IL-17RA is essential for optimal localization of follicular Th cells in the germinal center light zone to promote autoantibody-producing B cells

Academic Article

Abstract

  • Germinal centers (GCs) provide a microenvironment that promotes and regulates the interactions of B cells with follicular Th (TFH) cells. In this study, we show that there are significantly higher frequencies of CXCR5+ICOS+ TFH cells in autoimmune BXD2 mice, and these cells express both IL-21R and IL-17RA. Although IL-17 and IL-21 are both important for the formation of spontaneous GCs and development of pathogenic autoantibodies, IL-21, but not IL-17, is required for the proper development of TFH cells in BXD2 mice. The total numbers of T FH cells and their ability to induce B cell responses in vitro were not affected by a deficiency of IL-17RA in BXD2-Il17ra-/- mice, the majority of CXCR5+ TFH cells from BXD2-Il17ra -/- mice were, however, not localized in the GC light zone (LZ). Interruption of IL-17 signaling, either acutely by AdIL-17R:Fc or chronically by Il17ra-/-, disrupted TFH-B interactions and abrogated the generation of autoantibody-forming B cells in BXD2 mice. IL-17 upregulated the expression of regulator of G-protein signaling 16 (RGS16) to promote the ability of TFH to form conjugates with B cells, which was abolished in TFH cells from BXD2-Rgs16-/- mice. The results suggests that IL-17 is an extrinsic stop signal that it acts on postdifferentiated IL-17RA+ TFH to enable its interaction with responder B cells in the LZ niche. These data suggest a novel concept that TFH differentiation and its stabilization in the LZ are two separate checkpoints and that IL-21 and IL-17 act at each checkpoint to enable pathogenic GC development. © 2013 by The American Association of Immunologists, Inc.
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    Digital Object Identifier (doi)

    Author List

  • Ding Y; Li J; Wu Q; Yang P; Luo B; Xie S; Druey KM; Zajac AJ; Hsu HC; Mountz JD
  • Start Page

  • 1614
  • End Page

  • 1624
  • Volume

  • 191
  • Issue

  • 4