T cell activation is efficient for cellular and humoral immune responses. This process helps the development of high-affinity antibody generation and cytotoxic T cell responses. However, the T cell activation must be tightly controlled to avoid autoimmunity. With the improved understanding of self-tolerance, a series of proteins have been identified to control T cell activation.
CTLA-4 is the transmembrane protein membrane of the immunoglobulin gene superfamily predominantly expressed on activated T cells. On the contrary, CD28 is always found on the surface of resting T cells. The low expression level of CTLA-4 on the cell surface is due to its rapid internalization by a clathrin pit mechanism. There are two natural ligands CD80 and CD86, for CD28/CTLA-4 receptor interactions. They are only approximately 25% identical in sequence and can both interact with CD28/CTAL-4. CD80 and CD86 can be found on various antigen-presenting cells, including monocytes, dendritic cells, and activated B cells. Some studies have shown that CD28 is highly expressed but with low affinity, while CTLA-4 is low abundance but with higher affinity.
It has been proved that blocking CTLA-4 enhances T cell proliferation. It is interesting that both CD28 and CTLA-4 interact with the same ligands but have opposite effects. The most important model showed that low levels of ligands result in stronger competitive binding of CTLA-4 compared to CD28. In addition, CTLA-4 can interfere with TCR-derived signals and block early signaling events. Nowadays, a series of drugs targeting CTLA-4 and CD80/CD86 pathways have been discovered.
Fig.1 A schematic diagram of CD28 and CTLA-4 interactions with their ligands is depicted. (Sansom, 2000)
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