The biology of interleukin-2 and interleukin-15: implications for cancer therapy and vaccine design

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Abstract
Interleukin-2 (IL-2) and IL-15 have both similar and contrasting functional roles in the life and death of lymphocytes. The heterotrimeric receptors for these cytokines have two subunits in common: IL-2/15Rβ (also known as the IL-2 receptor β-chain (IL-2Rβ) and IL-15Rβ); and the common cytokine-receptor γ-chain (γc). The two cytokine receptors also have distinct α-subunits. In many adaptive immune responses, IL-2 and IL-15 have distinct, and often competing, actions. IL-2 has a role in activation-induced cell death and in maintenance of regulatory T cells. In this way, it is involved in the elimination of self-reactive T cells, which if left unregulated could lead to the development of autoimmune diseases. By contrast, IL-15 is pivotal in the maintenance of long-lasting, high-avidity CD8+ memory T cells that are involved in the elimination of invading pathogens, thereby protecting the host against infection. IL-2 is a secreted cytokine and binds pre-formed heterotrimeric receptors on the surface of activated cells. By contrast, IL-15 is mainly membrane bound, and it induces signalling in the context of cell–cell contact, at the immunological synapse. The unique subunit of the IL-15R, IL-15Rα, presents IL-15 in trans to neighbouring natural killer (NK) cells and CD8+ T cells. IL-15 activates T cells and NK cells and has a role in persistence of CD8+ memory T cells. It therefore might be better than IL-2 for the treatment of cancer and as a component of molecular vaccines against infectious diseases. Because IL-15 activates tumour-necrosis-factor expression and facilitates memory CD8+ T-cell maintenance, dysregulation of IL-15 is associated with a range of autoimmune inflammatory diseases. Therapeutic strategies that inhibit the actions of IL-15 are being developed for the treatment of T-cell-mediated autoimmune inflammatory diseases.