Revisiting IL-2: Biology and therapeutic prospects

Interleukin-2 (IL-2), the first cytokine that was molecularly cloned, was shown to be a T cell growth factor essential for the proliferation of T cells and the generation of effector and memory cells. On the basis of this activity, the earliest therapeutic application of IL-2 was to boost immune responses in cancer patients. Therefore, it was a surprise that genetic deletion of the cytokine or its receptor led not only to the expected immune deficiency but also to systemic autoimmunity and lymphoproliferation. Subsequent studies established that IL-2 is essential for the maintenance of Foxp3⁺ regulatory T cells (T_reg cells), and in its absence, there is a profound deficiency of T_reg cells and resulting autoimmunity. We now know that IL-2 promotes the generation, survival, and functional activity of T_reg cells and thus has dual and opposing functions: maintaining T_reg cells to control immune responses and stimulating conventional T cells to promote immune responses. It is well documented that certain IL-2 conformations result in selective targeting of T_reg cells by increasing reliance on CD25 binding while compromising CD122 binding. Recent therapeutic strategies have emerged to use IL-2, monoclonal antibodies to IL-2, or IL-2 variants to boost T_reg cell numbers and function to treat autoimmune diseases while dealing with the continuing challenges to minimize the generation of effector and memory cells, natural killer cells, and other innate lymphoid populations.