IL-21 contributes to fatal inflammatory disease in the absence of Foxp3+ T regulatory cells
The cytokine IL-21 has been shown to influence immune responses through both costimulatory effects on effector T cells and opposing inhibitory effects on T regulatory cells (Tregs). To distinguish the effect of IL-21 on the immune system from that of its effect on Tregs, we analyzed 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 multiorgan inflammatory disease. Our findings demonstrate that in the absence of IL-21/IL-21R signaling, Il2(-/-) mice retained a deficiency in Tregs yet exhibited a reduced and delayed inflammatory disease. The improved health of Il2(-/-)Il21r(-/-) mice was reflected in reduced pancreatitis and hemolytic 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.
|ISBN||1550-6606 (Electronic) 0022-1767 (Linking)|
|Authors||Vogelzang, A.; McGuire, H. M.; Liu, S. M.; Gloss, B.; Mercado, K.; Earls, P.; Dinger, M. E.; Batten, M.; Sprent, J.; King, C.;|
|Responsible Garvan Author|
|Publisher Name||JOURNAL OF IMMUNOLOGY|
|URL link to publisher's version||http://www.ncbi.nlm.nih.gov/pubmed/24446516|
|OpenAccess link to author's accepted manuscript version||https://publications.gimr.garvan.org.au/open-access/12476|