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

Abstract

IL-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 naive 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 naive human CD4+ T cells with IL-2 and IGF1 enhanced Treg proliferation in vitro, without the need for T cell receptor ligation. This synergism was attributed to increased high-affinity IL-2R expression on naive Tregs, in contrast to intermediate-affinity IL-2R{beta} and IL-2R{gamma} subunit enhancement on naive conventional T cells (Tconv). We then demonstrated that IGF1 and IL-2 or the IL2R{gamma}-chain-dependent cytokine, IL-7, can be used to induce proliferation of genetically-engineered naive Treg or Tconv cells, respectively. These data support the potential use of IGF1 in combination with common {gamma}-chain cytokines to drive T cell expansions both in vitro and in vivo for cellular therapeutics and genetic modifications.