| Primary Identifier | IPR008093 | Type | Family |
| Short Name | CD28 |
| description | Antigen (Ag) recognition by the T cell receptor (TCR) induces activation ofT lymphocytes. However, TCR-mediated signals alone are insufficient forefficient 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 themajority of human peripheral T cells and lymphocytes. Stimulation of CD4+ Tcells 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 apoptosisof activated T cells, suggesting its importance in regulating long-term T cell survival [, , , ].Ligands for CD28 and the structurally related CTLA-4 (CD152) are themolecules B7.1 (CD80) and B7.2 (CD86). B7.1 and B7.2 are expressed onprofessional antigen presenting cells (APCs) and their expression is up-regulated during an immune response. Ligation of CD28 by its natural ligandsresults in tyrosine phosphorylation at a YMNM motif within its cytoplasmictail. The phosphorylated motif subsequently interacts with the Src homology2 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 substitutefor CD28 signals, and stimulates IL-2 production when introduced into matureCD28-deficient cells. Another molecule affected by CD28 stimulation is theproto-oncogene Vav, which acts as a guanine-nucleotide exchange factor forRac and CDC42, allowing these molecules to switch from the inactive GDP-bound state to the active GTP-bound state [, ].Another interesting feature of CD28, is its ability to induce expression ofPDE7, a cAMP phosphodiesterase, thus reducing cellular cAMP levels. cAMP hasbeen reported to affect nearly every pathway important for lymphocyteactivation, leading to inhibition of T cell proliferation. Specifically,increased intracellular cAMP has been implicated in the induction of T cellanergy, a non-responsive state that occurs after T cells are stimulatedthrough TCR/CD3 in the absence of co-stimulation. This can have therapeutic implications, in that blockage of CD28 co-stimulation can be profoundlyimmunosuppressive, preventing induction of pathogenic T cell responses inautoimmune disease models, and allowing for prolonged acceptance of allografts in models of organ transplantation []. Finally, CD28 co-stimulation directly controls T cell cycle progression by down-regulating the cdk inhibitor p27kip1, which actually integratesmitogenic MEK and P13K-dependent signals from both TCR and CD28 []. |
