Antibodies that block the immune checkpoint receptors PD1 and CTLA4 have revolutionized the treatment of melanoma and several other cancers, but in the process, a new class of drug side effect has emerged—immune related adverse events. The observation that therapeutic blockade of these inhibitory receptors is sufficient to break self-tolerance, highlights their crucial role in the physiological modulation of immune responses. Here, we discuss the rationale for targeting immune checkpoint receptors with agonistic agents in autoimmunity, to restore tolerance when it is lost. We review progress that has been made to date, using Fc-fusion proteins, monoclonal antibodies or other novel constructs to induce immunosuppressive signaling through these pathways. Finally, we explore potential mechanisms by which these receptors trigger and modulate immune cell function, and how understanding these processes might shape the design of more effective therapeutic agents in future.
CD28 and CTLA-4 (CD152) play essential roles in regulating T cell immunity, balancing the activation and inhibition of T cell responses, respectively. Although both receptors share the same ligands, CD80 and CD86, the specific requirement for two distinct ligands remains obscure. In the present study, we demonstrate that, although CTLA-4 targets both CD80 and CD86 for destruction via transendocytosis, this process results in separate fates for CTLA-4 itself. In the presence of CD80, CTLA-4 remained ligand bound, and was ubiquitylated and trafficked via late endosomes and lysosomes. In contrast, in the presence of CD86, CTLA-4 detached in a pH-dependent manner and recycled back to the cell surface to permit further transendocytosis. Furthermore, we identified clinically relevant mutations that cause autoimmune disease, which selectively disrupted CD86 transendocytosis, by affecting either CTLA-4 recycling or CD86 binding. These observations provide a rationale for two distinct ligands and show that defects in CTLA-4-mediated transendocytosis of CD86 are associated with autoimmunity.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.