Figure 1
CD28 and cytotoxic T-lymphocyte antigen-4 (CTLA-4) recruit similar and distinct signalling molecules. (a) The unphosphorylated CTLA-4 molecule binds the medium-chain subunit of the clathrin adaptor AP-2. This interaction leads to a rapid internalization of CTLA-4 and tight regulation of surface CTLA-4. CTLA-4 is also able to bind the serine/threonine phosphatase protein phosphatase 2A (PP2A). PP2A seems to act as a negative regulator of CTLA-4 function and dissociates from CTLA-4 upon ligand binding. The ligands are the dimeric CD80 and the monomeric CD86. Binding of CD80 to the divalent CTLA-4 leads to the formation of a lattice-like structure on the cell surface. This pattern formation cannot occur by the interaction of CD86 with CTLA-4. Activation of CTLA-4 by binding to its ligands leads to the phosphorylation of tyrosine residues in the cytoplasmic tail of CTLA-4 and its association with phosphoinositide 3-kinase (PI-3K) and (perhaps indirectly) the tyrosine phosphatase SHP-2. The immediate consequences of these interactions are unclear but eventually lead to an inhibition of T cell activation. This includes decreased raft recruitment to the plasma membrane, decreased phosphorylation of CD3-ζ and ZAP-70, downregulation of mitogen-activated protein kinases such as extracellular signal-related kinase and c-Jun N-terminal kinase, and inhibition of the nuclear translocation of the transcription factors AP-1 and nuclear factor of activated T-cells (NFAT). This results in decreased interleukin (IL)-2 production and cell-cycle arrest. (b) In its unphosphorylated state CD28 binds the serine/threonine phosphatase PP2A. CD28 shares the same ligands, CD80 and CD86, as CTLA-4. However, because CD28 is monovalent it is not able to form higher-order structures after interaction with CD80. The tyrosine phosphorylation of CD28 after stimulation by CD80 or CD86 is followed by the association of PI-3K and Grb-2 to the cytoplasmic tail of CD28. This leads to increased T cell activation, indicated by enhanced raft expression and upregulated production of IL-2. The increased survival is a consequence of upregulated Bcl-XL and the activation of nuclear factor (NF)-κB