Signal Transduction and Targeted Therapy (Jan 2023)

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

  • Bo Zhang,
  • 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

DOI
https://doi.org/10.1038/s41392-022-01208-3
Journal volume & issue
Vol. 8, no. 1
pp. 1 – 18

Abstract

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Abstract 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.