A Receptor-Clamped IL-2 Uncouples Treg Expansion from Injection Site Reactions

Low-dose interleukin-2 (IL-2) and IL-2 muteins are being developed to expand regulatory T cells (Tregs) as therapies for autoimmune diseases, but IL-2 mediated injection site reactions (ISRs) remain frequent and poorly understood. Here we show IL2Mut24, a murine surrogate of IL-2 mutein with reduced CD122 binding and extended half-life, robustly promotes Treg expansion yet causes more severe ISRs than wild-type IL-2. Through studies using immune-deficient mice, antibody blockade, and adoptive transfers, we identify CD25⁺ group 2 innate lymphoid cells (ILC2s) as key ISR mediators and sufficient to trigger ISR. To address safety, we engineered anti-CD25–IL2Mut24 fusion proteins (“receptor clamps”) with graded CD25 antagonism. This approach reveals an optimal window that preserves Treg selectivity, suppresses ISRs, and outperforms IL2Mut24 in experimental autoimmune encephalomyelitis. These findings uncover cellular basis of IL-2-induced ISRs and support the development of receptor-tuned IL-2 fusion proteins as a next-generation therapeutic strategy for autoimmune diseases.