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 (top 4% of genes corpus-wide)
• Clinical variants (ClinVar): 26 total — 2 pathogenic
• GTEx eGene: eQTL in 12 tissues, sQTL in 0 (q < 0.05)
• Phenotypes (HPO): 56
• Drug target: yes — 2 curated mechanism-of-action drugs
• Constraint (gnomAD): pLI 0.78 (intermediate), LOEUF 0.63 (unconstrained)
• MANE Select transcript: NM_006139
• Interaction hub: 3,050 STRING partners (top 2% of genes corpus-wide)

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: 5 — 5 protein_coding

MANE Select: ENST00000324106

Transcript support level (Ensembl TSL; 1 = fully mRNA-supported): TSL 1: 3

ENST00000324106, ENST00000374481, ENST00000458610, ENST00000718458, ENST00001139826

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.

Highest expression (Bgee): lymph node, vermiform appendix, blood, granulocyte, caecum.

Genetic regulation across tissues (GTEx eQTL / sQTL)

CD28 is an eGene in GTEx v10 — its expression is genetically regulated (eQTL) in 12 tissues and its splicing (sQTL) in 0 (q < 0.05). Strongest associations first; slope = normalized effect of the lead variant’s alternative allele.

12 significant tissue × QTL associations:

Tissue	QTL	q-value	Slope	Lead variant
Muscle Skeletal	eqtl	3.0e-03	-0.21	2:203712053:G:A
Breast Mammary Tissue	eqtl	5.3e-03	-0.21	2:203707417:A:C
Lung	eqtl	6.2e-03	-0.32	2:204229824:C:T
Artery Tibial	eqtl	1.0e-02	-0.18	2:203769281:C:T
Artery Aorta	eqtl	1.6e-02	-0.20	2:203707417:A:C
Esophagus Mucosa	eqtl	2.8e-02	-0.16	2:203722439:G:A
Whole Blood	eqtl	2.9e-02	+0.07	2:203771749:C:T
Cells EBV-transformed lymphocytes	eqtl	3.3e-02	+0.84	2:204477349:G:A
Spleen	eqtl	4.4e-02	-0.23	2:204283829:A:T
Heart Left Ventricle	eqtl	4.5e-02	-0.32	2:203829824:A:G
Bladder	eqtl	4.8e-02	-0.94	2:203441710:T:C
Nerve Tibial	eqtl	4.9e-02	-0.18	2:203769281:C:T

