Antibodies to Interleukin-2 Elicit Selective T Cell Subset Potentiation through Distinct Conformational Mechanisms

Interleukin-2 (IL-2) is a pleiotropic cytokine that regulates immune cell homeostasis and has been used to treat a range of disorders including cancer and autoimmune disease. IL-2 signals via interleukin-2 receptor-beta (IL-2R beta):IL-2R gamma heterodimers on cells expressing high (regulatory T cells, Treg) or low (effector cells) amounts of IL-2R alpha (CD25). When complexed with IL-2, certain anti-cytokine antibodies preferentially stimulate expansion of Treg (JES6-1) or effector (S4B6) cells, offering a strategy for targeted disease therapy. We found that JES6-1 sterically blocked the IL-2:IL-2R beta and IL-2:IL-2Rg interactions, but also allosterically lowered the IL-2:IL-2R alpha affinity through a triggered exchange'' mechanism favoring IL-2R alpha hi Treg cells, creating a positive feedback loop for IL-2R alpha hi cell activation. Conversely, S4B6 sterically blocked the IL-2:IL-2R alpha interaction, while also conformationally stabilizing the IL-2:IL-2R beta interaction, thus stimulating all IL-2-responsive immune cells, particularly IL-2R beta hi effector cells. These insights provide a molecular blueprint for engineering selectively potentiating therapeutic antibodies.