IL-21 promotes lupus-like disease in chronic graft-versus-host disease through both CD4 T cell- and b cell-intrinsic mechanisms

Vinh Nguyen, Irina Luzina, Horea Rus, Cosmin Tegla, Ching Chen, Violeta Rus*

*Corresponding author for this work

Research output: Contribution to journalArticle

23 Scopus citations

Abstract

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 TFH cell pathway that contributes to lupus pathogenesis.

Original languageEnglish (US)
Pages (from-to)1081-1093
Number of pages13
JournalJournal of Immunology
Volume189
Issue number2
DOIs
StatePublished - Jul 15 2012

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

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