Cargando…
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...
Autores principales: | , , , , , , , , , , , , , , , , , , , , , , , , , |
---|---|
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 |
_version_ | 1784877091370565632 |
---|---|
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. |
format | Online Article Text |
id | pubmed-9871032 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2023 |
publisher | Nature Publishing Group UK |
record_format | MEDLINE/PubMed |
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 |
work_keys_str_mv | AT zhangbo proximityenabledcovalentbindingofil2toil2raselectivelyactivatesregulatorytcellsandsuppressesautoimmunity AT sunjiaqi proximityenabledcovalentbindingofil2toil2raselectivelyactivatesregulatorytcellsandsuppressesautoimmunity AT yuanyeshuang proximityenabledcovalentbindingofil2toil2raselectivelyactivatesregulatorytcellsandsuppressesautoimmunity AT jidezhong proximityenabledcovalentbindingofil2toil2raselectivelyactivatesregulatorytcellsandsuppressesautoimmunity AT sunyeting proximityenabledcovalentbindingofil2toil2raselectivelyactivatesregulatorytcellsandsuppressesautoimmunity AT liuyudong proximityenabledcovalentbindingofil2toil2raselectivelyactivatesregulatorytcellsandsuppressesautoimmunity AT lishengjie proximityenabledcovalentbindingofil2toil2raselectivelyactivatesregulatorytcellsandsuppressesautoimmunity AT zhuxingxing proximityenabledcovalentbindingofil2toil2raselectivelyactivatesregulatorytcellsandsuppressesautoimmunity AT wuxunyao proximityenabledcovalentbindingofil2toil2raselectivelyactivatesregulatorytcellsandsuppressesautoimmunity AT hujin proximityenabledcovalentbindingofil2toil2raselectivelyactivatesregulatorytcellsandsuppressesautoimmunity AT xieqiu proximityenabledcovalentbindingofil2toil2raselectivelyactivatesregulatorytcellsandsuppressesautoimmunity AT wuling proximityenabledcovalentbindingofil2toil2raselectivelyactivatesregulatorytcellsandsuppressesautoimmunity AT liululu proximityenabledcovalentbindingofil2toil2raselectivelyactivatesregulatorytcellsandsuppressesautoimmunity AT chengboyang proximityenabledcovalentbindingofil2toil2raselectivelyactivatesregulatorytcellsandsuppressesautoimmunity AT zhangyuanjie proximityenabledcovalentbindingofil2toil2raselectivelyactivatesregulatorytcellsandsuppressesautoimmunity AT jianglingjuan proximityenabledcovalentbindingofil2toil2raselectivelyactivatesregulatorytcellsandsuppressesautoimmunity AT zhaolidan proximityenabledcovalentbindingofil2toil2raselectivelyactivatesregulatorytcellsandsuppressesautoimmunity AT yufei proximityenabledcovalentbindingofil2toil2raselectivelyactivatesregulatorytcellsandsuppressesautoimmunity AT songwei proximityenabledcovalentbindingofil2toil2raselectivelyactivatesregulatorytcellsandsuppressesautoimmunity AT wangmin proximityenabledcovalentbindingofil2toil2raselectivelyactivatesregulatorytcellsandsuppressesautoimmunity AT xuyue proximityenabledcovalentbindingofil2toil2raselectivelyactivatesregulatorytcellsandsuppressesautoimmunity AT mashiliang proximityenabledcovalentbindingofil2toil2raselectivelyactivatesregulatorytcellsandsuppressesautoimmunity AT feiyunyun proximityenabledcovalentbindingofil2toil2raselectivelyactivatesregulatorytcellsandsuppressesautoimmunity AT zhanglihe proximityenabledcovalentbindingofil2toil2raselectivelyactivatesregulatorytcellsandsuppressesautoimmunity AT zhoudemin proximityenabledcovalentbindingofil2toil2raselectivelyactivatesregulatorytcellsandsuppressesautoimmunity AT zhangxuan proximityenabledcovalentbindingofil2toil2raselectivelyactivatesregulatorytcellsandsuppressesautoimmunity |