T cell antigen CD28 (IPR008093)
Short name: CD28
Overlapping homologous superfamilies
- Cytotoxic T-lymphocyte protein 4/CD28 (IPR040216)
- T cell antigen CD28 (IPR008093)
Antigen (Ag) recognition by the T cell receptor (TCR) induces activation of T lymphocytes. However, TCR-mediated signals alone are insufficient for efficient T cell activation, and additional co-stimulatory signals are required. One of the most important surface molecules that delivers co-stimulatory signals for T cells is CD28. The human T lymphocyte Ag CD28 (Tp44) is a homodimeric 90kDa glycoprotein expressed on the surface of the majority of human peripheral T cells and lymphocytes. Stimulation of CD4+ T cells in the absence of CD28 co-signalling causes impaired proliferation, reduced cytokine production and altered generation of helper T cell subsets. Co-stimulation via CD28 promotes T cell viability, clonal expansion, cytokine production and effector functions, while also regulating apoptosis of activated T cells, suggesting its importance in regulating long-term T cell survival [PMID: 2162892, PMID: 2157764, PMID: 11698433, PMID: 11698427].
Ligands for CD28 and the structurally related CTLA-4 (CD152) are the molecules B7.1 (CD80) and B7.2 (CD86). B7.1 and B7.2 are expressed on professional antigen presenting cells (APCs) and their expression is up-regulated during an immune response. Ligation of CD28 by its natural ligands results in tyrosine phosphorylation at a YMNM motif within its cytoplasmic tail. The phosphorylated motif subsequently interacts with the Src homology 2 domain in the p85 regulatory subunit of P13K, activating the p110 catalytic subunit. One of the P13K-dependent downstream targets, resulting from the antibody cross-linking of CD28, is the phoshporylation and activation of Akt (or PKB). Constitutively active Akt is able to substitute for CD28 signals, and stimulates IL-2 production when introduced into mature CD28-deficient cells. Another molecule affected by CD28 stimulation is the proto-oncogene Vav, which acts as a guanine-nucleotide exchange factor for Rac and CDC42, allowing these molecules to switch from the inactive GDP- bound state to the active GTP-bound state [PMID: 11884439, PMID: 11827987].
Another interesting feature of CD28, is its ability to induce expression of PDE7, a cAMP phosphodiesterase, thus reducing cellular cAMP levels. cAMP has been reported to affect nearly every pathway important for lymphocyte activation, leading to inhibition of T cell proliferation. Specifically, increased intracellular cAMP has been implicated in the induction of T cell anergy, a non-responsive state that occurs after T cells are stimulated through TCR/CD3 in the absence of co-stimulation. This can have therapeutic implications, in that blockage of CD28 co-stimulation can be profoundly immunosuppressive, preventing induction of pathogenic T cell responses in autoimmune disease models, and allowing for prolonged acceptance of allografts in models of organ transplantation [PMID: 11827987].
Finally, CD28 co-stimulation directly controls T cell cycle progression by down-regulating the cdk inhibitor p27kip1, which actually integrates mitogenic MEK and P13K-dependent signals from both TCR and CD28 [PMID: 11884439].
- PR01717 (CD28ANTIGEN)