Metabolic reprogramming of naïve regulatory T cells by IL-7 and IL-15 promotes their persistence and performance upon adoptive transfer
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
Abstract
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. Regulatory T cells expanded with IL-7 and IL-15 exhibit enhanced survival both in vitro and in vivo. These improvements are driven by dynamic metabolic reprogramming, promoting greater functionality and adaptability.