![]() These signals result in the activation of transcription factors such as NF-κB and AP-1, which are important in functional outcomes including IL-2 production and T cell survival. Co-stimulatory signals from the CD28 cytoplasmic tail result from interactions with a number of signaling molecules including the p85 subunit of PI3 kinase, the Src family kinase Lck, IL-2 inducible family kinase Itk, protein kinase C theta and adaptor proteins such as Grb2 and GADS 13 – 16. CD28 is the archetypal co-stimulatory molecule involved in the activation of T cells upon binding to either CD80 or CD86. Perhaps the most surprising feature of CD28 and CTLA-4 is that whilst they share the same ligands, they have opposing functions. Thus, at present, differences between the two ligands revolve mostly around different expression patterns, whereas clear functional distinctions have yet to emerge. Human peripheral blood monocytes express CD86 and not CD80, whereas some human T cells can express both CD80 and CD86 under different conditions of activation 11, 12. In contrast CD80 is thought to be upregulated later by DC. There is considerable variation in ligand expression making generalisation difficult, CD86 is often expressed constitutively on dendritic cells (DC) and is induced to high levels following inflammatory stimuli. Knockout mice show impaired immune responses consistent with reduced CD28 co-stimulation, with CD86 deficiency arguably demonstrating a more severe phenotype 9. Both ligands are found on antigen presenting cells such as dendritic cells and B cells, although they have different expression patterns, inducibility and kinetics 8 – 10. Whilst the biophysical characteristics of CD80 and CD86 are well defined, their functional differences are less clear and the ligands are often referred to together as B7 molecules or CD80/CD86. LRBA may mediate recycling of CTLA-4 to the plasma membrane, whereas AP1 may mediate CTLA-4 trafficking to lysosomal compartments resulting in subsequent degradation. LRBA and AP1 proteins have also been found to bind to the YVKM motif on CTLA-4, which appear to impose different fates on CTLA-4. The AP2 (μ2 subunit) binds to the tyrosine-based (YVKM) motif of the cytoplasmic domain of CTLA-4 and mediates rapid internalization. In the absence of the ligand, CTLA-4 is mainly found in intracellular compartments following clathrin-mediated endocytosis mediated through CTLA-4 interaction with the AP2 molecule. CTLA-4 is constitutively expressed in Treg or induced following T cell activation via CD28 and TCR signaling. ( B) CTLA-4 expressed in T-cells is highly endocytic. The relative affinities go from high to low from left to right. CTLA-4 has a higher affinity and avidity for CD80 than CD86. CD80 is a dimeric high affinity ligand and CD86 is a monomeric lower affinity ligand for both receptors. ( A) CTLA-4 and CD28 receptors share two ligands CD80 and CD86. These interactions are thought to take place at the immune synapse between T cells and APCs where CTLA-4 has been shown to recruit CD80 thereby limiting its interactions with CD28 6, 7. Amongst several possibilities, this raises the concept that CTLA-4 can compete with CD28 for ligand binding and thereby act as an antagonist of CD28-mediated co-stimulation 4, 5. CTLA-4 interacts with both ligands with higher affinity and avidity than CD28 1 – 3 with CTLA-4-CD80 forming the highest avidity interaction and CD28-CD86 the weakest ( Figure 1A). In contrast, interactions of the ligands with CTLA-4 serve to inhibit T cell responses, although the precise mechanisms are not fully understood. CD28 interacts with the CD80 dimer with relatively high affinity and the CD86 monomer with lower affinity, mediating T cell co-stimulation in conjunction with T cell receptor (TCR) signals. Both receptors share a pair of ligands expressed on the surface of antigen presenting cells (APCs). ![]() CTLA-4 and CD28 share two ligands, CD80 and CD86Ĭytotoxic T Lymphocyte antigen 4 (CTLA-4) (CD152) and CD28 are homologous receptors expressed by both CD4 + and CD8 + T cells, which mediate opposing functions in T cell activation. ![]()
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