Insulin-like Growth Factor-1 Synergizes with IL-2 to Induce Homeostatic Proliferation of Regulatory T Cells
Copyright © 2023 by The American Association of Immunologists, Inc..
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.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2023 |
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| Erschienen: |
2023 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:211 |
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| Enthalten in: |
Journal of immunology (Baltimore, Md. : 1950) - 211(2023), 7 vom: 01. Okt., Seite 1108-1122 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Shapiro, Melanie R [VerfasserIn] |
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| Links: |
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| Themen: |
67763-96-6 |
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| Anmerkungen: |
Date Completed 20.09.2023 Date Revised 28.09.2023 published: Print Citation Status MEDLINE |
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| doi: |
10.4049/jimmunol.2200651 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| 520 | |a Copyright © 2023 by The American Association of Immunologists, Inc. | ||
| 520 | |a 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 | ||
| 650 | 4 | |a Journal Article | |
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| 700 | 1 | |a Brown, Matthew E |e verfasserin |4 aut | |
| 700 | 1 | |a Cabello-Kindelan, Cecilia |e verfasserin |4 aut | |
| 700 | 1 | |a Posgai, Amanda L |e verfasserin |4 aut | |
| 700 | 1 | |a Bayer, Allison L |e verfasserin |4 aut | |
| 700 | 1 | |a Brusko, Todd M |e verfasserin |4 aut | |
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