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Proximity-enabled covalent binding of IL-2 to IL-2Rα selectively activates regulatory T cells and suppresses autoimmunity

Interleukin-2 (IL-2) is a pleiotropic cytokine that orchestrates bidirectional immune responses via regulatory T cells (Tregs) and effector cells, leading to paradoxical consequences. Here, we report a strategy that exploited genetic code expansion-guided incorporation of the latent bioreactive arti...

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Autores principales: Zhang, Bo, Sun, Jiaqi, Yuan, Yeshuang, Ji, Dezhong, Sun, Yeting, Liu, Yudong, Li, Shengjie, Zhu, Xingxing, Wu, Xunyao, Hu, Jin, Xie, Qiu, Wu, Ling, Liu, Lulu, Cheng, Boyang, Zhang, Yuanjie, Jiang, Lingjuan, Zhao, Lidan, Yu, Fei, Song, Wei, Wang, Min, Xu, Yue, Ma, Shiliang, Fei, Yunyun, Zhang, Lihe, Zhou, Demin, Zhang, Xuan
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9871032/
https://www.ncbi.nlm.nih.gov/pubmed/36690610
http://dx.doi.org/10.1038/s41392-022-01208-3
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author Zhang, Bo
Sun, Jiaqi
Yuan, Yeshuang
Ji, Dezhong
Sun, Yeting
Liu, Yudong
Li, Shengjie
Zhu, Xingxing
Wu, Xunyao
Hu, Jin
Xie, Qiu
Wu, Ling
Liu, Lulu
Cheng, Boyang
Zhang, Yuanjie
Jiang, Lingjuan
Zhao, Lidan
Yu, Fei
Song, Wei
Wang, Min
Xu, Yue
Ma, Shiliang
Fei, Yunyun
Zhang, Lihe
Zhou, Demin
Zhang, Xuan
author_facet Zhang, Bo
Sun, Jiaqi
Yuan, Yeshuang
Ji, Dezhong
Sun, Yeting
Liu, Yudong
Li, Shengjie
Zhu, Xingxing
Wu, Xunyao
Hu, Jin
Xie, Qiu
Wu, Ling
Liu, Lulu
Cheng, Boyang
Zhang, Yuanjie
Jiang, Lingjuan
Zhao, Lidan
Yu, Fei
Song, Wei
Wang, Min
Xu, Yue
Ma, Shiliang
Fei, Yunyun
Zhang, Lihe
Zhou, Demin
Zhang, Xuan
author_sort Zhang, Bo
collection PubMed
description Interleukin-2 (IL-2) is a pleiotropic cytokine that orchestrates bidirectional immune responses via regulatory T cells (Tregs) and effector cells, leading to paradoxical consequences. Here, we report a strategy that exploited genetic code expansion-guided incorporation of the latent bioreactive artificial amino acid fluorosulfate-L-tyrosine (FSY) into IL-2 for proximity-enabled covalent binding to IL-2Rα to selectively promote Treg activation. We found that FSY-bearing IL-2 variants, such as L72-FSY, covalently bound to IL-2Rα via sulfur-fluoride exchange when in proximity, resulting in persistent recycling of IL-2 and selectively promoting the expansion of Tregs but not effector cells. Further assessment of L72-FSY-expanded Tregs demonstrated that L72-FSY maintained Tregs in a central memory phenotype without driving terminal differentiation, as demonstrated by simultaneously attenuated expression of lymphocyte activation gene-3 (LAG-3) and enhanced expression of programmed cell death protein-1 (PD-1). Subcutaneous administration of L72-FSY in murine models of pristane-induced lupus and graft-versus-host disease (GvHD) resulted in enhanced and sustained therapeutic efficacy compared with wild-type IL-2 treatment. The efficacy of L72-FSY was further improved by N-terminal PEGylation, which increased its circulatory retention for preferential and sustained effects. This proximity-enabled covalent binding strategy may accelerate the development of pleiotropic cytokines as a new class of immunomodulatory therapies.
