CTLA-4: Acting at the Synapse

Successful immune cell control requires a delicate balance of positive and negative regulatory signals. Costimulatory pathways involving molecules such as CD28, inducible costimulator (ICOS), 4-1BB, and CD40L are essential coactivators of proliferation, cytokine production, and cell migration. To balance these signals, cell surface molecules like Fas, tumor necrosis factor- receptor (TNFR), and programmed death-1 (PD-1) decrease T cell responses. Most prominent among these T cell regulators is cytotoxic T lymphocyte antigen-4 (CTLA-4), a homolog of CD28 that can interact with the CD28 ligands CD80 and CD86 (1). CTLA-4 inhibits T cell responses in a T cell receptor- (TCR)-dependent manner. For example, T cells treated with soluble CTLA-4 monoclonal antibody (mAb) have enhanced T cell proliferation and cytokine production, whereas surface-immobilized CTLA-4 mAb inhibits interleukin-2 (IL-2) production