CD28

Summary

CD28 (CD28 molecule, HGNC:1653) is a protein-coding gene on chromosome 2q33.2, encoding T-cell-specific surface glycoprotein CD28 (P10747). Receptor that plays a role in T-cell activation, proliferation, survival and the maintenance of immune homeostasis.

The protein encoded by this gene is essential for T-cell proliferation and survival, cytokine production, and T-helper type-2 development. Several alternatively spliced transcript variants encoding different isoforms have been found for this gene.

Source: NCBI Gene 940 — RefSeq curated summary.

At a glance

• Gene–disease (curated): immunodeficiency 123 with HPV-related verrucosis (Moderate, ClinGen)
• GWAS associations: 31
• Clinical variants (ClinVar): 26 total — 2 pathogenic
• Phenotypes (HPO): 56
• Druggable target: yes
• MANE Select transcript: NM_006139

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:1653
Approved symbol	CD28
Name	CD28 molecule
Location	2q33.2
Locus type	gene with protein product
Status	Approved
Ensembl gene	ENSG00000178562
Ensembl biotype	protein_coding
OMIM	186760
Entrez	940

Gene structure

Transcript identifiers

Ensembl transcripts: 4 — 4 protein_coding

ENST00000324106, ENST00000374481, ENST00000458610, ENST00000718458

RefSeq mRNA: 4 — MANE Select: NM_006139 NM_001243077, NM_001243078, NM_001410981, NM_006139

CCDS: CCDS2361, CCDS58749, CCDS92935

Canonical transcript exons

ENST00000324106 — 4 exons

Exon	Start	End
ENSE00001246021	203729648	203729772
ENSE00001375713	203726633	203726989
ENSE00001821960	203706639	203706748
ENSE00004035154	203734784	203738912

Expression profiles

Bgee: expression breadth ubiquitous, 154 present calls, max score 85.36.

FANTOM5 (CAGE): breadth broad, TPM avg 7.6944 / max 572.6609, expressed in 225 samples.

FANTOM5 promoters (5 alternative TSS)

Promoter ID	TPM avg	Samples expressed
24766	3.5141	161
24767	2.2252	158
24765	1.3191	110
24768	0.3349	59
24764	0.3010	81

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
lymph node	UBERON:0000029	85.36	gold quality
vermiform appendix	UBERON:0001154	82.05	gold quality
blood	UBERON:0000178	80.55	gold quality
granulocyte	CL:0000094	76.77	gold quality
caecum	UBERON:0001153	74.83	gold quality
colonic epithelium	UBERON:0000397	74.54	gold quality
gall bladder	UBERON:0002110	73.72	gold quality
amniotic fluid	UBERON:0000173	71.95	gold quality
thymus	UBERON:0002370	70.64	silver quality
tonsil	UBERON:0002372	70.42	gold quality
spleen	UBERON:0002106	70.00	gold quality
buccal mucosa cell	CL:0002336	69.61	gold quality
rectum	UBERON:0001052	66.97	gold quality
placenta	UBERON:0001987	66.74	gold quality
omental fat pad	UBERON:0010414	65.67	gold quality
peritoneum	UBERON:0002358	65.60	gold quality
bone marrow cell	CL:0002092	65.52	silver quality
adipose tissue of abdominal region	UBERON:0007808	64.83	gold quality
right coronary artery	UBERON:0001625	64.61	gold quality
smooth muscle tissue	UBERON:0001135	64.21	gold quality
descending thoracic aorta	UBERON:0002345	64.12	gold quality
pancreatic ductal cell	CL:0002079	62.68	silver quality
bone marrow	UBERON:0002371	62.52	gold quality
leukocyte	CL:0000738	62.17	gold quality
thoracic aorta	UBERON:0001515	62.01	gold quality
germinal epithelium of ovary	UBERON:0001304	61.84	gold quality
ascending aorta	UBERON:0001496	61.80	gold quality
adipose tissue	UBERON:0001013	61.17	gold quality
small intestine Peyer’s patch	UBERON:0003454	60.55	gold quality
subcutaneous adipose tissue	UBERON:0002190	60.47	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	10.32

Regulation

Is transcription factor: yes

Downstream targets (CollecTRI)

6 targets.

Target	Regulation
LGALS12	Repression
LGALS2	Repression
LGALS3	Repression
LGALS4	Repression
LGALS8	Activation
LGALS9	Activation

Upstream regulators (CollecTRI, top): AIRE, AP1, DNMT1, EGR1, FOS, GATA3, HAND2, HMGA1, NFATC2, NFIL3, NFKB1, NFKB2, NFKB, NR4A3, PGR, RARA, REL, RELA, SP1

miRNA regulators (miRDB)

