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Sustained in vivo signaling by long-lived IL-2 induces prolonged increases of regulatory T cells.

ABSTRACT: Regulatory T cells (Tregs) expressing FOXP3 are essential for the maintenance of self-tolerance and are deficient in many common autoimmune diseases. Immune tolerance is maintained in part by IL-2 and deficiencies in the IL-2 pathway cause reduced Treg function and an increased risk of autoimmunity. Recent studies expanding Tregs in vivo with low-dose IL-2 achieved major clinical successes highlighting the potential to optimize this pleiotropic cytokine for inflammatory and autoimmune disease indications. Here we compare the clinically approved IL-2 molecule, Proleukin, with two engineered IL-2 molecules with long half-lives owing to their fusion in monovalent and bivalent stoichiometry to a non-FcR? binding human IgG1. Using nonhuman primates, we demonstrate that single ultra-low doses of IL-2 fusion proteins induce a prolonged state of in vivo activation that increases Tregs for an extended period of time similar to multiple-dose Proleukin. One of the common pleiotropic effects of high dose IL-2 treatment, eosinophilia, is eliminated at doses of the IL-2 fusion proteins that greatly expand Tregs. The long half-lives of the IL-2 fusion proteins facilitated a detailed characterization of an IL-2 dose response driving Treg expansion that correlates with increasingly sustained, suprathreshold pSTAT5a induction and subsequent sustained increases in the expression of CD25, FOXP3 and Ki-67 with retention of Treg-specific epigenetic signatures at FOXP3 and CTLA4.

SUBMITTER: Bell CJ

PROVIDER: S-EPMC4298360 | biostudies-literature | 2015 Jan

REPOSITORIES: biostudies-literature

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Sustained in vivo signaling by long-lived IL-2 induces prolonged increases of regulatory T cells.

Bell Charles J M CJ Sun Yongliang Y Nowak Urszula M UM Clark Jan J Howlett Sarah S Pekalski Marcin L ML Yang Xin X Ast Oliver O Waldhauer Inja I Freimoser-Grundschober Anne A Moessner Ekkehard E Umana Pablo P Klein Christian C Hosse Ralf J RJ Wicker Linda S LS Peterson Laurence B LB

Journal of autoimmunity 20141030

Regulatory T cells (Tregs) expressing FOXP3 are essential for the maintenance of self-tolerance and are deficient in many common autoimmune diseases. Immune tolerance is maintained in part by IL-2 and deficiencies in the IL-2 pathway cause reduced Treg function and an increased risk of autoimmunity. Recent studies expanding Tregs in vivo with low-dose IL-2 achieved major clinical successes highlighting the potential to optimize this pleiotropic cytokine for inflammatory and autoimmune disease in ...[more]

PMID: 25457307

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Sustained in vivo signaling by long-lived IL-2 induces prolonged increases of regulatory T cells.

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Sustained in vivo signaling by long-lived IL-2 induces prolonged increases of regulatory T cells.

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