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<p>Although transplantation is the preferred treatment for end-stage organ disease, long-term outcomes are limited by immunosuppressive drug toxicity and immune-mediated injury. Selective in vivo expansion of regulatory T cells (Tregs) using interleukin-2 (IL-2) analogs has emerged as a strategy to induce antigen-specific transplant tolerance with fewer side effects. Herein, we investigate the therapeutic efficacy of an IL-2 mutein molecule (mIL-2) with enhanced receptor specificity and extended half-life in murine models of solid organ transplantation. mIL-2 therapy significantly improves allograft survival in an antigen-specific manner, accompanied by increased Treg activation, decreased effector T cell activation and reduced donor-specific antibody production. Transcriptional profiling reveals expansion of Tregs expressing the suppression of tumorigenicity 2 (ST2) Tregs with heightened activation status and suppressive function. Accordingly, the mIL-2-induced long-term allograft survival is abrogated in Treg-specific ST2 knockout graft recipients, underscoring the critical role of ST2<sup>+</sup> Tregs. These findings identify mIL-2 as an approach to promote long-term transplant tolerance while reducing reliance on conventional immunosuppression.</p>

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IL-2 mutein promotes antigen-specific transplant acceptance in mice through expansion of ST2+ regulatory T cells

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2026年6月22日

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  • Yoshikazu Ganchiku,
  • Guilherme T. Ribas,
  • Karina Lima,
  • Rodrigo B. Gassen,
  • Kaifeng Liu,
  • Orhan Efe,
  • Jason W. Griffith,
  • Andrew D. Luster,
  • Zachary Shriver,
  • Gregory J. Babcock,
  • Ivy A. Rosales,
  • Christian LeGuern,
  • Thiago J. Borges,
  • Leonardo V. Riella

摘要

Although transplantation is the preferred treatment for end-stage organ disease, long-term outcomes are limited by immunosuppressive drug toxicity and immune-mediated injury. Selective in vivo expansion of regulatory T cells (Tregs) using interleukin-2 (IL-2) analogs has emerged as a strategy to induce antigen-specific transplant tolerance with fewer side effects. Herein, we investigate the therapeutic efficacy of an IL-2 mutein molecule (mIL-2) with enhanced receptor specificity and extended half-life in murine models of solid organ transplantation. mIL-2 therapy significantly improves allograft survival in an antigen-specific manner, accompanied by increased Treg activation, decreased effector T cell activation and reduced donor-specific antibody production. Transcriptional profiling reveals expansion of Tregs expressing the suppression of tumorigenicity 2 (ST2) Tregs with heightened activation status and suppressive function. Accordingly, the mIL-2-induced long-term allograft survival is abrogated in Treg-specific ST2 knockout graft recipients, underscoring the critical role of ST2+ Tregs. These findings identify mIL-2 as an approach to promote long-term transplant tolerance while reducing reliance on conventional immunosuppression.