The role of interleukin-2 during homeostasis and activation of the immune system

Under steady-state resting conditions, interleukin-2 (IL-2) is mainly produced by activated CD4+ T cells in secondary lymphoid organs. The secreted IL-2 is then consumed at the same site by cells that express the IL-2 receptor subunit CD25 (also known as IL-2Rα), notably regulatory T (TReg) cells. During an immune response, activated antigen-specific CD4+ and CD8+ T cells produce large amounts of IL-2, which is then consumed by CD25+ effector T cells and TReg cells.The strength and duration of the IL-2 signal controls both the primary and secondary expansion of antigen-specific CD8+ T cell populations. Suboptimal IL-2 signals during priming lead to reduced primary expansion and severely impaired secondary expansion, whereas exposure to prolonged, strong IL-2 signals during priming generates short-lived terminally differentiated effector CD8+ T cells.IL-2 signals act via signal transducer and activator of transcription 5 (STAT5) and influence the differentiation of T helper (TH) cell subsets (including TH1, TH2 and TH17 cells) as well as the homeostasis of TReg cells. Moreover, similarly to the case of effector CD8+ T cells, strong IL-2 signals drive antigen-specific CD4+ T cells to become short-lived terminally differentiated effector T cells; conversely, low-level IL-2 signals allow effector CD4+ T cells to differentiate into follicular helper or central memory T cells.Activated dendritic cells (DCs) express CD25 on their cell surface for binding either T cell- or DC-derived IL-2, in order to present IL-2 in trans to adjacent effector T cells. This mechanism presumably operates very early during T cell stimulation, before the responding T cells start to express CD25.IL-2 is produced chiefly by activated T cells in secondary lymphoid organs, where it is consumed by these cells and other CD25+ cells, including TReg cells. In addition to cells of the immune system, non-immune cells express CD25 molecules, and these CD25+ cells might contribute to the control of IL-2 homeostasis in peripheral organs.The ability of IL-2 to activate both TReg cells and cytotoxic lymphocytes might be circumvented by using low-dose IL-2 immunotherapy to increase only TReg cell numbers in autoimmunity, chronic inflammatory conditions and graft rejection; conversely, high-dose IL-2 administration might serve to expand cytotoxic lymphocyte populations for the treatment of metastatic cancer. An alternative approach for selective IL-2 immunotherapy would be to use improved IL-2 formulations, such as IL-2 bound to particular IL-2-specific monoclonal antibodies, or IL-2 muteins with increased affinity for CD25 or CD122 (also known as IL-2Rβ).