128 targeting CD28, 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-4481	100.00	66.42	1669
HSA-MIR-5692A	100.00	74.40	6850
HSA-MIR-3925-3P	100.00	69.95	1237
HSA-MIR-4531	99.99	69.70	3181
HSA-MIR-3662	99.99	73.82	5684
HSA-MIR-4500	99.99	72.72	2367
HSA-MIR-4745-5P	99.98	65.95	1028
HSA-MIR-4775	99.98	75.00	6394
HSA-MIR-27A-3P	99.98	72.13	2955
HSA-MIR-27B-3P	99.98	72.13	2955
HSA-MIR-9985	99.98	72.11	2939
HSA-MIR-607	99.97	73.62	5593
HSA-MIR-590-3P	99.96	74.34	6478
HSA-MIR-1250-3P	99.96	70.04	4038
HSA-MIR-144-3P	99.94	73.98	2698
HSA-MIR-552-5P	99.93	68.56	1583
HSA-MIR-497-5P	99.92	71.83	2674
HSA-MIR-205-3P	99.92	69.92	3165
HSA-MIR-8063	99.91	69.76	3146
HSA-MIR-3671	99.90	73.04	3897
HSA-MIR-15A-5P	99.90	72.80	2787
HSA-MIR-15B-5P	99.90	72.78	2798
HSA-MIR-16-5P	99.90	72.80	2780
HSA-MIR-195-5P	99.90	72.81	2805
HSA-MIR-4753-3P	99.90	71.03	3786
HSA-MIR-95-5P	99.89	72.17	3973
HSA-MIR-424-5P	99.89	71.90	2641
HSA-MIR-6838-5P	99.89	71.94	2690
HSA-MIR-10395-5P	99.86	67.35	676
HSA-MIR-4698	99.84	71.41	4303

Literature-anchored findings (GeneRIF, showing 40)

• Participation of this protein augments T cell receptor/CD3 antigen phosphoinositide signaling. (PMID:11500828)
• role in t lymphocyte activation (PMID:11713465)
• T cells grafted with a recombinant CD28/CDzeta signaling receptor secrete high amounts of IL-2 upon antigen binding without exogenous B7/CD28 costimulation, demonstrating that complete T cell activation can be delivered by one chimeric receptor molecule. (PMID:11714771)
• CD28 gene region is associated with genetic susceptibility to celiac disease in UK families. (PMID:11826026)
• The B7-CD28/CTLA-4 costimulatory pathway has a dominant role in regulating T-cell activation. Antagonists enable graft survival and suppress autoimmunity. (PMID:11826754)
• Blockade of B7/CD28 costimulation in mixed lymphocyte reaction cultures results in the generation of alternatively activated macrophages, which suppress T-cell responses,and perhaps play a critical role in the induction of transplantation tolerance. (PMID:11830501)
• characterizion of a splice variant (isoform)CD28i which, via noncovalent association with CD28, plays a role as a costimulatory signal amplifier in human T cells (PMID:11877290)
• The phosphatidylinositol 3-hydroxykinase-protein kinase B pathway links CD28 to cell cycle progression in primary T cells. (PMID:11884439)
• novel simultaneous presence of eight different mRNA isoforms, all observed together in normal human T cells; this is an interesting finding in the study of CD28 mRNA structural variants (PMID:11916166)
• PTEN expression was up-regulated on RNA and protein level in freshly isolated human CD4(+) T cells following stimulation with CD28 or CD2. (PMID:11932928)
• CD28 function: a balance of costimulatory and regulatory signals. Review. (PMID:11958588)
• Endotoxin-induced lymphopenia was constituted mainly by cells with an immature phenotype (CD45RA(+) CD45RO(-)) that were less likely to undergo apoptosis (CD28(+)) (PMID:11986289)
• The signaling event mediated by CD28 engagement has been proposed to have 2 pathways; the Cyclosporin A-resistant pathway is sensitive to the immunosuppressive drug rapamycin. (PMID:12036883)
• results suggest that there is an unusual CD28 expression pattern in patients with acute infectious mononucleosis, namely, the presence of a functional CD28-intermediate subset among CD8 T cells (PMID:12050373)
• CD28-dependent signaling directly influences HIV-1 replication by targeting the activity of the viral factor Tat. (PMID:12077252)
• Neutrophil-expressed CD28 modulates not only granulocyte migration in vitro but also induction and secretion of IFN-gamma at the site of cocultured Leishmania-infected macrophages. (PMID:12097397)
• CD28 costimulation functions to increase glycolytic flux, allowing T cells to anticipate energetic and biosynthetic needs associated with a sustained response. (PMID:12121659)
• integration of the CD28 costimulatory signal in T cell activation (PMID:12195013)
• role of ligation in modulating TCR-induced transcriptional profiles (PMID:12195015)
• CD28 reversely regulates IL-10 on re-activation of human effector T cells with mature dendritic cells. The CD28/B7 pathway acted as a potent attenuator of IL-10 release. (PMID:12207353)
• APC-dependent impairment of T cell proliferation in aging: role of CD28- and IL-12/IL-15-mediated signaling (PMID:12297341)
• nucleolin and the A isoform of heterogeneous nuclear ribonucleoprotein-D0 (hnRNP-D0A), were identified to be among the key components of the site alpha complex in cells with inactive CD28 (PMID:12324461)
• CD28 ligation, IL-13 was released by eosinophils (PMID:12377947)
• dependence of differential chemokine expression profiles in human peripheral blood T lymphocytes on CD28 and calcineurin signaling (PMID:12393716)
• CD28, but not CD40L, expression is indispensable for the generation of CD4+ CD25+ regulatory T-cells that suppress GVH reactivity after BMT. (PMID:12434947)
• dependence of antigen-specific telomerase inducibility on CD28 (PMID:12482386)
• Cytokines were tested for ability to reinduce CD28 expression on T4 cells. Costimulation of the T-cell & IL-12 receptors induced CD28 transcription in about 50%. CD28 up-regulation by IL-12 correlated with CD28-initiator protein complex reassemby. (PMID:12506015)
• CD28 activates NF-kappa B independently of T cell receptor by cooperating with Vav-1 and IKK alpha subunit of I kappa B kinase in both Jurkat and primary T cells. (PMID:12626540)
• Tyrosine 200 of CD28 is required for efficient expression of HIV-1 transcription in activated T cells. (PMID:12842899)
• Polymorphism of CD28 (CD28-I3 + 17) does not affect the risk of developing multiple sclerosis and has no influence on the course and progression of disease. (PMID:12864988)
• CD28 appears to mediate actin polymerization in human T cells through the activation of the small Rho GTPase Cdc42. (PMID:12928366)
• transition within memory CD4+ T cells from CD28 dependence in central memory cells to functional independence and then loss of CD28 expression in effector cells. (PMID:12952926)
• Results suggest that the loss of CD28 expression during differentiation of memory/effector CD8+ T cells represents a decisive step in establishing regulation of responding CD8+ T cells. (PMID:12963692)
• CD28 has a role in regulating the signaling cascades for T-cell proliferation and IL-10 production (PMID:14550257)
• apoptosis plays a key role in the age-related decline of CD28 expression and in immunosenescence (PMID:14642527)
• The number of CD4+CD28- cells in patients after renal transplantation, especially in graft recipients with chronic graft rejection, suggests a role of these cells in chronic graft destruction. (PMID:14697933)
• There was a significant increase of the CD28 -372 G allele frequency in multiple sclerosis (MS) patients vs. controls. (PMID:14975605)
• CD28 phenotype of anti-HIV CTL evolves in parallel with disease progression and disease activity (PMID:14984593)
• a significant decrease of CD28+CD4+ and CD28+CD8+ T-cell percentage stimulated by PIII compared to its non-infected counterparts (PMID:15019278)
• CD28i, by functioning as a signaling adaptor, transduces CD40L signaling as well as CD28 signaling in human T cells. (PMID:15067037)