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

showing 100 of 277 tissues 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
superficial temporal artery	UBERON:0001614	60.46	silver quality
connective tissue	UBERON:0002384	60.34	gold quality
parietal pleura	UBERON:0002400	60.28	silver quality
left coronary artery	UBERON:0001626	60.01	gold quality
mononuclear cell	CL:0000842	59.88	gold quality
decidua	UBERON:0002450	59.39	gold quality
coronary artery	UBERON:0001621	59.29	gold quality
monocyte	CL:0000576	59.20	gold quality
mucosa of transverse colon	UBERON:0004991	59.02	gold quality
pleura	UBERON:0000977	58.98	silver quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	58.87	silver quality
small intestine	UBERON:0002108	58.45	gold quality
epithelium of nasopharynx	UBERON:0001951	58.43	silver quality
upper lobe of left lung	UBERON:0008952	57.45	gold quality
left uterine tube	UBERON:0001303	57.21	gold quality
upper lobe of lung	UBERON:0008948	56.37	gold quality
calcaneal tendon	UBERON:0003701	55.53	gold quality
lung	UBERON:0002048	55.48	gold quality
right lung	UBERON:0002167	55.08	gold quality
aorta	UBERON:0000947	54.72	gold quality
ileal mucosa	UBERON:0000331	54.21	gold quality
tibialis anterior	UBERON:0001385	54.02	silver quality
right lobe of liver	UBERON:0001114	53.75	gold quality
skin of hip	UBERON:0001554	53.56	gold quality
urinary bladder	UBERON:0001255	53.24	gold quality
intestine	UBERON:0000160	52.54	gold quality
transverse colon	UBERON:0001157	52.47	gold quality
hair follicle	UBERON:0002073	52.43	gold quality
cerebellar vermis	UBERON:0004720	52.38	gold quality
liver	UBERON:0002107	52.34	gold quality
epithelial cell of pancreas	CL:0000083	51.66	silver quality
adrenal tissue	UBERON:0018303	51.58	gold quality
tendon	UBERON:0000043	51.19	gold quality
quadriceps femoris	UBERON:0001377	50.84	gold quality
mucosa of stomach	UBERON:0001199	50.61	gold quality
colon	UBERON:0001155	50.55	gold quality
large intestine	UBERON:0000059	50.50	gold quality
duodenum	UBERON:0002114	50.41	gold quality
frontal pole	UBERON:0002795	50.41	gold quality
thoracic mammary gland	UBERON:0005200	50.35	gold quality
middle frontal gyrus	UBERON:0002702	50.30	gold quality
muscle tissue	UBERON:0002385	50.24	gold quality
mammary gland	UBERON:0001911	50.18	gold quality
paraflocculus	UBERON:0005351	50.18	gold quality
Brodmann (1909) area 10	UBERON:0013541	50.18	gold quality
myometrium	UBERON:0001296	49.89	gold quality
tibial nerve	UBERON:0001323	49.88	gold quality
stomach	UBERON:0000945	49.80	gold quality
heart	UBERON:0000948	49.72	gold quality
fallopian tube	UBERON:0003889	49.70	gold quality
upper leg skin	UBERON:0004262	49.70	gold quality
apex of heart	UBERON:0002098	49.69	gold quality
cortex of kidney	UBERON:0001225	49.45	gold quality
vastus lateralis	UBERON:0001379	49.45	gold quality
cranial nerve II	UBERON:0000941	49.42	silver quality
tibial artery	UBERON:0007610	49.40	gold quality
popliteal artery	UBERON:0002250	49.39	gold quality
Brodmann (1909) area 46	UBERON:0006483	49.30	gold quality
blood vessel layer	UBERON:0004797	49.29	gold quality
material anatomical entity	UBERON:0000465	49.21	gold quality
multicellular organism	UBERON:0000468	49.21	gold quality
cervix squamous epithelium	UBERON:0006922	49.20	gold quality
uterine cervix	UBERON:0000002	49.18	gold quality
hindlimb stylopod muscle	UBERON:0004252	49.18	gold quality
cardiac atrium	UBERON:0002081	49.15	gold quality
oviduct epithelium	UBERON:0004804	49.10	gold quality
right atrium auricular region	UBERON:0006631	49.07	gold quality
anatomical system	UBERON:0000467	49.01	gold quality
olfactory bulb	UBERON:0002264	48.92	gold quality
choroid plexus epithelium	UBERON:0003911	48.89	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

HPA expression

RNA tissue specificity: Group enriched

showing 60 of 76 HPA tissues / cells by nTPM:

Tissue / cell	Axis	nTPM	Protein (IHC)
Thymus	tissue	28.7
Lymph node	tissue	26.1	medium
Tonsil	tissue	17.4	medium
Appendix	tissue	14.0	low
Placenta	tissue	13.9	not detected
Spleen	tissue	6.8	low
Urinary bladder	tissue	4.3	not detected
Gallbladder	tissue	3.9	not detected
Adipose tissue	tissue	3.7	not detected
Olfactory bulb	tissue	3.7
Cerebellum	tissue	3.3	not detected
Bone marrow	tissue	3.1	low
Cerebral cortex	tissue	3.0	not detected
Amygdala	tissue	3.0
Retrosplenial cortex	tissue	3.0
Insular cortex	tissue	3.0
Retrosplenial and cingulate cortex	tissue	2.9
Temporal cortex	tissue	2.9
Hippocampal formation	tissue	2.8
Entorhinal cortex	tissue	2.8
Prefrontal cortex	tissue	2.6
Basal ganglia	tissue	2.6	not detected
Occipital cortex	tissue	2.6
Motor cortex	tissue	2.5
Corpus callosum	tissue	2.5
Stomach 1	tissue	2.4	not detected
Ventral forebrain	tissue	2.4
Somatosensory cortex	tissue	2.4
Choroid plexus	tissue	2.3
Septum	tissue	2.2
Putamen	tissue	2.1
Periaqueductal gray	tissue	2.1
Hypothalamus	tissue	2.0
Rectum	tissue	1.8	not detected
Lung	tissue	1.8	not detected
Midbrain	tissue	1.7
Colon	tissue	1.6	not detected
Medulla oblongata	tissue	1.6
Thalamus	tissue	1.5
Substantia nigra	tissue	1.5
Spinal cord	tissue	1.5
Pons	tissue	1.3
Smooth muscle	tissue	1.3	not detected
Superior colliculi	tissue	1.2
Liver	tissue	1.2	not detected
Small intestine	tissue	1.2	not detected
Cervix	tissue	1.1	not detected
Duodenum	tissue	1.0	not detected
Esophagus	tissue	0.9	not detected
Prostate	tissue	0.9
Breast	tissue	0.7	not detected
Seminal vesicle	tissue	0.7	not detected
Testis	tissue	0.6	not detected
Heart muscle	tissue	0.6	not detected
Salivary gland	tissue	0.6	not detected
Endometrium 1	tissue	0.6	not detected
Pancreas	tissue	0.5	not detected
Ovary	tissue	0.4	not detected
Nucleus accumbens	tissue	0.4
Kidney	tissue	0.4	not detected

