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.
Department of Immunology, Garvan Institute of Medical Research, Darlinghurst, New South Wales 2010, Australia;
Alexis
A
Vogelzang
Helen M
HM
McGuire
Sue M
SM
Liu
Brian
B
Gloss
Karessa
K
Mercado
Peter
P
Earls
Marcel E
ME
Dinger
Marcel
M
Batten
Jonathan
J
Sprent
Cecile
C
King
D000743:Anemia, Hemolytic / Q000235:genetics / Q000276:immunology*; D000818:Animals; D000906:Antibodies / Q000097:blood; D000917:Antibody Formation / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000166:cytology / Q000276:immunology; D002454:Cell Differentiation / Q000276:immunology; D051858:Forkhead Transcription Factors / Q000172:deficiency / Q000235:genetics; D007376:Interleukin-2 / Q000235:genetics; D053738:Interleukin-21 Receptor alpha Subunit / Q000235:genetics / Q000378:metabolism*; D007378:Interleukins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010195:Pancreatitis / Q000235:genetics / Q000276:immunology*; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology; D050378:T-Lymphocytes, Regulatory / Q000166:cytology / Q000276:immunology* / Q000378:metabolism; D058504:Th17 Cells / Q000166:cytology / Q000276:immunology; D000097043:Interleukin-22; D000098546:Interleukin-21
D000906:Antibodies; D051858:Forkhead Transcription Factors; D007376:Interleukin-2; D053738:Interleukin-21 Receptor alpha Subunit; D007378:Interleukins; D000097043:Interleukin-22; D000098546:Interleukin-21; C498833:Foxp3 protein, mouse; C508118:Il21r protein, mouse