Cross-species orthologs

2 orthologs

Organism	Symbol	Gene ID
danio_rerio	si:dkey-1h24.6	ENSDARG00000092653
mus_musculus	Cd28	ENSMUSG00000026012

Paralogs (1): CTLA4 (ENSG00000163599)

Protein

Protein identifiers

T-cell-specific surface glycoprotein CD28 — P10747 (reviewed: P10747)

Alternative names: TP44

All UniProt accessions (1): P10747

UniProt curated annotations — full annotation on UniProt →

Function. Receptor that plays a role in T-cell activation, proliferation, survival and the maintenance of immune homeostasis. Functions not only as an amplifier of TCR signals but delivers unique signals that control intracellular biochemical events that alter the gene expression program of T-cells. Stimulation upon engagement of its cognate ligands CD80 or CD86 increases proliferation and expression of various cytokines in particular IL2 production in both CD4(+) and CD8(+) T-cell subsets. Mechanistically, ligation induces recruitment of protein kinase C-theta/PRKCQ and GRB2 leading to NF-kappa-B activation via both PI3K/Akt-dependent and -independent pathways. In conjunction with TCR/CD3 ligation and CD40L costimulation, enhances the production of IL4 and IL10 in T-cells. Enhances CD40L-mediated activation of NF-kappa-B and kinases MAPK8 and PAK2 in T-cells.

Subunit / interactions. Homodimer; disulfide-linked. Interacts with DUSP14. Binds to CD80/B7-1 and CD86/B7-2/B70. Interacts with GRB2. Interacts with PIK3R1. Interacts with PRKCQ. Interacts with CD40LG.

Subcellular location. Cell membrane Cell surface.

Tissue specificity. Expressed in T-cells and plasma cells, but not in less mature B-cells.

Post-translational modifications. Phosphorylated by LCK. Dephosphorylated by PTPN11. Tyrosine phosphorylated induced by CD40LG.

Disease relevance. Immunodeficiency 123 with HPV-related verrucosis (IMD123) [MIM:620901] An autosomal recessive immunologic disorder characterized by susceptibility to human papilloma virus (HPV) infections and the development of HPV-related common verrucosis in the first decade of life. In some patients with HPV2 infection, warts may progress to severe generalized hyperkeratotic cutaneous papillomatosis with cutaneous horns (’tree-man’ phenotype). In patients with HPV4 infection, warts remains stable and may even regress with age. The disease may be caused by variants affecting the gene represented in this entry.

Isoforms (7)

UniProt ID	Names	Canonical?
P10747-1	1	yes
P10747-2	2, CD28-S2
P10747-3	3, CD28i
P10747-4	4, CD28-S1
P10747-5	5
P10747-6	6, CD28-S3
P10747-7	7

RefSeq proteins (4): NP_001230006, NP_001230007, NP_001397910, NP_006130* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR008093	CD28	Family
IPR013106	Ig_V-set	Domain
IPR013783	Ig-like_fold	Homologous_superfamily
IPR036179	Ig-like_dom_sf	Homologous_superfamily
IPR040216	CTLA4/CD28	Family

Pfam: PF15910

UniProt features (41 total): strand 11, splice variant 7, glycosylation site 5, mutagenesis site 3, modified residue 3, disulfide bond 2, topological domain 2, helix 2, signal peptide 1, chain 1, sequence variant 1, transmembrane region 1, domain 1, region of interest 1

Structure

Experimental structures (PDB)

10 structures.

