Document Detail

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.
MedLine Citation:
PMID:  23278180     Owner:  NLM     Status:  MEDLINE    
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.
Alessandra Battaglia; Alexia Buzzonetti; Cinzia Baranello; Mara Fanelli; Marco Fossati; Valentina Catzola; Giovanni Scambia; Andrea Fattorossi
Publication Detail:
Type:  Clinical Trial; Journal Article; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  Immunology     Volume:  139     ISSN:  1365-2567     ISO Abbreviation:  Immunology     Publication Date:  2013 May 
Date Detail:
Created Date:  2013-04-09     Completed Date:  2013-06-07     Revised Date:  2014-05-07    
Medline Journal Info:
Nlm Unique ID:  0374672     Medline TA:  Immunology     Country:  England    
Other Details:
Languages:  eng     Pagination:  109-20     Citation Subset:  IM    
Copyright Information:
© 2012 Blackwell Publishing Ltd.
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MeSH Terms
CD8-Positive T-Lymphocytes / cytology,  immunology
Cell Proliferation / drug effects
Interleukin-2 / immunology*,  pharmacology
Interleukins / immunology*,  pharmacology
Lymphocyte Activation / drug effects,  physiology*
Receptors, Antigen, T-Cell / immunology*
STAT3 Transcription Factor / immunology
T-Lymphocytes, Regulatory / cytology,  immunology*
Transforming Growth Factor beta / immunology*,  pharmacology
Reg. No./Substance:
0/IL2 protein, human; 0/Interleukin-2; 0/Interleukins; 0/Receptors, Antigen, T-Cell; 0/STAT3 Transcription Factor; 0/STAT3 protein, human; 0/Transforming Growth Factor beta; 0/interleukin-21

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