Parallel costimulation of effector and regulatory T cells by OX40, GITR, TNFRSF25, CD27, and CD137: Implications for cancer immunotherapy

Abstract

Adaptive immune responses are triggered by antigen presenting cells that display particular antigens in the context of MHC molecules and in the presence of appropriate costimulatory molecules. These costimulatory molecules are diverse, and include members of the Immunoglobulin (Ig) and TNF receptor superfamilies. In general, costimulatory molecules are induced by innate immune stimuli and their expression is transient, signaling the presence of a potential threat. The presence of costimulatory molecules is critical to overcome the predominance of inhibitory immune signals needed to initiate an adaptive immune response. TNF receptor superfamily molecules are particularly important for the fine-tuning of adaptive immune responses, and often have dual effects toward both effector and regulatory T cells. Five of the better studied effector T cell costimulators: 4-1BB, GITR, OX40, TNFRSF25, and CD27, can all augment effector and regulatory T cell biology in unique ways. An understanding of how these pathways are similar, and where they diverge, may facilitate the clinical development of receptor agonists for use in cancer immunotherapy.