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spelling pubmed-98710322023-01-25 Proximity-enabled covalent binding of IL-2 to IL-2Rα selectively activates regulatory T cells and suppresses autoimmunity Zhang, Bo Sun, Jiaqi Yuan, Yeshuang Ji, Dezhong Sun, Yeting Liu, Yudong Li, Shengjie Zhu, Xingxing Wu, Xunyao Hu, Jin Xie, Qiu Wu, Ling Liu, Lulu Cheng, Boyang Zhang, Yuanjie Jiang, Lingjuan Zhao, Lidan Yu, Fei Song, Wei Wang, Min Xu, Yue Ma, Shiliang Fei, Yunyun Zhang, Lihe Zhou, Demin Zhang, Xuan Signal Transduct Target Ther Article Interleukin-2 (IL-2) is a pleiotropic cytokine that orchestrates bidirectional immune responses via regulatory T cells (Tregs) and effector cells, leading to paradoxical consequences. Here, we report a strategy that exploited genetic code expansion-guided incorporation of the latent bioreactive artificial amino acid fluorosulfate-L-tyrosine (FSY) into IL-2 for proximity-enabled covalent binding to IL-2Rα to selectively promote Treg activation. We found that FSY-bearing IL-2 variants, such as L72-FSY, covalently bound to IL-2Rα via sulfur-fluoride exchange when in proximity, resulting in persistent recycling of IL-2 and selectively promoting the expansion of Tregs but not effector cells. Further assessment of L72-FSY-expanded Tregs demonstrated that L72-FSY maintained Tregs in a central memory phenotype without driving terminal differentiation, as demonstrated by simultaneously attenuated expression of lymphocyte activation gene-3 (LAG-3) and enhanced expression of programmed cell death protein-1 (PD-1). Subcutaneous administration of L72-FSY in murine models of pristane-induced lupus and graft-versus-host disease (GvHD) resulted in enhanced and sustained therapeutic efficacy compared with wild-type IL-2 treatment. The efficacy of L72-FSY was further improved by N-terminal PEGylation, which increased its circulatory retention for preferential and sustained effects. This proximity-enabled covalent binding strategy may accelerate the development of pleiotropic cytokines as a new class of immunomodulatory therapies. Nature Publishing Group UK 2023-01-23 /pmc/articles/PMC9871032/ /pubmed/36690610 http://dx.doi.org/10.1038/s41392-022-01208-3 Text en © The Author(s) 2022 https://creativecommons.org/licenses/by/4.0/Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) .
spellingShingle Article
Zhang, Bo
Sun, Jiaqi
Yuan, Yeshuang
Ji, Dezhong
Sun, Yeting
Liu, Yudong
Li, Shengjie
Zhu, Xingxing
Wu, Xunyao
Hu, Jin
Xie, Qiu
Wu, Ling
Liu, Lulu
Cheng, Boyang
Zhang, Yuanjie
Jiang, Lingjuan
Zhao, Lidan
Yu, Fei
Song, Wei
Wang, Min
Xu, Yue
Ma, Shiliang
Fei, Yunyun
Zhang, Lihe
Zhou, Demin
Zhang, Xuan
Proximity-enabled covalent binding of IL-2 to IL-2Rα selectively activates regulatory T cells and suppresses autoimmunity
title Proximity-enabled covalent binding of IL-2 to IL-2Rα selectively activates regulatory T cells and suppresses autoimmunity
title_full Proximity-enabled covalent binding of IL-2 to IL-2Rα selectively activates regulatory T cells and suppresses autoimmunity
title_fullStr Proximity-enabled covalent binding of IL-2 to IL-2Rα selectively activates regulatory T cells and suppresses autoimmunity
title_full_unstemmed Proximity-enabled covalent binding of IL-2 to IL-2Rα selectively activates regulatory T cells and suppresses autoimmunity
title_short Proximity-enabled covalent binding of IL-2 to IL-2Rα selectively activates regulatory T cells and suppresses autoimmunity
title_sort proximity-enabled covalent binding of il-2 to il-2rα selectively activates regulatory t cells and suppresses autoimmunity
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9871032/
https://www.ncbi.nlm.nih.gov/pubmed/36690610
http://dx.doi.org/10.1038/s41392-022-01208-3
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