The shared and contrasting roles of IL2 and IL15 in the life and death of normal and neoplastic lymphocytes: implications for cancer therapy

Abstract

IL2 and IL15, members of the 4α-helix bundle family of cytokines, play pivotal roles in the control of the life and death of lymphocytes. Although their heterotrimeric receptors have two receptor subunits in common, these two cytokines have contrasting roles in adaptive immune responses. The unique role of IL2 through maintenance of fitness of regulatory T cells and activation-induced cell death is the elimination of self-reactive T cells to prevent autoimmunity. In contrast with IL2, IL15 is dedicated to the prolonged maintenance of memory T-cell responses to invading pathogens. Blockade of IL2 and IL15 using monoclonal antibodies has been reported to be of value in the treatment of patients with leukemia, autoimmune disorders, and in the prevention of allograft rejection. IL2 has been approved by the FDA for the treatment of patients with malignant renal cell cancer and metastatic malignant melanoma. Clinical trials involving recombinant human IL15 given by bolus infusions have been completed, and studies assessing subcutaneous and continuous intravenous infusions are under way in patients with metastatic malignancy. Furthermore, clinical trials are being initiated that employ the combination of IL15 with IL15Rα(+/-) IgFc.

Figure 1. Mode of interaction of IL2 and IL15 with their receptors

IL2 and IL15 share the common γc and IL2/IL15Rβ chains. Furthermore, the high-affinity forms of IL2R and IL15R contain a third cytokine-specific receptor α subunit, IL2Rα or IL15Rα. IL2 is predominantly a secreted cytokine that binds to preformed high-affinity heterotrimeric receptors. By contrast, IL15 is a membrane-associated molecule that signals at an immunological synapse between antigen-presenting cells and CD8 T cells or NK cells. IL15Rα on the surface of activated monocytes or dendritic cells presents IL15 in trans to cells that express IL2/IL15Rβ and γc, thereby allowing signaling through these complexes.