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Interleukin-7–Engineered Mesenchymal Cells: In Vitro Effects on Naive T-Cell Population

2006; Elsevier BV; Volume: 12; Issue: 12 Linguagem: Inglês

10.1016/j.bbmt.2006.09.001

1523-6536

Paolo Sportoletti, Beatrice Del Papa, Mariangela De Ioanni, Lorenzo Moretti, Ezio Bonifacio, Vania Lanterna, Alain Sylvin Bell, Katia Fettucciari, E. Carnevali, Tiziana Zei, Franca Falzetti, Maria Paola Martelli, Antonio Tabilio, Mauro Di Ianni,

Immune Cell Function and Interaction

T-cell homeostasis is regulated by several molecules; among these, interleukin (IL)-7 plays an essential role in the survival and homeostatic proliferation of peripheral naive T cells. In a previous study, we investigated whether human mesenchymal stromal cells (MSCs) could be engineered with the IL-7 gene to produce functional level of this cytokine. In the present study, we analyzed the impact of different quantities of IL-7 produced by MSCs on the survival and proliferation of a negative immunoselected naive (CD3+/CD45RA+) T-cell population. Co-cultivation of peripheral naive T cells with MSCs producing low (16 pg/mL) or high (1000 pg/mL) IL-7 levels or in the presence of exogenous IL-7 (0.01 ng/mL and 100 ng/mL) maintained the CD3+/CD45RA+ naive T-cell phenotype. Chemokine receptor CCR7+ expression was also maintained among this T-cell population. Naive T-cell molecular characteristics were maintained as assessed by the Vβ spectratyping complexity score, which showed the maintenance of a broad T-cell repertoire. No Th1 or Th2 differentiation was observed, as assessed by interferon-γ or IL-4 accumulation. In contrast, only MSCs producing high amounts of IL-7 caused increased activation (CD25 31.2% ± 12% vs 10% ± 3.5%; P < .05), proliferation (CD71 17.8±7% vs 9.3%±3, P < .05), apoptosis (assessed by annexin V: 18.6% ± 5% vs 14.9% ± 2.6%; P > .05), and the phase S cell cycle (15% vs 6.9%, P > .05). Exogenous IL-7 exhibited no significant effect. In conclusion, we demonstrated that IL-7 produced by MSCs has a dose-independent effect on naive T-cell survival while exerting a dose-dependent effect on activation/proliferation. Due to the continuous production of IL-7 by engineered cells, our system is more efficacious than exogenous IL-7.