacyclo[45.3.0.03,7.012,16.021,25]pentacontane-35-carbonyl]amino]-4-methylpentanoyl]amino]-3-phenylpropanoyl]amino]-4-oxobutanoic acid	2115250: Inhibition of ICOS/ICOSL (unknown origin) interaction by ELISA method	ic50	1.8700	uM
(1R,4S,10S,13S,19S,22S,28S,34S,37S,40S,43S,46R,49S,55S,58S,61S)-37,40,58-tribenzyl-4,22,61-tris[(4-hydroxyphenyl)methyl]-43,49-bis(2-methylpropyl)-13-propan-2-yl-65,66-dithia-3,6,12,15,21,24,30,36,39,42,45,48,51,57,60,63-hexadecazaheptacyclo[44.17.4.06,10.015,19.024,28.030,34.051,55]heptahexacontane-2,5,11,14,20,23,29,35,38,41,44,47,50,56,59,62-hexadecone	2115249: Inhibition of ICOS/ICOSL (unknown origin) interaction by TR-FRET assay	ic50	3.6800	uM
N-[3-(benzylamino)-6-chloro-9H-pyrido[3,4-b]indol-8-yl]pyridine-3-carboxamide	1977233: Inhibition of C-terminal IgG1 Fc region fused human ICOS extracellular domain (1 to 141 residues)/C-terminal polyhistidine tagged human ICOSL extracellular domain (1 to 258 residues) interaction incubated for 1 hr by TR-FRET assay	ic50	4.6800	uM
N-(6-chloro-7-methoxy-9H-pyrido[3,4-b]indol-8-yl)-4-methylpyrimidine-5-carboxamide	1977233: Inhibition of C-terminal IgG1 Fc region fused human ICOS extracellular domain (1 to 141 residues)/C-terminal polyhistidine tagged human ICOSL extracellular domain (1 to 258 residues) interaction incubated for 1 hr by TR-FRET assay	ic50	5.6500	uM

CTD chemical–gene interactions

51 total (human), top 30 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
potassium chromate(VI)	decreases expression, increases expression, affects cotreatment	2
Benzo(a)pyrene	increases expression	2
Cisplatin	increases expression, decreases expression, affects cotreatment	2
Ozone	affects cotreatment, increases expression, increases oxidation	2
Tetrachlorodibenzodioxin	increases expression	2
p-Chloromercuribenzoic Acid	affects cotreatment, increases expression	2
aristolochic acid I	increases expression	1
bisphenol A	affects cotreatment, increases expression	1
dimethylselenide	increases expression, increases oxidation	1
epigallocatechin gallate	affects cotreatment, decreases expression	1
chromium hexavalent ion	affects expression	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, increases expression	1
nutlin 3	affects cotreatment, increases expression	1
bisphenol B	increases expression	1
abrine	increases expression	1
dorsomorphin	affects cotreatment, increases expression	1
jinfukang	affects cotreatment, increases expression	1
Aripiprazole	affects cotreatment, increases expression	1
Sunitinib	increases expression	1
Zoledronic Acid	increases expression	1
Arsenic Trioxide	decreases expression	1
Leflunomide	increases expression	1
Acetaminophen	increases expression	1
Vehicle Emissions	increases expression	1
Dactinomycin	affects cotreatment, increases expression	1
Dexamethasone	affects cotreatment, increases expression	1
Estradiol	increases expression	1
Ethyl Methanesulfonate	increases expression	1
Formaldehyde	increases expression	1
Gallic Acid	increases expression	1

ChEMBL screening assays

6 unique, capped per target: 6 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL5329816	Binding	Inhibition of C-terminal IgG1 Fc region fused human ICOS extracellular domain (1 to 141 residues)/C-terminal polyhistidine tagged human ICOSL extracellular domain (1 to 258 residues) interaction incubated for 1 hr by TR-FRET assay	First-in-class small molecule inhibitors of ICOS/ICOSL interaction as a novel class of immunomodulators. — RSC Med Chem

Cellosaurus cell lines

8 cell lines: 4 cancer cell line, 4 spontaneously immortalized cell line

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

Cellosaurus	Name	Category	Sex
CVCL_B8HR	Abcam HCT 116 ICOSLG KO	Cancer cell line	Male
CVCL_B9K1	Abcam A-549 ICOSLG KO	Cancer cell line	Male
CVCL_D2FN	Abcam MCF-7 ICOSLG KO	Cancer cell line	Female
CVCL_D7BK	Abeomics CHO-K1 ICOSL	Spontaneously immortalized cell line	Female
CVCL_E2Z7	L929/CD275	Spontaneously immortalized cell line	Male
CVCL_E5IT	CHO-K1/B7-H2	Spontaneously immortalized cell line	Female
CVCL_E6QR	Genomeditech CHO-K1 H_ICOSLG(CD275)	Spontaneously immortalized cell line	Female
CVCL_RP37	JEM493	Cancer cell line	Male

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT02737384	PHASE2	TERMINATED	Hematopoietic Stem Cells Transplantation in Children With Combined Immunodeficiency (CID)
NCT02915406	Not specified	NO_LONGER_AVAILABLE	cliniMACs HUD for T Cell Depletion
NCT04902807	Not specified	RECRUITING	Conception of a Diagnosis, Prognosis and Therapeutic Decision Tool for Patients With Autoimmunity and Inflammation
NCT06659588	Not specified	RECRUITING	Study of Populations at Risk of Developing Chronic Hepatitis Linked to Chronic Enteric Virus Infection in Patients With Primary Immunodeficiency and Secondary Humoral Deficiency