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Delivering IL-2 to Tregs
Interleukin-2 (IL-2) not only promotes activation and expansion of conventional T cells but also plays a crucial role in regulating homeostasis and functions of regulatory T (Treg) cells. As expression of the high-affinity IL-2 receptor is largely restricted to Treg cells, engineering IL-2 variants, called muteins, that selectively bind to the high-affinity IL-2 receptor and potentiate Treg functions can be used in the treatment of autoimmune diseases. Here, Khoryati et al. have engineered a murine IL-2 mutein that selectively promotes expansion of Treg cells. They demonstrate that administration of this IL-2 mutein resolved ongoing diabetes in nonobese diabetic mice. This proof-of-principle study raises the possibility that engineered human IL-2 muteins could be used in the treatment of autoimmune diseases.
Abstract
Interleukin-2 (IL-2) controls the homeostasis and function of regulatory T (Treg) cells, and defects in the IL-2 pathway contribute to multiple autoimmune diseases. Although recombinant IL-2 therapy has been efficacious in certain inflammatory conditions, the capacity for IL-2 to also activate inflammatory effector responses highlights the need for IL-2–based therapeutics with improved Treg cell specificity. From a panel of rationally designed murine IL-2 variants, we identified IL-2 muteins with reduced potency and enhanced Treg cell selectivity due to increased dependence on the IL-2 receptor component CD25. As an Fc-fused homodimer, the optimal Fc.IL-2 mutein induced selective Treg cell enrichment and reduced agonism of effector cells across a wide dose range. Furthermore, despite being a weaker agonist, overall Treg cell growth was greater and more sustained due to reduced receptor-mediated clearance of the Fc.IL-2 mutein compared with Fc-fused wild-type IL-2. Preferential Treg cell enrichment was also observed in the presence of activated pathogenic T cells in the pancreas of nonobese diabetic (NOD) mice, despite a loss of Treg cell selectivity in an IL-2R proximal response. These properties facilitated potent and extended resolution of NOD diabetes with infrequent dosing schedules.
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