IL-21 promotes lupus-like disease in chronic graft-versus-host disease through both CD4 T cell- and B cell-intrinsic mechanisms.
T cell-driven B cell hyperactivity plays an essential role in driving autoimmune disease development in systemic lupus erythematosus. IL-21 is a member of the type I cytokine family with pleiotropic activities. It regulates B cell differentiation and function, promotes T follicular helper (T(FH)) cell and Th17 cell differentiation, and downregulates the induction of T regulatory cells. Although IL-21 has been implicated in systemic lupus erythematosus, the relative importance of IL-21R signaling in CD4(+) T cells versus B cells is not clear. To address this question, we took advantage of two induced models of lupus-like chronic graft-versus-host disease by using wild-type or IL-21R(-/-) mice as donors in the parent-into-F1 model and as hosts in the Bm12→B6 model. We show that IL-21R expression on donor CD4(+) T cells is essential for sustaining T(FH) cell number and subsequent help for B cells, resulting in autoantibody production and more severe lupus-like renal disease, but it does not alter the balance of Th17 cells and regulatory T cells. In contrast, IL-21R signaling on B cells is critical for the induction and maintenance of germinal centers, plasma cell differentiation, autoantibody production, and the development of renal disease. These results demonstrate that IL-21 promotes autoimmunity in chronic graft-versus-host disease through both CD4(+) T cell- and B cell-intrinsic mechanisms and suggest that IL-21 blockade may attenuate B cell hyperactivity, as well as the aberrant T(FH) cell pathway that contributes to lupus pathogenesis.
Department of Medicine, University of Maryland School of Medicine, Baltimore, MD, USA.
Vinh
V
Nguyen
Irina
I
Luzina
Horea
H
Rus
Cosmin
C
Tegla
Ching
C
Chen
Violeta
V
Rus
D000818:Animals; D016175:B-Lymphocyte Subsets / Q000276:immunology* / Q000473:pathology; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology* / Q000473:pathology; D002454:Cell Differentiation / Q000235:genetics / Q000276:immunology; D002908:Chronic Disease; D015536:Down-Regulation / Q000235:genetics / Q000276:immunology; D006086:Graft vs Host Disease / Q000150:complications / Q000276:immunology* / Q000473:pathology; D053738:Interleukin-21 Receptor alpha Subunit / Q000096:biosynthesis / Q000172:deficiency / Q000502:physiology*; D007378:Interleukins / Q000096:biosynthesis / Q000502:physiology*; D008180:Lupus Erythematosus, Systemic / Q000209:etiology / Q000276:immunology* / Q000473:pathology; D008211:Lymphocyte Cooperation / Q000235:genetics / Q000276:immunology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D050378:T-Lymphocytes, Regulatory / Q000276:immunology / Q000473:pathology; D058504:Th17 Cells / Q000276:immunology / Q000473:pathology; D015854:Up-Regulation / Q000235:genetics / Q000276:immunology; D000098546:Interleukin-21
C508118:Il21r protein, mouse; D053738:Interleukin-21 Receptor alpha Subunit; D007378:Interleukins; D000098546:Interleukin-21