T细胞
生物
PI3K/AKT/mTOR通路
细胞生物学
免疫学
记忆T细胞
T细胞受体
白细胞介素15
生长因子
癌症研究
信号转导
受体
细胞因子
白细胞介素
免疫系统
遗传学
作者
Melanie R. Shapiro,Leeana D. Peters,Megan Brown,Cecilia Cabello-Kindelan,Amanda L. Posgai,Allison L. Bayer,Todd M. Brusko
出处
期刊:Journal of Immunology
[The American Association of Immunologists]
日期:2023-08-18
卷期号:211 (7): 1108-1122
被引量:3
标识
DOI:10.4049/jimmunol.2200651
摘要
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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