Brain sub-regions (HPA Brain Atlas): detected in 189; highest nTPM — Subiculum (2.6), White matter (2.5), Ventral hippocampus (2.4), Dorsal hippocampus (2.2), Blood vessel (1.8).

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)

Targeting CD28 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific).

showing 30 of 128 miRNAs:

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

Functional genomics

gnomAD constraint: pLI 0.78, LOEUF 0.634, missense Z 0.927 — population loss-of-function intolerance (pLI ≥ 0.9 = LoF-intolerant; lower LOEUF = more constrained). gnomAD

Regional missense constraint (gnomAD)

ENST00000324106 splits into 3 regions with different missense tolerance; 0 are missense-constrained. Missense variants in a constrained region (low observed/expected) are more likely to be pathogenic. gnomAD

Region (GRCh38)	Missense obs / exp	o/e	Constrained
2:203,706,697–203,726,862	104 / 108.5	0.96	no
2:203,726,863–203,729,652	23 / 50.9	0.45	no
2:203,729,653–203,734,909	112 / 112.8	0.99	no

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

1 orthologs

Organism	Symbol	Gene ID
mus_musculus	Cd28	ENSMUSG00000026012

Paralogs (1): CTLA4 (ENSG00000163599)

Mouse-model phenotypes

Observed phenotypes of the mouse ortholog (MGI:88327) from MGI (Alliance of Genome Resources) — knockout/mutant phenotypes, ranked by annotation count. 54 distinct phenotype terms.

Mouse phenotype (MP)	Records
decreased T cell proliferation	9
decreased interleukin-2 secretion	7
abnormal class switch recombination	3
decreased regulatory T cell number	3
decreased immunoglobulin level	2
decreased susceptibility to experimental autoimmune encephalomyelitis	2
increased susceptibility to autoimmune diabetes	2
abnormal cytotoxic T cell physiology	2
abnormal CD4-positive, alpha-beta T cell physiology	2
decreased IgG1 level	2
decreased IgG2a level	2
increased leukocyte cell number	1
focal hair loss	1
ruffled hair	1
enlarged spleen	1
enlarged lymph nodes	1
enlarged thymus	1
skin lesions	1
abnormal eyelid morphology	1
decreased locomotor activity	1
hunched posture	1
decreased IgM level	1
increased activated T cell number	1
brain inflammation	1
abnormal lymphopoiesis	1

+29 more (showing top 25).

Additional cross-species homologs

Sequence homologs in species beyond Ensembl Compara’s model organisms, by Diamond local protein alignment (% sequence identity; best hit per species). Lower-identity rows are more distant homologs. The matched accessions’ gene symbols aren’t in biobtree yet, so each row shows the UniProt accession.

Organism	UniProt	Identity	Method
Rattus norvegicus	P31042	91.7%	Diamond
Canis lupus familiaris	Q9XSI1	90.1%	Diamond
Felis catus	O02757	83.3%	Diamond
Oryctolagus cuniculus	P42069	83.3%	Diamond
Bos taurus	Q28071	82.2%	Diamond
Gallus gallus	P31043	53.8%	Diamond

Genomic neighbors (locus context)

Genes flanking this one on the chromosome (NCBI/Entrez gene neighborhood). Positional context only — some neighbors share regulatory elements (bidirectional promoters, antisense/overlapping transcripts), but chromosomal adjacency is not itself a functional relationship (see Interactions for that).

