Insulin-like Growth Factor-1 Synergizes with IL-2 to Induce Homeostatic Proliferation of Regulatory T cells

Abstract

ABSTRACTIL-2 has been proposed to restore tolerance via regulatory T cell (Treg) expansion in autoimmunity, yet off-target effects necessitate identification of a combinatorial approach. We recently reported reduced levels of immunoregulatory insulin-like growth factor-1 (IGF1) during type 1 diabetes (T1D) progression. Thus, we hypothesized that IGF1 would synergize with IL-2 to expand Tregs. We observed IGF1R was elevated on murine memory and human naïve Treg subsets. IL-2 and IGF1 promoted murine PI3K/Akt and human STAT5 signaling in Tregs. IL-2 and IGF1 treatment expanded Tregs beyond either agent alone in NOD mice. Incubation of naïve human CD4+T cells with IL-2 and IGF1 enhanced Treg proliferationin vitro, without the need for T cell receptor ligation. This synergism was attributed to increased high-affinity IL-2Rα expression on naïve Tregs, in contrast to intermediate-affinity IL-2Rβ and IL-2Rγ subunit enhancement on naïve conventional T cells (Tconv). We then demonstrated that IGF1 and IL-2 or the IL2Rγ-chain-dependent cytokine, IL-7, can be used to induce proliferation of genetically-engineered naïve Treg or Tconv cells, respectively. These data support the potential use of IGF1 in combination with common γ-chain cytokines to drive T cell expansions bothin vitroandin vivofor cellular therapeutics and genetic modifications.