Alt. symbols: Tp44

Approved name: CD28 molecule
Alt. names: CD28 antigen (Tp44) | T-cell-specific surface glycoprotein

Location: 2q33.2: 203706517 - 203739756 (+)
Gene type: protein_coding, 4 transcripts.

Scores: LoFtool: 0.254000 | pLI: 0.51198920 | LOEUF: 0.711

HGNC: 1653

NCBI: 940, RefSeq: NG_029618.1

Ensembl: ENSG00000178562.19

LRG_ | Status: none

OMIM: 186760

Expression | ProteinAtlas

Gene Ontology (GO)

• Molecular function:
• Cell component: external side of plasma membrane [GO:0009897]
• Biological process: T cell receptor signaling pathway [GO:0050852]; positive regulation of T cell proliferation [GO:0042102]; T cell costimulation [GO:0031295]; T cell activation [GO:0042110]

Normal function

CD28 encodes a critical costimulatory receptor expressed on T cells. It provides the essential "second signal" required for full activation of naive T cells, working alongside T cell receptor (TCR) signaling. CD28 enhances TCR signal transduction, cytoskeletal remodeling, and the recruitment of signaling molecules at the immunological synapse, thereby optimizing T cell responses. Without CD28-mediated costimulation, T cells may become anergic or undergo apoptosis rather than becoming fully activated. CD28 ligand (CD80/CD86) engagement enhances transcription and secretion of cytokines such as IL-2, IFN-gamma, TNF, and others, and upregulates anti-apoptotic proteins like Bcl-xL, promoting T cell survival and proliferation. CD28 signaling is crucial not only for conventional effector T cell responses but also for the development, survival, and function of Tregs, helping to maintain peripheral immune tolerance. B Cell Help: CD28 is necessary for T cell-dependent B cell responses, including the formation of germinal centers and antibody production

Dysfunction and disease

To date, only one homozygous variant in the gene has been linked to disease (p.G18R) in one family (PMID:34214472). This variant was thought to possibly affect splicing. Indeed, patient-derived T cells showed significantly decreased CD28 mRNA levels compared to controls. About 79% of the transcripts used the canonical splicing donor site (containing the p.G18R change), whereas 21% of the transcripts used an alternative donor splice site, which led to the creation of frame-shifted transcripts tha t were predicted to have a premature stop codon. These alternative transcripts were likely subjected to nonsense-mediated mRNA decay. HEK293 cells transiently overexpressing the CD28-G18R variant showed that CD28 was normally expressed on the cell surface, whereas truncated isoforms were not detected. Functional studies showed that the CD28-G18R variant retained the ability to induce NF-kB activation upon binding to an anti-CD28 antibody; however, patient cells had extremely low levels (less than 1% of normal) of functional G18R CD28 protein. Patient T-cell blasts lacked CD28 expression and showed no CD28-dependent downstream signaling responses, indicating that the mutation is a loss-of-function allele (PMID:34214472). [Load More]