Symbol	Type	Entrez
CTLA4	protein-coding	1493
RAPH1	protein-coding	65059
ABI2	protein-coding	10152

Protein

Protein identifiers

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

Alternative names: TP44

All UniProt accessions (2): A0ABB0MVH3, 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 (42 total): strand 11, splice variant 7, glycosylation site 5, mutagenesis site 3, helix 3, modified residue 3, disulfide bond 2, topological domain 2, signal peptide 1, chain 1, sequence variant 1, transmembrane region 1, domain 1, region of interest 1

Structure

Experimental structures (PDB)

10 structures by resolution:

PDB	Title	Method	Resolution (Å)
5GJI	PI3K p85 N-terminal SH2 domain/CD28-derived peptide complex	X-RAY DIFFRACTION	0.9
5AUL	PI3K p85 C-terminal SH2 domain/CD28-derived peptide complex	X-RAY DIFFRACTION	1.1
5GJH	Gads SH2 domain/CD28-derived peptide complex	X-RAY DIFFRACTION	1.2
3WA4	Grb2 SH2 domain/CD28-derived peptide complex	X-RAY DIFFRACTION	1.35
7PPN	SHP2 catalytic domain in complex with CD28 (183-198) phosphopeptide (pTyr-191, p-Thr-195)	X-RAY DIFFRACTION	1.9
1YJD	Crystal structure of human CD28 in complex with the Fab fragment of a mitogenic antibody …	X-RAY DIFFRACTION	2.7
8S6Z	CD28 in complex with the antibody Fab fragment AI3	X-RAY DIFFRACTION	3.05
6O8D	Anti-CD28xCD3 CODV Fab bound to CD28	X-RAY DIFFRACTION	3.55
7VU5	Structure of the transmembrane domain of the CD28 dimer	SOLUTION NMR
8W2V	Solution Structure of the CD28 hinge used in chimeric antigen receptor (CAR) T-cells	SOLUTION NMR

Predicted structure (AlphaFold)

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

Antibody-complex structures (SAbDab)

3 antibodies co-crystallized with this protein: 1YJD, 6O8D, 8S6Z

Human Protein Atlas

Protein class: CD markers, Predicted membrane proteins

Protein evidence: Evidence at protein level

Subcellular location (HPA, imaging): plasma membrane

Antibody reliability (HPA): IH enhanced · IF supported

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)

Type	Positions
Phosphoserine	189
Phosphotyrosine	191, 209

Disulfide bonds (2)

Type	Positions
Disulfide bond	40–112, 66–86

Glycosylation sites (5)

Type	Positions
N-linked (glcnac…) asparagine	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

7 curated (TAS) of 22; 10 disease pathways. Curated-first; evidence = TAS (manually curated) vs IEA (electronic inference).

22 pathways:

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

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 (22): positive regulation of cytokine production (GO:0001819), 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), positive regulation of T cell proliferation (GO:0042102), T cell activation (GO:0042110), negative regulation of apoptotic process (GO:0043066), regulatory T cell differentiation (GO:0045066), positive regulation of viral genome replication (GO:0045070), positive regulation of translation (GO:0045727), positive regulation of mitotic nuclear division (GO:0045840), T cell receptor signaling pathway (GO:0050852), positive regulation of T cell receptor signaling pathway (GO:0050862), immune system process (GO:0002376), immune response (GO:0006955), 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

15 top-level categories:

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

56 GO namespaces:

Category	Terms
cellular anatomical structure	4
positive regulation of cytokine production	3
positive regulation of gene expression	2
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 multicellular organismal process	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
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
T cell differentiation	1
viral genome replication	1
regulation of viral genome replication	1
positive regulation of viral process	1
translation	1
regulation of translation	1
positive regulation of protein metabolic process	1
regulation of mitotic nuclear division	1
positive regulation of nuclear division	1
positive regulation of cell cycle process	1
mitotic nuclear division	1
antigen receptor-mediated signaling pathway	1
T cell receptor signaling pathway	1
regulation of T cell receptor signaling pathway	1
positive regulation of antigen receptor-mediated signaling pathway	1
biological_process	1
immune system process	1
response to stimulus	1
kinase binding	1
protein binding	1
binding	1
cytoplasm	1
membrane	1
cell periphery	1
cell surface	1
side of membrane	1
protein-containing complex	1

Experimentally-supported GO annotations

GO terms backed by direct experimental evidence (ECO experimental codes) — 15 of 34 annotations. The rest are phylogenetic / computational / electronic (IEA).

