title: IL-17RA is essential for optimal localization of follicular Th cells in the germinal center light zone to promote autoantibody-producing B cells.
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 TFH 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.
authors.affiliation: Department of Medicine, University of Alabama at Birmingham, Birmingham, AL 35294, USA.
authors.forename: Yanna
authors.initials: Y
authors.lastname: Ding
authors.forename: Jun
authors.initials: J
authors.lastname: Li
authors.forename: Qi
authors.initials: Q
authors.lastname: Wu
authors.forename: Pingar
authors.initials: P
authors.lastname: Yang
authors.forename: Bao
authors.initials: B
authors.lastname: Luo
authors.forename: Shutao
authors.initials: S
authors.lastname: Xie
authors.forename: Kirk M
authors.initials: KM
authors.lastname: Druey
authors.forename: Allan J
authors.initials: AJ
authors.lastname: Zajac
authors.forename: Hui-Chen
authors.initials: HC
authors.lastname: Hsu
authors.forename: John D
authors.initials: JD
authors.lastname: Mountz
mesh_terms: D019264:Adoptive Transfer; D000818:Animals; D001323:Autoantibodies / Q000096:biosynthesis*; D016175:B-Lymphocyte Subsets / Q000276:immunology*; D002465:Cell Movement; D060833:Cellular Microenvironment / Q000276:immunology; D018920:Coculture Techniques; D003433:Crosses, Genetic; D018858:Germinal Center / Q000276:immunology* / Q000648:ultrastructure; D006241:Haptens / Q000276:immunology; D007074:Immunoglobulin G / Q000276:immunology; D020381:Interleukin-17 / Q000276:immunology*; D007378:Interleukins / Q000276:immunology*; D007668:Kidney / Q000473:pathology; D008211:Lymphocyte Cooperation / Q000276:immunology; D038041:Lymphopoiesis; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009596:Nitrophenols / Q000276:immunology; D010648:Phenylacetates / Q000276:immunology; D053722:Receptors, Interleukin-17 / Q000172:deficiency / Q000276:immunology*; D006377:T-Lymphocytes, Helper-Inducer / Q000276:immunology*; D000098546:Interleukin-21
chemical_list: D001323:Autoantibodies; D006241:Haptens; C491673:Il17ra protein, mouse; D007074:Immunoglobulin G; D020381:Interleukin-17; D007378:Interleukins; D009596:Nitrophenols; D010648:Phenylacetates; D053722:Receptors, Interleukin-17; C026242:4-hydroxy-5-nitrophenyl acetic acid; D000098546:Interleukin-21