The role of the PD‐1 pathway in autoimmunity and peripheral tolerance

Programmed death‐1 (PD‐1) is a surface receptor critical for the regulation of T cell function during immunity and tolerance. PD‐1 interactions with its ligands PD‐L1 and PD‐L2 inhibit T cell effector functions in an antigen‐specific manner. This paper examines the role of PD‐1 in limiting autoreactivity and establishing self‐tolerance and discusses the hypothesis that PD‐1 ligand (PD‐L) expression both spatially and temporally dictates the fate of self‐reactive T cells during the breakdown of peripheral tolerance and development of autoimmunity. We focus our discussion on the role of PD‐1/PD‐L interactions during peripheral tolerance, the differential role for PD‐L1 and PD‐L2 in response to environmental or self‐antigens, and the impact of PD‐1 signaling on dynamic T cell motility and the T cell receptor (TCR) stop signal. Finally, we discuss the potential to selectively target the PD‐1 pathway therapeutically to alter T cell function during autoimmunity.