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<p>Tregs for adoptive therapy are traditionally expanded ex vivo using high doses of IL-2. However, the final Treg product has limited survival once infused in patients, potentially affecting therapeutic effectiveness. Here, we tested a novel expansion protocol in which highly purified naïve Tregs were expanded with a combination of IL-7 and IL-15, in the absence of IL-2. The final Treg product was enriched with cells displaying an immature CD45RA+CD62L+CD95+ phenotype, reminiscent of conventional memory stem T cells. The combination of IL-7 and IL-15 confers Tregs a glycolytic metabolism and improved metabolic fitness, characterized by an increased capacity to adapt metabolism according to glucose and oxygen availability. Tregs expanded with IL-7 and IL-15 showed longer persistence and an improved capacity to control xeno-GvHD in NSG mice. This work suggests that metabolic reprogramming induced by IL-7 and IL-15 provides better Treg performance for adoptive therapy.</p>

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Metabolic reprogramming of naïve regulatory T cells by IL-7 and IL-15 promotes their persistence and performance upon adoptive transfer

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年1月21日

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  • Jessica Filoni,
  • Arianna Ferrari,
  • Tatiana Jofra,
  • Anna Rita Putignano,
  • Lorenzo Da Dalt,
  • Susanna Cesarano,
  • Carla Di Dedda,
  • Fabrizia Bonacina,
  • Federica Marchesi,
  • Giuseppe Danilo Norata,
  • Chiara Bonini,
  • Lorenzo Piemonti,
  • Paolo Monti

摘要

Tregs for adoptive therapy are traditionally expanded ex vivo using high doses of IL-2. However, the final Treg product has limited survival once infused in patients, potentially affecting therapeutic effectiveness. Here, we tested a novel expansion protocol in which highly purified naïve Tregs were expanded with a combination of IL-7 and IL-15, in the absence of IL-2. The final Treg product was enriched with cells displaying an immature CD45RA+CD62L+CD95+ phenotype, reminiscent of conventional memory stem T cells. The combination of IL-7 and IL-15 confers Tregs a glycolytic metabolism and improved metabolic fitness, characterized by an increased capacity to adapt metabolism according to glucose and oxygen availability. Tregs expanded with IL-7 and IL-15 showed longer persistence and an improved capacity to control xeno-GvHD in NSG mice. This work suggests that metabolic reprogramming induced by IL-7 and IL-15 provides better Treg performance for adoptive therapy.