Unifying concepts in CD28, ICOS and CTLA4 co-receptor signalling

The co-stimulatory receptors CD28, inducible co-stimulatory molecule (ICOS) and cytotoxic T lymphocyte antigen 4 (CTLA4) share a common Tyr-Xaa-Xaa-Met motif for the recruitment of phosphatidylinositol 3-kinase (PI3K), which allows for the membrane recruitment and activation of proteins with pleckstrin-homology domains, such as phosphoinositide-dependent kinase 1 (PDK1), protein kinase B (PKB) and glycogen synthase kinase 3 (GSK3). In turn, this implies a role for co-receptors in events such as cellular metabolism, protein translation and apoptosis.Increasing evidence points to CD28 as a signalling unit that can generate intracellular signals independently of the T-cell receptor (TCR).CD28 also has unique properties that are indicated by the presence of a Tyr-Met-Asn-Met motif and several proline residues. The presence of an Asp residue in the plus two position that is absent in ICOS and CTLA4 allows for the binding of growth-factor receptor-bound protein 2 (GRB2), and possibly the binding of GRB2-related adaptor protein (GADS), connecting the co-receptor to VAV and the up-regulation of JUN N-terminal kinase (JNK).Recent studies have implicated PKB, PKC and members of the membrane-associated guanylate kinase (MAGUK) family in the regulation of nuclear factor-κB (NF-κB) and the inhibitor of NF-κB kinase (IKK) complex by CD28.Although ICOS has a Tyr-Xaa-Xaa-Met motif for the binding of PI3K, it lacks other crucial residues that are found in CD28 and CTLA4 and, as a consequence, has a more limited signalling capacity. PI3K–PKB activation might be insufficient to account for ICOS-mediated upregulation of T helper 2 cytokines.Besides binding to PI3K, CTLA4 also has unique proline residues and a Tyr-Val-Lys-Met site that, in a non-phosphorylated state, binds clathrin adaptor complexes, AP1 and AP2. Present models to account for negative signalling include associated phosphatases SHP2 and PP2A.Despite the complexity of co-receptor signalling, the positive versus negative roles of CD28 and CTLA4 on T-cell function is indicated by the ability of the co-receptors to modulate the release of lipid microdomains or rafts to the surface of cells. This will indirectly increase or limit the availability of signalling proteins, such as linker for activation of T cells (LAT), that are required for TCR signalling.