摘要
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-2Rαto selectively promote Treg activation.We found that FSY-bearing IL-2 variants,such as L72-FSY,covalently bound to IL-2Rαvia 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.
基金
This study was supported by grants from the National Key Research and Development Program of China(2019ZX09739)
National Natural Science Foundation of China(82230060,82271831,81788101,82204258)
Chinese Academy of Medical Science Innovation Fund for Medical Sciences(CIFMS,2021-I2M-1-016,2021-I2M-1-017,2021-I2M-1-047,2021-I2M-1-040,2021-I2M-1-016,2021-I2M-1-026)
Natural Science Foundation of Beijing(7222263)
Beijing Capital Health Development Fund(2020-2-4019)
Fundamental Research Funds for the Central Universities(3332022108).