PDB	Method	Resolution (Å)
5GJI	X-RAY DIFFRACTION	0.9
5AUL	X-RAY DIFFRACTION	1.1
5GJH	X-RAY DIFFRACTION	1.2
3WA4	X-RAY DIFFRACTION	1.35
7PPN	X-RAY DIFFRACTION	1.9
1YJD	X-RAY DIFFRACTION	2.7
8S6Z	X-RAY DIFFRACTION	3.05
6O8D	X-RAY DIFFRACTION	3.55
7VU5	SOLUTION NMR
8W2V	SOLUTION NMR

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P10747-F1	81.16	0.49

Antibody-complex structures (SAbDab): 3 — 1YJD, 6O8D, 8S6Z

Functional residue map

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

Post-translational modifications (3): 189, 191, 209

Disulfide bonds (2): 40–112, 66–86

Glycosylation sites (5): 37, 71, 92, 105, 129

Mutagenesis-validated functional residues (3):

Position	Phenotype
160	about 75% loss of il2 release.
164	about 75% loss of il2 release.
191	greatly reduced phosphorylation by lck.

Function

Pathways and Gene Ontology

Reactome pathways

22 pathways

ID	Pathway
R-HSA-1257604	PIP3 activates AKT signaling
R-HSA-164939	Nef mediated downregulation of CD28 cell surface expression
R-HSA-2219530	Constitutive Signaling by Aberrant PI3K in Cancer
R-HSA-389356	Co-stimulation by CD28
R-HSA-389357	CD28 dependent PI3K/Akt signaling
R-HSA-389359	CD28 dependent Vav1 pathway
R-HSA-6811558	PI5P, PP2A and IER3 Regulate PI3K/AKT Signaling
R-HSA-1280218	Adaptive Immune System
R-HSA-162582	Signal Transduction
R-HSA-162906	HIV Infection
R-HSA-162909	Host Interactions of HIV factors
R-HSA-1643685	Disease
R-HSA-164938	Nef-mediates down modulation of cell surface receptors by recruiting them to clathrin adapters
R-HSA-164952	The role of Nef in HIV-1 replication and disease pathogenesis
R-HSA-168256	Immune System
R-HSA-199418	Negative regulation of the PI3K/AKT network
R-HSA-2219528	PI3K/AKT Signaling in Cancer
R-HSA-388841	Regulation of T cell activation by CD28 family
R-HSA-5663202	Diseases of signal transduction by growth factor receptors and second messengers
R-HSA-5663205	Infectious disease
R-HSA-9006925	Intracellular signaling by second messengers
R-HSA-9824446	Viral Infection Pathways

MSigDB gene sets: 586 (showing top): GSE45365_NK_CELL_VS_CD8A_DC_DN, GOBP_REGULATION_OF_T_CELL_RECEPTOR_SIGNALING_PATHWAY, GOBP_REGULATION_OF_CELL_ACTIVATION, GOBP_REGULATION_OF_ANTIGEN_RECEPTOR_MEDIATED_SIGNALING_PATHWAY, GOBP_POSITIVE_REGULATION_OF_MITOTIC_NUCLEAR_DIVISION, GOBP_REGULATION_OF_DNA_RECOMBINATION, GOBP_REGULATION_OF_LEUKOCYTE_PROLIFERATION, WALLACE_PROSTATE_CANCER_RACE_UP, GOBP_REGULATION_OF_INFLAMMATORY_RESPONSE_TO_ANTIGENIC_STIMULUS, GOBP_POSITIVE_REGULATION_OF_ADAPTIVE_IMMUNE_RESPONSE, GOBP_REGULATION_OF_ALPHA_BETA_T_CELL_ACTIVATION, REACTOME_ADAPTIVE_IMMUNE_SYSTEM, GOBP_REGULATION_OF_NUCLEAR_DIVISION, GOBP_INFLAMMATORY_RESPONSE, TGCTGCT_MIR15A_MIR16_MIR15B_MIR195_MIR424_MIR497

GO Biological Process (34): positive regulation of cytokine production (GO:0001819), positive regulation of inflammatory response to antigenic stimulus (GO:0002863), transcription by RNA polymerase II (GO:0006366), humoral immune response (GO:0006959), cell surface receptor signaling pathway (GO:0007166), positive regulation of gene expression (GO:0010628), negative regulation of gene expression (GO:0010629), T cell costimulation (GO:0031295), positive regulation of interleukin-10 production (GO:0032733), positive regulation of interleukin-2 production (GO:0032743), positive regulation of interleukin-4 production (GO:0032753), CD4-positive, alpha-beta T cell proliferation (GO:0035739), positive regulation of T cell proliferation (GO:0042102), T cell activation (GO:0042110), negative regulation of apoptotic process (GO:0043066), phosphatidylinositol 3-kinase/protein kinase B signal transduction (GO:0043491), negative thymic T cell selection (GO:0045060), regulatory T cell differentiation (GO:0045066), positive regulation of viral genome replication (GO:0045070), regulation of regulatory T cell differentiation (GO:0045589), positive regulation of translation (GO:0045727), positive regulation of mitotic nuclear division (GO:0045840), positive regulation of transcription by RNA polymerase II (GO:0045944), positive regulation of isotype switching to IgG isotypes (GO:0048304), T cell receptor signaling pathway (GO:0050852), positive regulation of T cell receptor signaling pathway (GO:0050862), positive regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction (GO:0051897), apoptotic signaling pathway (GO:0097190), positive regulation of CD4-positive, alpha-beta T cell proliferation (GO:2000563), immune system process (GO:0002376), immune response (GO:0006955), T cell proliferation (GO:0042098), regulation of T cell proliferation (GO:0042129), positive regulation of T cell activation (GO:0050870)