15 experimentally-supported GO terms:

GO term	NS	Evidence
T cell activation	BP	direct assay
negative regulation of gene expression	BP	mutant phenotype
positive regulation of T cell proliferation	BP	direct assay
positive regulation of T cell receptor signaling pathway	BP	direct assay
positive regulation of gene expression	BP	mutant phenotype
positive regulation of interleukin-10 production	BP	direct assay
positive regulation of interleukin-2 production	BP	direct assay
positive regulation of interleukin-4 production	BP	direct assay
positive regulation of mitotic nuclear division	BP	direct assay
regulatory T cell differentiation	BP	direct assay
cell surface	CC	direct assay
external side of plasma membrane	CC	direct assay
plasma membrane	CC	direct assay
protein complex involved in cell adhesion	CC	direct assay
transmembrane signaling receptor activity	MF	direct assay

Protein interactions and networks

STRING

showing 15 of 3,050 interactions by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
CD28	CD4	P01730	963
CD28	IL2	P01585	956
CD28	CD80	P33681	955
CD28	CD8A	P01732	946
CD28	IFNG	P01579	945
CD28	CD86	P42081	945
CD28	CD274	Q9NZQ7	925
CD28	CD247	P20963	924
CD28	FOXP3	Q9BZS1	924
CD28	CD276	Q5ZPR3	898
CD28	IL10	P22301	897
CD28	PDCD1	Q15116	896
CD28	TNFRSF9	Q07011	881
CD28	CD27	P26842	880
CD28	IL4	P05112	869

IntAct

Human interaction partners of CD28 in IntAct, one row per partner (best MIscore; records = supporting IntAct interaction records).

10 partners by confidence:

Partner	Interaction type	MIscore	Records
PIK3R1	association	0.900	11
CD80	physical association	0.710	3
CD86	physical association	0.610	2
GRAP2	association	0.460	2
ICOSLG	physical association	0.400	1
OR56B4	physical association	0.400	1
SFN	physical association	0.400	1
EIF2B2	association	0.350	1
GRB2	association	0.350	1
LGALS1	association	0.350	1

BioGRID (44 interactions; top human partners by supporting records): PIK3R1 (Affinity Capture-Western; 14 records), GRAP2 (Reconstituted Complex; 6 records), GRB2 (Reconstituted Complex; 4 records), CD80 (Reconstituted Complex; 3 records), DUSP14 (Two-hybrid; 3 records), DOK1 (Affinity Capture-Western), EFNB2 (Affinity Capture-MS), HBA2 (Affinity Capture-MS), LGALS1 (Affinity Capture-MS), OR56B4 (Affinity Capture-MS), PIK3CA (Affinity Capture-Western), PIK3R2 (Affinity Capture-Western), PLXDC2 (Affinity Capture-MS), TMEM192 (Affinity Capture-MS), VAV1 (Affinity Capture-Western)

SIGNOR signaling

showing 5 of 13 signaling 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

Protein complexes (CORUM) (2)

Experimentally-characterized complexes this protein is a subunit of (★ = the complex contains a known drug target).

2 complexes by size:

Complex	Subunits	Members
★ CD28-ITK complex	2	ITK, CD28
CD28-transactivation complex	2	CD28, NCL

Ligand–receptor pairs (CellPhoneDB) (2)

Curated ligand–receptor partners (cell-cell communication), distinct from the protein–protein interactions above.

2 ligand–receptor pairs:

Partner	This gene’s role	Signaling class
CD86	receptor
CD80	receptor

Disease & clinical

Genetic variants

Variant evidence for CD28: 26 ClinVar records (2 pathogenic / likely pathogenic); 31 GWAS associations. Per-variant detail is on Sugi Variant.

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)

Showing all 2 pathogenic / likely-pathogenic ClinVar records, ranked by ClinVar review status (expert panel → multiple submitters → single submitter), then by number of submitting labs.

