CD28 costimulation and checkpoint inhibition in T cells

Background The induction of protective T cell responses requires two signals: Signal 1 is generated by activation of the T cell receptor (TCR) and signal 2 results from ligation of the CD28 molecule. Costimulation of the TCR and CD28 is necessary, as the TCR is very good at discriminating between endogenous and foreign structures (antigens), but not all foreign antigens (such as food antigens) are dangerous to the body. A strong CD28 signal, thus, indicates to the T cell that there is indeed a threat and that an immune response is urgently required. However, to avoid autoimmunity and excessive immune responses, further regulatory circuits, provided by immune checkpoints, are necessary. Objectives To provide an introduction to immunoregulation mediated by checkpoint molecules. Materials and methods Review of basic science papers and reports on clinical studies. Results The most prominent and best characterized checkpoint molecules, cytotoxic T lymphocyte-associated protein-4 (CTLA-4) and programmed cell death-1 (PD-1), both physiologically dampen CD28-mediated costimulation. Pathologically, malignancies exploit the immunoregulatory function of checkpoint molecules by, for example, expressing ligands for PD-1 on the cell surface, thus, avoiding being attacked by T cells. Our understanding of these negative feedback regulations has led to the development of checkpoint inhibitors, which have already become part of routine clinical care of cancer patients. Conclusions Due to the clinical success of checkpoint inhibitors, the concept of cancer immunotherapy has received a massive boost and hopes are high that many more clinical advancements in cancer therapy can be achieved with novel forms of immunotherapy.