GO Molecular Function (5): transmembrane signaling receptor activity (GO:0004888), coreceptor activity (GO:0015026), protein kinase binding (GO:0019901), identical protein binding (GO:0042802), protein binding (GO:0005515)

GO Cellular Component (7): immunological synapse (GO:0001772), cytosol (GO:0005829), plasma membrane (GO:0005886), external side of plasma membrane (GO:0009897), cell surface (GO:0009986), protein complex involved in cell adhesion (GO:0098636), membrane (GO:0016020)

Reactome top-level categories

Rollup of top-15 pathways:

Category	Pathways
Co-stimulation by CD28	2
Disease	2
Intracellular signaling by second messengers	1
Nef-mediates down modulation of cell surface receptors by recruiting them to clathrin adapters	1
PI3K/AKT Signaling in Cancer	1
Regulation of T cell activation by CD28 family	1
Negative regulation of the PI3K/AKT network	1
Immune System	1
Viral Infection Pathways	1
HIV Infection	1
The role of Nef in HIV-1 replication and disease pathogenesis	1
Host Interactions of HIV factors	1
PIP3 activates AKT signaling	1
Diseases of signal transduction by growth factor receptors and second messengers	1
Adaptive Immune System	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	4
positive regulation of cytokine production	3
gene expression	2
regulation of gene expression	2
positive regulation of T cell activation	2
signaling receptor activity	2
plasma membrane	2
cytokine production	1
regulation of cytokine production	1
positive regulation of gene expression	1
positive regulation of multicellular organismal process	1
inflammatory response to antigenic stimulus	1
regulation of inflammatory response to antigenic stimulus	1
positive regulation of inflammatory response	1
positive regulation of immune response	1
DNA-templated transcription	1
immune response	1
signal transduction	1
positive regulation of macromolecule biosynthetic process	1
negative regulation of macromolecule biosynthetic process	1
lymphocyte costimulation	1
interleukin-10 production	1
regulation of interleukin-10 production	1
interleukin-2 production	1
regulation of interleukin-2 production	1
interleukin-4 production	1
regulation of interleukin-4 production	1
CD4-positive, alpha-beta T cell activation	1
alpha-beta T cell proliferation	1
T cell proliferation	1
regulation of T cell proliferation	1
positive regulation of lymphocyte proliferation	1
lymphocyte activation	1
apoptotic process	1
regulation of apoptotic process	1
negative regulation of programmed cell death	1
intracellular signaling cassette	1
negative T cell selection	1
thymic T cell selection	1
T cell differentiation	1

Protein interactions and networks

STRING

2886 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
CD28	CD80	P33681	999
CD28	CD86	P42081	999
CD28	CD276	Q5ZPR3	998
CD28	A0A087X1L8	A0A087X1L8	997
CD28	ICOSLG	O75144	997
CD28	CD40	P25942	997
CD28	CD40LG	P29965	997
CD28	CD274	Q9NZQ7	997
CD28	LCK	P06239	996
CD28	TNFSF9	P41273	992
CD28	CTLA4	P16410	987
CD28	TNFSF4	P23510	981
CD28	CD2	P06729	981
CD28	CD70	P32970	979
CD28	ICAM1	P05362	977

IntAct

28 interactions, top by confidence:

A	B	Type	Score
CD28	PIK3R1	psi-mi:“MI:0914”(association)	0.900
PIK3R1	CD28	psi-mi:“MI:0914”(association)	0.900
CD28	CD80	psi-mi:“MI:0915”(physical association)	0.710
CD80	CD28	psi-mi:“MI:0915”(physical association)	0.710
CD28	CD80	psi-mi:“MI:0407”(direct interaction)	0.710
CD28	CD86	psi-mi:“MI:0915”(physical association)	0.610
CD28	CD86	psi-mi:“MI:0407”(direct interaction)	0.610
CTLA4	B4GALT5	psi-mi:“MI:0914”(association)	0.530
PRKCQ	LCK	psi-mi:“MI:0914”(association)	0.500
GRAP2	CD28	psi-mi:“MI:0914”(association)	0.460
SFN	CD28	psi-mi:“MI:0915”(physical association)	0.400
OR56B4	CD28	psi-mi:“MI:0915”(physical association)	0.400
ICOSLG	CD28	psi-mi:“MI:0915”(physical association)	0.400
CD28	LGALS1	psi-mi:“MI:0914”(association)	0.350
CD28	EIF2B2	psi-mi:“MI:0914”(association)	0.350
GRB2	CD28	psi-mi:“MI:0914”(association)	0.350
Pik3r1	CD28	psi-mi:“MI:0914”(association)	0.350
PIK3R1	CD28	psi-mi:“MI:0914”(association)	0.350

BioGRID (44): CD80 (Reconstituted Complex), PIK3R1 (Affinity Capture-Western), CD28 (Affinity Capture-Western), CD28 (Reconstituted Complex), GRB2 (Reconstituted Complex), GRAP2 (Reconstituted Complex), PIK3R1 (Reconstituted Complex), PIK3R1 (Affinity Capture-Western), PIK3R1 (Reconstituted Complex), CD28 (Co-crystal Structure), CD28 (Co-crystal Structure), CD28 (Reconstituted Complex), CD28 (Reconstituted Complex), CD28 (Reconstituted Complex), PIK3R1 (Affinity Capture-Western)