Variant ID	HGVS	Classification	Review	Submitters
833421	NC_000002.12:g.(?203444868)(203957883_?)del	Pathogenic	criteria provided, single submitter	1
3256912	NM_006139.4(CD28):c.52G>A (p.Gly18Arg)	Pathogenic	no assertion criteria provided	1

Per-variant reference — Sugi Variant

Explore CD28’s pathogenic and likely-pathogenic variants individually — each with its ClinVar classification and conditions, applied ACMG criteria (ClinGen expert panel, where curated), the calibrated in-silico predictors (AlphaMissense, REVEL, SaProt, conservation), gnomAD frequency, and the predictor-disagreement QC signal — on Sugi Variant.

SpliceAI

Top 10 splice-impact sites by Δscore (adjacent positions with the same effect merged into one range; 29 predictions of 241):

Position(s)	Effect	Δscore	Sites
2:203706749–203706750	donor_loss	1.0000	4
2:203706749	donor_loss	0.9900
2:203726631–203726632	acceptor_loss	0.9900	5
2:203726770	donor_gain	0.9900
2:203726990–203726991	donor_loss	0.9900	6
2:203734782–203734783	acceptor_loss	0.9900	6
2:203726632	acceptor_loss	0.9800
2:203726700	donor_gain	0.9700
2:203726989	donor_loss	0.9700	3
2:203734982	donor_gain	0.9700

AlphaMissense

413 missense substitutions predicted likely pathogenic (of 1,437 scored), across 113 residues. Top 20 hotspot residues, ranked by the number of likely-pathogenic substitutions (of those reachable by a single-nucleotide change), then by mean score:

Residue	Likely-pathogenic substitutions	Mean am_pathogenicity	Max am_pathogenicity
F97	8	0.928	0.996
D108	8	0.908	0.994
D190	8	0.897	0.951
F51	8	0.895	0.991
N193	8	0.825	0.959
C112	7	0.993	0.997
C40	7	0.988	0.996
C66	7	0.982	0.995
C86	7	0.980	0.992
F84	7	0.881	0.969
F215	7	0.875	0.968
M194	7	0.855	0.955
F111	7	0.849	0.978
D214	7	0.699	0.807
P119	6	0.967	0.981
P121	6	0.958	0.981
Q25	6	0.936	0.983
K57	6	0.923	0.991
P120	6	0.923	0.971
T107	6	0.892	0.986

HPA cancer prognostics

RNA cancer specificity: Low cancer specificity

Human Protein Atlas survival analysis — favorable = higher expression predicts better survival.

1 prognostic cancer types:

Cancer	Prognostic	p-value
Head and Neck Squamous Cell Carcinoma (TCGA)	favorable	0.000676

Disease associations

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

GenCC curated gene-disease

1 curated gene-disease records:

Disease	Classification	Inheritance	Records
immunodeficiency 123 with HPV-related verrucosis	Moderate	Autosomal recessive	2

ClinGen Gene-Disease Validity

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

1 validity classifications:

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

Genomics England panels (PanelApp)

Clinical diagnostic gene panels including this gene (1 panels, 0 green/diagnostic-grade). Confidence: green = diagnostic, amber = moderate.

1 panels:

Panel	Rating
COVID-19 research	amber

Mondo (2): immunodeficiency 123 with HPV-related verrucosis (MONDO:0971177), autoimmune lymphoproliferative syndrome due to CTLA4 haploinsufficiency (MONDO:0014493)

Orphanet (1): Autoimmune lymphoproliferative syndrome due to CTLA4 haploinsuffiency (Orphanet:436159)

HPO phenotypes

56 phenotypes (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
HP:0005561	Abnormal bone marrow cell morphology
HP:0007400	Irregular hyperpigmentation
HP:0007488	Diffuse skin atrophy
HP:0008069	Neoplasm of the skin
HP:0008404	Nail dystrophy
HP:0009830	Peripheral neuropathy
HP:0010701	Abnormal circulating immunoglobulin concentration
HP:0010783	Erythema
HP:0012192	Cutaneous T-cell lymphoma
HP:0020072	Persistent EBV viremia
HP:0025143	Chills
HP:0025144	Shivering
HP:0025475	Erythematous macule
HP:0030166	Night sweats
HP:0032163	Unusual molluscum contagiosum
HP:0032215	Disseminated cutaneous warts
HP:0032247	Persistent CMV viremia
HP:0032301	Genital warts
HP:0033221	Increased CD4:CD8 ratio
HP:0033510	Cutaneous horn
HP:0100725	Lichenification
HP:0100758	Gangrene
HP:0200035	Skin plaque
HP:0200042	Skin ulcer
HP:0200043	Verrucae
HP:0550004	Verruca plana

