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bioRxiv · 10.1101/2023.05.24.541283

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.
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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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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. Transcriptional reprogramming by IL-2 variant generates metabolically active stem-like T cells. https://doi.org/10.1101/2023.05.24.541283

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