ESM2 similar proteins: A6NJW9, O02757, P01730, P01731, P01732, P05541, P07725, P09793, P0DSE1, P10300, P10747, P10966, P15530, P16003, P16004, P16410, P30433, P30434, P31041, P31042, P31043, P31783, P33705, P33706, P40259, P41688, P42069, P42072, P50283, P79184, P79336, Q08338, Q08340, Q28071, Q2YFS1, Q2YFS2, Q2YFS3, Q3LRV9, Q495A1, Q5JXA9

Diamond homologs: O02757, P09793, P10747, P16410, P31041, P31042, P31043, P42069, P42072, Q28071, Q9XSI1, Q9MYX7

SIGNOR signaling

13 interactions.

A	Effect	B	Mechanism
CD28	up-regulates	PIK3CG	binding
ITK	up-regulates	CD28	phosphorylation
LCK	up-regulates	CD28	phosphorylation
CD28	up-regulates	GRB2	binding
ITK	“up-regulates activity”	CD28	phosphorylation

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 15 IntAct physical interaction partners (hypergeometric vs the genome-wide background, BH-FDR, gene-set size 15–500, ranked by fold). A functional readout of the neighbourhood — distinct from this gene’s own memberships above, and biased toward well-studied / hub proteins, so read it as themes rather than proof.

Reactome pathways:

Pathway	Partners	Fold	FDR
Co-stimulation by CD28	5	135.9×	4e-08
Constitutive Signaling by Aberrant PI3K in Cancer	5	45.3×	2e-06
PI5P, PP2A and IER3 Regulate PI3K/AKT Signaling	5	34.6×	6e-06
PIP3 activates AKT signaling	5	23.9×	3e-05

GO biological processes:

GO term	Partners	Fold	FDR
T cell activation	5	92.6×	3e-07

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	2
Likely pathogenic	0
Uncertain significance	19
Likely benign	1
Benign	2

Top pathogenic / likely-pathogenic (2)

Variant ID	HGVS	Classification
3256912	NM_006139.4(CD28):c.52G>A (p.Gly18Arg)	Pathogenic
833421	NC_000002.12:g.(?203444868)(203957883_?)del	Pathogenic

SpliceAI

555 predictions. Top by Δscore:

Variant	Effect	Δscore
2:203726770:G:GT	donor_gain	1.0000
2:203726628:CCCA:C	acceptor_loss	0.9900
2:203726629:CCAG:C	acceptor_loss	0.9900
2:203726630:CAG:C	acceptor_loss	0.9900
2:203726631:A:AC	acceptor_loss	0.9900
2:203726631:A:AG	acceptor_gain	0.9900
2:203726632:G:GA	acceptor_loss	0.9900
2:203726632:G:GG	acceptor_gain	0.9900
2:203726632:GGA:G	acceptor_gain	0.9900
2:203726727:G:GT	donor_gain	0.9900
2:203726768:TGG:T	donor_gain	0.9900
2:203726770:G:T	donor_gain	0.9900
2:203726986:AAAG:A	donor_gain	0.9900
2:203726987:AAGGT:A	donor_loss	0.9900
2:203726988:AG:A	donor_loss	0.9900
2:203726989:G:GC	donor_loss	0.9900
2:203726990:G:A	donor_loss	0.9900
2:203726991:T:G	donor_loss	0.9900
2:203734778:CTGCA:C	acceptor_loss	0.9900
2:203734779:TGCAG:T	acceptor_loss	0.9900
2:203734780:GCAGG:G	acceptor_loss	0.9900
2:203734781:CAGGT:C	acceptor_loss	0.9900
2:203734782:A:C	acceptor_loss	0.9900
2:203726753:G:GT	donor_gain	0.9800
2:203734783:GGT:G	acceptor_gain	0.9800
2:203734783:GGTGA:G	acceptor_gain	0.9800
2:203735091:G:GT	donor_gain	0.9800
2:203706745:ACAG:A	donor_gain	0.9700
2:203711823:G:GT	donor_gain	0.9700
2:203726631:AG:A	acceptor_gain	0.9700

AlphaMissense

1437 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
2:203726908:T:G	Y110D	0.998
2:203726744:T:A	L55H	0.997
2:203726914:T:A	C112S	0.997
2:203726914:T:C	C112R	0.997
2:203726915:G:C	C112S	0.997
2:203726698:T:A	C40S	0.996
2:203726699:G:C	C40S	0.996
2:203726870:T:C	F97S	0.996
2:203726915:G:A	C112Y	0.996
2:203726744:T:C	L55P	0.995
2:203726776:T:C	C66R	0.995
2:203726916:C:G	C112W	0.995
2:203726698:T:C	C40R	0.994
2:203726699:G:A	C40Y	0.994
2:203726740:T:C	S54P	0.994
2:203726876:T:C	L99P	0.994
2:203726903:A:T	D108V	0.994
2:203726909:A:G	Y110C	0.994
2:203729737:A:C	S167R	0.994
2:203729739:C:A	S167R	0.994
2:203729739:C:G	S167R	0.994
2:203726693:T:C	L38P	0.993
2:203726978:T:A	I133N	0.993
2:203726776:T:A	C66S	0.992
2:203726777:G:A	C66Y	0.992
2:203726777:G:C	C66S	0.992
2:203726836:T:A	C86S	0.992
2:203726837:G:C	C86S	0.992
2:203726978:T:G	I133S	0.992
2:203726732:T:C	F51S	0.991

