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Interleukin-21 contributes to fatal inflammatory disease in the absence of FoxP3+ T regulatory cells

Abstract

The cytokine interleukin-21 has been shown to influence immune responses through both costimulatory effects on effector T cells and opposing inhibitory effects on T regulatory cells. To distinguish the effect of IL-21 on the immune system from that of its effect on Tregs, we analysed the role of IL-21:IL-21R signaling in mice made genetically deficient in IL-2, which exhibit a deficit in IL-2-dependent FoxP3 regulatory T cells and suffer from a fatal multi-organ inflammatory disease. Our findings demonstrate that in the absence of IL-21:IL-21R signaling, Il2-/- mice retained a deficiency in T regulatory cells, yet exhibited a reduced and delayed inflammatory disease. The improved health of Il2-/-Il21r-/- mice was reflected in reduced pancreatitis and haemolytic anemia and this was associated with distinct changes in lymphocyte effector populations; including the reduced expansion of both T follicular helper cells and Th17 cells and a compensatory increase in IL-22 in the absence of IL-21R. IL-21:IL-21R interactions were also important for the expansion of effector and memory CD8+ T cells, which were critical for the development of pancreatitis in Il2-/- mice. These findings demonstrate that IL-21 is a major target of immune system regulation.

Type Journal
Authors Alexis Vogelzang1,2, Helen M. McGHuire1,2, Sue M. Liu1,2, Brian Gloss4, Karessa Mercado1,2, Peter Earls3, Marcel Dinger4, Marcel Batten1,2, Jonathan Sprent1,2 and Cecile King1,2
Garvan Authors A/Prof Cecile King
Publisher Name J IMMUNOL
Published Date 2014-02-15 00:00:00
Status Published