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-β-induced regulatory T-cell development.

Autor:	Battaglia, Alessandra, Buzzonetti, Alexia, Baranello, Cinzia, Fanelli, Mara, Fossati, Marco, Catzola, Valentina, Scambia, Giovanni, Fattorossi, Andrea
Předmět:	INTERLEUKIN-21 T cell receptors CELL proliferation TRANSFORMING growth factors-beta IMMUNOTHERAPY TOXICITY testing CYTOKINES MITOGENS
Zdroj:	Immunology; May2013, Vol. 139 Issue 1, p109-120, 12p
Abstrakt:	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. [ABSTRACT FROM AUTHOR]
Databáze:	Complementary Index
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