Sustained in vivo signaling by long-lived IL-2 induces prolonged increases of regulatory T cells
Bell, Charles JM
Nowak, Urszula M
Hosse, Ralf J
Journal of Autoimmunity
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Bell, C. J., Sun, Y., Nowak, U. M., Clark, J., Howlett, S., Pekalski, M., Yang, X., et al. (2014). Sustained in vivo signaling by long-lived IL-2 induces prolonged increases of regulatory T cells. Journal of Autoimmunity, 56 66-80. https://doi.org/10.1016/j.jaut.2014.10.002
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-FcRγ 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.
Cytokine therapy, Autoimmunity, Graft vs Host Disease, IL-2 fusion proteins, Regulatory T cells
This work was supported by Wellcome Trust Grant 091157, JDRF International Grant 9-2011-253, the National Institute for Health Research Cambridge Biomedical Research Centre, and the Medical Research Council Cusrow Wadia Fund. The Cambridge Institute for Medical Research (CIMR) is in receipt of a Wellcome Trust Strategic Award (100140). U.M.N. was the recipient of a Hoffmann-La Roche postdoctoral fellowship.
Wellcome Trust (100140/Z/12/Z)
Wellcome Trust (091157/Z/10/B)
External DOI: https://doi.org/10.1016/j.jaut.2014.10.002
This record's URL: https://www.repository.cam.ac.uk/handle/1810/246183
Attribution 2.0 UK: England & Wales
Licence URL: http://creativecommons.org/licenses/by/2.0/uk/