dbSNP variants (sampled 300 via entrez): RS1000155592 (2:203728751 T>C), RS1000270964 (2:203722483 T>A), RS1000319800 (2:203729105 G>A,C), RS1000328683 (2:203723087 T>G), RS1000364097 (2:203735615 A>C), RS1000470065 (2:203729391 T>C,G), RS1000475022 (2:203735803 A>G,T), RS1000603810 (2:203734026 G>T), RS1000673556 (2:203735395 A>G), RS1000803404 (2:203727718 C>T), RS1000889517 (2:203708938 G>A), RS1000961612 (2:203710809 G>A), RS1001061369 (2:203723977 G>T), RS1001115416 (2:203717454 T>C), RS1001145435 (2:203734398 A>C)

Disease associations

OMIM: gene MIM:186760 | disease phenotypes: MIM:607271, MIM:607594, MIM:620901, MIM:616100

GenCC curated gene-disease

Disease	Classification	Inheritance
immunodeficiency 123 with HPV-related verrucosis	Moderate	Autosomal recessive

ClinGen Gene-Disease Validity (1)

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

Disease	Classification	Inheritance
immunodeficiency 123 with HPV-related verrucosis	Moderate	AR

Mondo (4): autoimmune lymphoproliferative syndrome type 2B (MONDO:0011804), immunodeficiency, common variable, 1 (MONDO:0011864), immunodeficiency 123 with HPV-related verrucosis (MONDO:0971177), autoimmune lymphoproliferative syndrome due to CTLA4 haploinsufficiency (MONDO:0014493)

Orphanet (4): OBSOLETE: Common variable immunodeficiency (Orphanet:1572), Autoimmune lymphoproliferative syndrome-recurrent viral infections due to CASP8 deficiency (Orphanet:275517), Late-onset combined immunodeficiency due to ICOS deficiency (Orphanet:695183), Autoimmune lymphoproliferative syndrome due to CTLA4 haploinsuffiency (Orphanet:436159)

HPO phenotypes

56 total (30 of 56 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000403	Recurrent otitis media
HP:0000492	Abnormal eyelid morphology
HP:0000656	Ectropion
HP:0000958	Dry skin
HP:0000962	Hyperkeratosis
HP:0000964	Eczematoid dermatitis
HP:0000969	Edema
HP:0000982	Palmoplantar keratoderma
HP:0000988	Skin rash
HP:0000989	Pruritus
HP:0001019	Erythroderma
HP:0001029	Poikiloderma
HP:0001053	Hypopigmented skin patches
HP:0001337	Tremor
HP:0001596	Alopecia
HP:0001597	Abnormal nail morphology
HP:0001744	Splenomegaly
HP:0001824	Weight loss
HP:0001945	Fever
HP:0002045	Hypothermia
HP:0002103	Abnormal pleura morphology
HP:0002240	Hepatomegaly
HP:0002665	Lymphoma
HP:0002716	Lymphadenopathy
HP:0002721	Immunodeficiency
HP:0002843	Abnormal T cell morphology
HP:0003202	Skeletal muscle atrophy
HP:0003621	Juvenile onset
HP:0004332	Abnormal lymphocyte morphology

GWAS associations

31 associations (top):

Study	Trait	p-value
GCST000612_31	Celiac disease	6.000000e-09
GCST001200_2	Graves’ disease	2.000000e-17
GCST002318_150	Rheumatoid arthritis	2.000000e-13
GCST002318_22	Rheumatoid arthritis	3.000000e-14
GCST002579_5	Heschl’s gyrus morphology	5.000000e-06
GCST003043_183	Inflammatory bowel disease	5.000000e-07
GCST003045_68	Ulcerative colitis	1.000000e-07
GCST004030_2	Primary sclerosing cholangitis	2.000000e-16
GCST004302_16	Primary biliary cholangitis	1.000000e-13
GCST004866_12	Alopecia areata	2.000000e-20
GCST005091_1	Subcutaneous adipose tissue	3.000000e-07
GCST005523_12	Celiac disease	1.000000e-15
GCST005531_89	Multiple sclerosis	1.000000e-07
GCST005537_2	Chronic inflammatory diseases (ankylosing spondylitis, Crohn’s disease, psoriasis, primary sclerosing cholangitis, ulcerative colitis) (pleiotropy)	1.000000e-20
GCST005568_12	Rheumatoid arthritis (ACPA-positive)	3.000000e-07
GCST005568_31	Rheumatoid arthritis (ACPA-positive)	4.000000e-11
GCST005569_35	Rheumatoid arthritis	5.000000e-06
GCST005569_6	Rheumatoid arthritis	7.000000e-11
GCST005752_161	Systemic lupus erythematosus	4.000000e-06
GCST006048_47	Rheumatoid arthritis (ACPA-positive)	9.000000e-15
GCST006670_5	Primary sclerosing cholangitis	2.000000e-20
GCST006959_152	Rheumatoid arthritis	3.000000e-12
GCST006959_60	Rheumatoid arthritis	6.000000e-11
GCST008489_10	Celiac disease	4.000000e-08
GCST008489_11	Celiac disease	2.000000e-08
GCST008644_10	Celiac disease and Rheumatoid arthritis	2.000000e-17
GCST009597_106	Multiple sclerosis	6.000000e-12
GCST009873_32	Autoimmune traits (pleiotropy)	7.000000e-12
GCST90002381_56	Eosinophil count	2.000000e-19
GCST90002382_82	Eosinophil percentage of white cells	3.000000e-22

EFO canonical traits (3, from GWAS)

EFO ID	Trait name
EFO:0004842	eosinophil count
EFO:0007991	eosinophil percentage of leukocytes
EFO:0004587	lymphocyte count

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL5191 (SINGLE PROTEIN)

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

PharmGKB variants

1 variants.

