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Transcriptional reprogramming by IL-2 variant generates metabolically active stem-like T cells

Ortiz Miranda, Y.; Masid, M.; Jimenez-Luna, C.; Montalvo Bereau, G. M.; Muller, T.; Rayroux, N.; Cribioli, E.; Corria-Osorio, J.; Carrasco Hope, H.; Vuillefroy de Silly, R.; Seijo, B.; Ginefra, P.; Leon, K.; Vannini, N.; Ho, P.-C.; Crespo, I.; Hatzimanikatis, V.; Irving, M.; Coukos, G.

2023-05-24 systems biology
10.1101/2023.05.24.541283 bioRxiv
Show abstract

Interleukin-2 receptor (IL-2R)-mediated intracellular signaling is a key regulator of T-cell fate decisions. While the potent signals generated by IL-2 engagement execute effector differentiation, elevated metabolic activities and rapid cellular expansion, IL-15 binding induces a stemness/memory phenotype and a quiescent metabolic state. Here, we demonstrate that weak but sustained signaling generated by a non-IL-2R-binding variant of IL-2 (IL-2v) drive proliferation/metabolic and stemness transcriptional programs, thereby reprogramming CD8+ T cells into a hybrid metabolically active stem-like state. We further show that IL-2v-induced T cells are capable of superior engraftment, persistence, and tumor control when utilized in adoptive cell therapy. Taken together, our study highlights the ability to fine-tune cytokine engagement of cognate receptors in order to generate therapeutically relevant T-cell states and further reveals the metabolic plasticity of the T-cell memory program.

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