Interleukin-2 (IL-2) is a mainstay for current immunotherapeutic protocols but its usefulness in patients is reduced by severe toxicities and because IL-2 facilitates regulatory T (Treg) cell development. IL-21 is a type I cytokine acting as a potent T-cell co-mitogen but less efficient than IL-2 in sustaining T-cell proliferation. Using various in vitro models for T-cell receptor (TCR)-dependent human T-cell proliferation, we found that IL-21 synergized with IL-2 to make CD4(+) and CD8(+) T cells attain a level of expansion that was impossible to obtain with IL-2 alone. Synergy was mostly evident in naive CD4(+) cells. IL-2 and tumour-released transforming growth factor-β (TGF-β) are the main environmental cues that cooperate in Treg cell induction in tumour patients. Interleukin-21 hampered Treg cell expansion induced by IL-2/TGF-β combination in naive CD4(+) cells by facilitating non-Treg over Treg cell proliferation from the early phases of cell activation. Conversely, IL-21 did not modulate the conversion of naive activated CD4(+) cells into Treg cells in the absence of cell division. Treg cell reduction was related to persistent activation of Stat3, a negative regulator of Treg cells associated with down-modulation of IL-2/TGF-β-induced phosphorylation of Smad2/3, a positive regulator of Treg cells. In contrast to previous studies, IL-21 was completely ineffective in counteracting the suppressive activity of Treg cells on naive and memory, CD4(+) and CD8(+) T cells. Present data provide proof-of-concept for evaluating a combinatorial approach that would reduce the IL-2 needed to sustain T-cell proliferation efficiently, thereby reducing toxicity and controlling a tolerizing mechanism responsible for the contraction of the T-cell response.

Battaglia, A., Buzzonetti, A., Baranello, C., Fanelli, M., Fossati, M., Catzola, V., Scambia, G., Fattorossi, A., Interleukin-21 (IL-21) synergizes with IL-2 to enhance T-cell receptor-induced human T-cell proliferation and counteracts IL-2/transforming growth factor-beta-induced regulatory T-cell development, <<IMMUNOLOGY>>, 2013; 139 (1): 109-120. [doi:10.1111/imm.12061] [http://hdl.handle.net/10807/50638]

Interleukin-21 (IL-21) synergizes with IL-2 to enhance T-cell receptor-induced human T-cell proliferation and counteracts IL-2/transforming growth factor-beta-induced regulatory T-cell development

Battaglia, Alessandra;Scambia, Giovanni;
2013

Abstract

Interleukin-2 (IL-2) is a mainstay for current immunotherapeutic protocols but its usefulness in patients is reduced by severe toxicities and because IL-2 facilitates regulatory T (Treg) cell development. IL-21 is a type I cytokine acting as a potent T-cell co-mitogen but less efficient than IL-2 in sustaining T-cell proliferation. Using various in vitro models for T-cell receptor (TCR)-dependent human T-cell proliferation, we found that IL-21 synergized with IL-2 to make CD4(+) and CD8(+) T cells attain a level of expansion that was impossible to obtain with IL-2 alone. Synergy was mostly evident in naive CD4(+) cells. IL-2 and tumour-released transforming growth factor-β (TGF-β) are the main environmental cues that cooperate in Treg cell induction in tumour patients. Interleukin-21 hampered Treg cell expansion induced by IL-2/TGF-β combination in naive CD4(+) cells by facilitating non-Treg over Treg cell proliferation from the early phases of cell activation. Conversely, IL-21 did not modulate the conversion of naive activated CD4(+) cells into Treg cells in the absence of cell division. Treg cell reduction was related to persistent activation of Stat3, a negative regulator of Treg cells associated with down-modulation of IL-2/TGF-β-induced phosphorylation of Smad2/3, a positive regulator of Treg cells. In contrast to previous studies, IL-21 was completely ineffective in counteracting the suppressive activity of Treg cells on naive and memory, CD4(+) and CD8(+) T cells. Present data provide proof-of-concept for evaluating a combinatorial approach that would reduce the IL-2 needed to sustain T-cell proliferation efficiently, thereby reducing toxicity and controlling a tolerizing mechanism responsible for the contraction of the T-cell response.
2013
Inglese
Battaglia, A., Buzzonetti, A., Baranello, C., Fanelli, M., Fossati, M., Catzola, V., Scambia, G., Fattorossi, A., Interleukin-21 (IL-21) synergizes with IL-2 to enhance T-cell receptor-induced human T-cell proliferation and counteracts IL-2/transforming growth factor-beta-induced regulatory T-cell development, <<IMMUNOLOGY>>, 2013; 139 (1): 109-120. [doi:10.1111/imm.12061] [http://hdl.handle.net/10807/50638]
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/10807/50638
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