The IL-2 SYNTHORIN molecule promotes functionally adapted Tregs in a preclinical model of type 1 diabetes.

IF 6.3 1区 医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL
Fernando Alvarez, Nicole V Acuff, Glenn M La Muraglia, Nazila Sabri, Marcos E Milla, Jill M Mooney, Matthew F Mackey, Mark Peakman, Ciriaco A Piccirillo
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引用次数: 0

Abstract

Deficits in IL-2 signaling can precipitate autoimmunity by altering the function and survival of FoxP3+ regulatory T cells (Tregs) while high concentrations of IL-2 fuel inflammatory responses. Recently, we showed that the non-beta IL-2 SYNTHORIN molecule SAR444336 (SAR'336) can bypass the induction of autoimmune and inflammatory responses by increasing its reliance on IL-2 receptor α chain subunit (CD25) to provide a bona fide IL-2 signal selectively to Tregs, making it an attractive approach for the control of autoimmunity. In this report, we further demonstrate that SAR'336 can support non-beta IL-2 signaling in murine Tregs and limit NK and CD8+ T cells' proliferation and function. Using a murine model of spontaneous type 1 diabetes, we showed that the administration of SAR'336 slows the development of disease in mice by decreasing the degree of insulitis through the expansion of antigen-specific Tregs over Th1 cells in pancreatic islets. Specifically, SAR'336 promoted the differentiation of IL-33-responsive (ST2+), IL-10-producing GATA3+ Tregs over other Treg subsets in the pancreas, demonstrating the ability of this molecule to further orchestrate Treg adaptation. These results offer insight into the capacity of SAR'336 to generate highly specialized, tissue-localized Tregs that promote restoration of homeostasis during ongoing autoimmune disease.

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来源期刊
JCI insight
JCI insight Medicine-General Medicine
CiteScore
13.70
自引率
1.20%
发文量
543
审稿时长
6 weeks
期刊介绍: JCI Insight is a Gold Open Access journal with a 2022 Impact Factor of 8.0. It publishes high-quality studies in various biomedical specialties, such as autoimmunity, gastroenterology, immunology, metabolism, nephrology, neuroscience, oncology, pulmonology, and vascular biology. The journal focuses on clinically relevant basic and translational research that contributes to the understanding of disease biology and treatment. JCI Insight is self-published by the American Society for Clinical Investigation (ASCI), a nonprofit honor organization of physician-scientists founded in 1908, and it helps fulfill the ASCI's mission to advance medical science through the publication of clinically relevant research reports.
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