Variant	Genes	Level	Score	#Clin annots	Drugs
rs1980422	CD28		0.00	0

GtoPdb / IUPHAR curated pharmacology

(IUPHAR/BPS Guide to Pharmacology — expert-curated)

Target class: other protein — CD molecules

Most potent curated ligand interactions (1 total), top 1:

Ligand	Action	Affinity	Parameter
lulizumab pegol	Binding	9.44	pKd

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Tetradecanoylphorbol Acetate	decreases reaction, increases expression, increases phosphorylation, increases reaction, affects cotreatment (+1 more)	2
triphenyl phosphate	affects expression	1
bisphenol A	decreases methylation, affects cotreatment	1
rimexolone	affects cotreatment, decreases reaction, increases expression, increases secretion	1
manganese chloride	affects cotreatment, increases phosphorylation, increases reaction, decreases reaction	1
S-(1,2-dichlorovinyl)cysteine	affects response to substance, increases expression, affects cotreatment, decreases expression	1
di-n-butylphosphoric acid	affects expression	1
1,3-dihydroxy-4,4,5,5-tetramethyl-2-(4-carboxyphenyl)tetrahydroimidazole	decreases reaction, increases abundance	1
tebuconazole	decreases expression	1
manganese(III)-tetrakis(4-benzoic acid)porphyrin	decreases reaction, increases abundance	1
2-aminoethoxydiphenylborane	decreases reaction, increases abundance	1
5-diisopropoxyphosphoryl-5-methyl-1-pyrroline-N-oxide	decreases reaction, increases abundance	1
(+)-JQ1 compound	decreases expression	1
Fingolimod Hydrochloride	decreases expression	1
Arsenic Trioxide	increases expression	1
Fulvestrant	affects cotreatment, decreases methylation	1
Air Pollutants, Occupational	affects expression	1
Arsenates	affects cotreatment, increases expression	1
Atrazine	affects cotreatment, increases expression	1
Benzo(a)pyrene	affects methylation, increases methylation	1
Calcifediol	increases reaction, decreases reaction, affects binding, affects cotreatment, increases expression	1
Calcitriol	affects binding, affects cotreatment, increases expression, increases reaction, increases abundance (+1 more)	1
Calcium	decreases reaction, increases abundance	1
Dactinomycin	decreases reaction, increases expression	1
Dexamethasone	affects cotreatment, increases expression, decreases reaction, increases secretion	1
Diethylhexyl Phthalate	decreases expression	1
Endosulfan	increases expression	1
Ketoconazole	affects binding, affects cotreatment, decreases reaction, increases expression, increases reaction (+1 more)	1
Lipopolysaccharides	increases expression, affects cotreatment, decreases expression, affects response to substance	1
Methotrexate	decreases expression	1

ChEMBL screening assays

1 unique, capped per target: 1 functional

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL994898	Functional	Inhibition of CD28-induced NF-kappaB activation in human Jurkat cells by EMSA	3-Hydroxyanthranilic acid inhibits PDK1 activation and suppresses experimental asthma by inducing T cell apoptosis. — Proc Natl Acad Sci U S A

Cellosaurus cell lines

12 cell lines: 9 cancer cell line, 2 spontaneously immortalized cell line, 1 transformed cell line

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

Cellosaurus	Name	Category	Sex
CVCL_9V75	CHO CD28	Transformed cell line	Female
CVCL_B1MP	Abcam HeLa CD28 KO	Cancer cell line	Female
CVCL_B8CY	Abcam HCT 116 CD28 KO	Cancer cell line	Male
CVCL_B8TM	Abcam MCF-7 CD28 KO	Cancer cell line	Female
CVCL_B9F6	Abcam A-549 CD28 KO	Cancer cell line	Male
CVCL_D7BD	Abeomics CHO-K1 CD28	Spontaneously immortalized cell line	Female
CVCL_E3JD	Jurkat-Lucia NFAT-CD28	Cancer cell line	Male
CVCL_E6PH	Genomeditech CHO-K1 H_CD28	Spontaneously immortalized cell line	Female
CVCL_E8IM	Jurkat-NFAT-Luc2-CD28-KO-3A4	Cancer cell line	Male
CVCL_E8IN	Jurkat-NFAT-Luc2-CD28-KO-4A2	Cancer cell line	Male

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT05235438	PHASE1	UNKNOWN	Safety and Toxicity Study of IMM27M in Patients With Advanced Solid Tumor
NCT04377867	Not specified	UNKNOWN	New Biomarkers for Diagnosis and Follow-up of Patients With LRBA or CTLA4 Deficiencies
NCT05040256	Not specified	COMPLETED	Neurologic and Immunologic Characteristics of CTLA-4 and LRBA Hereditary Deficiency