A critical role for IL-21 receptor signaling in the pathogenesis of systemic lupus erythematosus in BXSB-Yaa mice.
Interleukin 21 (IL-21) is a pleiotropic cytokine produced by CD4 T cells that affects the differentiation and function of T, B, and NK cells by binding to a receptor consisting of the common cytokine receptor gamma chain and the IL-21 receptor (IL-21R). IL-21, a product associated with IL-17-producing CD4 T cells (T(H)17) and follicular CD4 T helper cells (T(FH)), has been implicated in autoimmune disorders including the severe systemic lupus erythematosus (SLE)-like disease characteristic of BXSB-Yaa mice. To determine whether IL-21 plays a significant role in this disease, we compared IL-21R-deficient and -competent BXSB-Yaa mice for multiple parameters of SLE. The deficient mice showed none of the abnormalities characteristic of SLE in IL-21R-competent Yaa mice, including hypergammaglobulinemia, autoantibody production, reduced frequencies of marginal zone B cells and monocytosis, renal disease, and premature morbidity. IL-21 production associated with this autoimmune disease was not a product of T(H)17 cells and was not limited to conventional CXCR5(+) T(FH) but instead was produced broadly by ICOS(+) CD4(+) splenic T cells. IL-21 arising from an abnormal population of CD4 T cells is thus central to the development of this lethal disease, and, more generally, could play an important role in human SLE and related autoimmune disorders.
Bubier
Jason A
JA
The Jackson Laboratory, 600 Main Street, Bar Harbor, ME 04609, USA.
Sproule
Thomas J
TJ
Foreman
Oded
O
Spolski
Rosanne
R
Shaffer
Daniel J
DJ
Morse
Herbert C
HC
Leonard
Warren J
WJ
Roopenian
Derry C
DC
D000818:Animals; D000917:Antibody Formation; D001483:Base Sequence; D017931:DNA Primers; D004797:Enzyme-Linked Immunosorbent Assay; D005434:Flow Cytometry; D007378:Interleukins / Q000235:genetics; D007674:Kidney Diseases / Q000517:prevention & control; D008180:Lupus Erythematosus, Systemic / Q000209:etiology* / Q000276:immunology / Q000378:metabolism; D016131:Lymphocyte Subsets; D051379:Mice; D053655:Receptors, Interleukin-21 / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D000098546:Interleukin-21
D017931:DNA Primers; D007378:Interleukins; D053655:Receptors, Interleukin-21; D000098546:Interleukin-21