Trans-presentation: a novel mechanism regulating IL-15 delivery and responses

Interleukin (IL)-15 is a cytokine that acts on a wide range of cell types but is most crucial for the development, homeostasis, and function of a specific group of immune cells that includes CD8 T cells, NK cells, NKT cells, and CD8 alpha alpha intraepithelial lymphocytes. IL-15 signals are transmitted through the IL-2/15R beta and common gamma (gamma C) chains; however, it is the delivery of IL-15 to these signaling components that is quite unique. As opposed to other cytokines that are secreted, IL-15 primarily exists bound to the high affinity IL-15R alpha. When IL-15/IL-15R alpha complexes are shuttled to the cell surface, they can stimulate opposing cells through the beta/gamma C receptor complex. This novel mechanism of IL-15 delivery has been called trans-presentation. This review discusses how the theory of trans-presentation came to be, evidence that it is the major mechanism of action, the current understanding of the cell types thought to mediate trans-presentation, and possible alternatives for IL-15 delivery.