Interleukin-2: Counteracting pleiotropy by compartmentalization

Interleukin-2 (IL-2) belongs to a series of mediators that are produced by T cells and exert multiple, pleiotropic effects in an autocrine or paracrine fashion. IL-2 plays a fundamental role in the ontogeny of developing T cells in the thymus and supports the growth or effector function of a wide array of immunologically relevant cells, including macrophages and B and NK lymphocytes, as well as a variety of different T-cell subpopulations. Nonetheless, the function of this lymphokine must be highly controlled in vivo to avoid systemic effects that might endanger the specificity of an immune response and result in autoimmune reactions. Accordingly, various mechanisms guarantee compartmentalization of IL-2, that is, chronological and spatial restriction of IL-2 production, bioavailability, and state of responsiveness. The secretion of IL-2, as well as the expression of the two components of the high-affinity IL-2 receptor (IL-2R), are developmentally controlled during ontogeny and, within the cellular immune system, are restricted to defined pre- and intrathymic stages of immature T cells or T-cell precursors. In the peripheral lymphoid organs, IL-2 is produced by a defined population of mature CD4⁺ T lymphocytes in which the IL-2 gene is transcribed or silenced, depending on the combination of antigenic and nonspecific activation signals to which the cell is exposed. Thus, the absence of certain costimulatory signals leads to a long-lasting inactivation of the IL-2 gene, a phenomenon that accompanies nondeletional T-cell tolerance. IL-2 has a short half-life and is secreted in apposition to the cell with which the T cell interacts. Expression of the high-affinity IL-2R is activation-dependent in most cell types. Thus, different mechanisms, intervening in all compartments relevant for the action of IL-2, together contribute to a restriction of IL-2 effects, conferring a relative specificity to this pleiotropic mediator.