GWAS associations

showing 30 of 31 associations:

Study	Trait	p-value
GCST90002382_99	Eosinophil percentage of white cells	3e-22
GCST005537_123	Chronic inflammatory diseases (ankylosing spondylitis, Crohn’s disease, psoriasis, primary sclerosing cholangitis, ulcerative colitis) (pleiotropy)	1e-20
GCST004866_12	Alopecia areata	2e-20
GCST006670_5	Primary sclerosing cholangitis	2e-20
GCST90002381_516	Eosinophil count	2e-19
GCST001200_2	Graves’ disease	2e-17
GCST008644_10	Celiac disease and Rheumatoid arthritis	2e-17
GCST004030_2	Primary sclerosing cholangitis	2e-16
GCST005523_12	Celiac disease	1e-15
GCST006048_22	Rheumatoid arthritis (ACPA-positive)	9e-15
GCST002318_94	Rheumatoid arthritis	3e-14
GCST004302_16	Primary biliary cholangitis	1e-13
GCST002318_95	Rheumatoid arthritis	2e-13
GCST006959_52	Rheumatoid arthritis	3e-12
GCST009597_48	Multiple sclerosis	6e-12
GCST009873_27	Autoimmune traits (pleiotropy)	7e-12
GCST90002388_634	Lymphocyte count	1e-11
GCST005568_6	Rheumatoid arthritis (ACPA-positive)	4e-11
GCST006959_140	Rheumatoid arthritis	6e-11
GCST005569_8	Rheumatoid arthritis	7e-11
GCST000612_31	Celiac disease	6e-9
GCST008489_11	Celiac disease	2e-8
GCST008489_10	Celiac disease	4e-8
GCST003045_68	Ulcerative colitis	1e-7
GCST005531_92	Multiple sclerosis	1e-7
GCST005091_1	Subcutaneous adipose tissue	3e-7
GCST005568_35	Rheumatoid arthritis (ACPA-positive)	3e-7
GCST003043_157	Inflammatory bowel disease	5e-7
GCST005752_161	Systemic lupus erythematosus	4e-6
GCST002579_30	Heschl’s gyrus morphology	5e-6

EFO canonical traits (from GWAS)

3 canonical traits:

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)

Drugs by curated mechanism of action (ChEMBL)

Drugs whose curated ChEMBL mechanism of action targets the CD28 protein itself — single-protein targets only (drugs acting on a protein family or complex that merely includes it are excluded). Includes antibodies and oligonucleotides that bioactivity screening does not capture.

2 curated-mechanism drugs:

Drug	Modality	Max phase
LULIZUMAB PEGOL	Antibody	2
TGN-1412	Unknown	2

PharmGKB: 1 entry (CPIC guideline: no)

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	increases reaction, affects cotreatment, affects localization, decreases reaction, increases expression (+1 more)	2
triphenyl phosphate	affects expression	1
bisphenol A	affects cotreatment, decreases methylation	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	decreases expression, affects response to substance, increases expression, affects cotreatment	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	affects binding, affects cotreatment, increases expression, increases reaction, decreases reaction	1
Calcitriol	increases abundance, decreases reaction, affects binding, affects cotreatment, increases expression (+1 more)	1
Calcium	decreases reaction, increases abundance	1
Dactinomycin	decreases reaction, increases expression	1
Dexamethasone	increases secretion, affects cotreatment, increases expression, decreases reaction	1
Diethylhexyl Phthalate	decreases expression	1
Endosulfan	increases expression	1
Ketoconazole	decreases reaction, increases expression, increases reaction, increases abundance, affects binding (+1 more)	1
Lipopolysaccharides	decreases expression, affects response to substance, increases expression, affects cotreatment	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)

Via MONDO — disease-level, not drug-specific.

3 trials:

NCT	Phase	Status	Title
NCT05235438	Phase 1	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