IL-21 induces death of marginal zone B cells during chronic inflammation.
Interleukin-2 (IL-2) and IL-21 share activities in the control of T- and B-cell maturation, proliferation, function, and survival. However, opposing roles for IL-2 and IL-21 have been reported in the development of regulatory T cells. To dissect unique, redundant, and opposing activities of IL-2 and IL-21, we compared T- and B-cell development and function in mice lacking both IL-2 receptor α (IL-2Rα) and IL-21R (double knockouts [DKO]) with single knockout and wild-type (WT) mice. Similarly to il2ra(-/-) mice, DKO showed reduced numbers of regulatory T cells and, consequently, hyper-activation and proliferation of T cells associated with inflammatory disease (ie, colitis), weight loss, and reduced survival. The absence of IL-2Rα resulted in overproduction of IL-21 by IFN-γ-producing CD4(+) T cells, which induced apoptosis of marginal zone (MZ) B cells. Hence, MZ B cells and MZ B-cell immunoglobulin M antibody responses to Streptococcus pneumoniae phosophorylcholine were absent in il2ra(-/-) mice but were completely restored in DKO mice. Our results highlight key roles of IL-2 in inhibiting IL-21 production by CD4(+) T cells and of IL-21 in negatively regulating MZ B-cell survival and antibody production.
Tortola
Luigi
L
Institute of Integrative Biology, Molecular Biomedicine, Eidgenössische Technische Hochschule Zürich, Schlieren, Switzerland.
Yadava
Koshika
K
Bachmann
Martin F
MF
Müller
Christoph
C
Kisielow
Jan
J
Kopf
Manfred
M
D000818:Animals; D000917:Antibody Formation; D001402:B-Lymphocytes / Q000166:cytology*; D015496:CD4-Positive T-Lymphocytes / Q000378:metabolism; D016923:Cell Death; D002908:Chronic Disease; D007249:Inflammation / Q000276:immunology*; D007376:Interleukin-2 / Q000502:physiology; D007378:Interleukins / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000502:physiology*; D051379:Mice; D018345:Mice, Knockout; D000098546:Interleukin-21
D007376:Interleukin-2; D007378:Interleukins; D000098546:Interleukin-21