Volume 8 Issue 2, Feb 2023

ISSN: 2095-9907 

EISSN: 2059-23635 

2023 impact factor 40.8 

 (Clarivate Analytics, 2024)

Volume 8 Issue 2, Feb 2023:
Article
Proximity-enabled covalent binding of IL-2 to IL-2Rα selectively activates regulatory T cells and suppresses autoimmunity
Bo Zhang  ORCID: orcid.org/0000-0002-9652-1120,Jiaqi Sun,Yeshuang Yuan,Dezhong Ji,Yeting Sun,Yudong Liu,Shengjie Li,Xingxing Zhu,Xunyao Wu,Jin Hu,Qiu Xie,Ling Wu,Lulu Liu,Boyang Cheng,Yuanjie Zhang,Lingjuan Jiang,Lidan Zhao,Fei Yu,Wei Song,Min Wang,Yue Xu,Shiliang Ma,Yunyun Fei,Lihe Zhang,Demin Zhou &…Xuan Zhang 
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.