title: 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.
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.
authors.affiliation: Department of Obstetrics and Gynaecology, Università Cattolica S. Cuore, Rome, Italy. abattaglia@rm.unicatt.it
authors.forename: Alessandra
authors.initials: A
authors.lastname: Battaglia
authors.forename: Alexia
authors.initials: A
authors.lastname: Buzzonetti
authors.forename: Cinzia
authors.initials: C
authors.lastname: Baranello
authors.forename: Mara
authors.initials: M
authors.lastname: Fanelli
authors.forename: Marco
authors.initials: M
authors.lastname: Fossati
authors.forename: Valentina
authors.initials: V
authors.lastname: Catzola
authors.forename: Giovanni
authors.initials: G
authors.lastname: Scambia
authors.forename: Andrea
authors.initials: A
authors.lastname: Fattorossi
mesh_terms: D000818:Animals; D018414:CD8-Positive T-Lymphocytes / Q000166:cytology / Q000276:immunology; D049109:Cell Proliferation / Q000187:drug effects; D005260:Female; D006801:Humans; D007376:Interleukin-2 / Q000276:immunology* / Q000494:pharmacology; D007378:Interleukins / Q000276:immunology* / Q000494:pharmacology; D008213:Lymphocyte Activation / Q000187:drug effects / Q000502:physiology*; D008297:Male; D011948:Receptors, Antigen, T-Cell / Q000276:immunology*; D050796:STAT3 Transcription Factor / Q000276:immunology; D050378:T-Lymphocytes, Regulatory / Q000166:cytology / Q000276:immunology*; D016212:Transforming Growth Factor beta / Q000276:immunology* / Q000494:pharmacology; D000098546:Interleukin-21
chemical_list: C508594:IL2 protein, human; D007376:Interleukin-2; D007378:Interleukins; D011948:Receptors, Antigen, T-Cell; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D016212:Transforming Growth Factor beta; D000098546:Interleukin-21