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 allowing for lower IL-2 dosing. We recently reported reduced levels of immunoregulatory insulin-like growth facto...

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Published inThe Journal of immunology (1950) Vol. 211; no. 7; pp. 1108 - 1122
Main Authors Shapiro, Melanie R., Peters, Leeana D., Brown, Matthew E., Cabello-Kindelan, Cecilia, Posgai, Amanda L., Bayer, Allison L., Brusko, Todd M.
Format Journal Article
LanguageEnglish
Published AAI 01.10.2023
Subjects
Immune Regulation
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Summary: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 allowing for lower IL-2 dosing. We recently reported reduced levels of immunoregulatory insulin-like growth factor-1 (IGF1) during type 1 diabetes progression. Thus, we hypothesized that IGF1 would synergize with IL-2 to expand Tregs. We observed IGF1 receptor was elevated on murine memory and human naive Treg subsets. IL-2 and IGF1 promoted PI3K/Akt signaling in Tregs, inducing thymically-derived Treg expansion beyond either agent alone in NOD mice. Increased populations of murine Tregs of naive or memory, as well as CD5lo polyclonal or CD5hi likely self-reactive, status were also observed. Expansion was attributed to increased IL-2Rγ subunit expression on murine Tregs exposed to IL-2 and IGF1 as compared with IL-2 or IGF1 alone. Assessing translational capacity, incubation of naive human CD4+ T cells with IL-2 and IGF1 enhanced thymically-derived Treg proliferation in vitro, without the need for TCR ligation. We then demonstrated that IGF1 and IL-2 or IL-7, which is also IL-2Rγ-chain dependent, can be used to induce proliferation of genetically engineered naive human Tregs or T conventional cells, respectively. These data support the potential use of IGF1 in combination with common γ-chain cytokines to drive homeostatic T cell expansion, both in vitro and in vivo, for cellular therapeutics and ex vivo gene editing.
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M.R.S. designed the studies, conducted experiments, acquired data, analyzed data, acquired funding, and wrote the manuscript; L.D.P. designed the studies, conducted experiments, acquired data, analyzed data, acquired funding, and edited the manuscript/edited the manuscript; M.E.B. designed the studies, conducted experiments, acquired data, analyzed data, and reviewed/edited the manuscript; C.C.-K. conducted experiments, acquired data, and reviewed/edited the manuscript; A.L.P. contributed to discussion and reviewed/edited the manuscript; A.L.B. designed the studies, analyzed data, acquired funding, and reviewed/edited the manuscript; T.M.B. conceptualized the project, designed studies, provided reagents, acquired funding, and reviewed/edited the manuscript.
ISSN:0022-1767
1550-6606
1550-6606
DOI:10.4049/jimmunol.2200651