Interleukin-21 contributes to fatal inflammatory disease in the absence of FoxP3+ T regulatory cells
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.
|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|
|Responsible Garvan Author|
|Publisher Name||J IMMUNOL|