The Shared and Contrasting Roles of IL2 and IL15 in the Life and Death of Normal and Neoplastic Lymphocytes: Implications for Cancer Therapy

摘要

Abstract IL2 and IL15, members of the 4a-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 IL15Ra+/~ IgFc. Introduction The immune system is dedicated to a series of goals, including the generation of a rapid innate and adaptive immune response to invading pathogens, the elimination of autoreactive T cells to generate tolerance to self, and the maintenance of specific memory responses to pathogens. Such immune responses are normally regulated by cytokines. The cytokines that share the common gamma-chain (yc) among their receptor subunits, including IL2, IL4, IL7, IL9, IL15, and IL21, play dominant roles in the regulation of immune responses (1, 2). IL2 and IL15 have particularly pivotal roles in the control of the life and death of lymphocytes (3). In addition to the common yc, the heterotrimeric receptors for IL2 and IL15 share another subunit referred to as IL2/IL15R|3 (also known as IL2R|3, CD122; refs. 4, 5).