title: Interleukin-21 promotes germinal center reaction by skewing the follicular regulatory T cell to follicular helper T cell balance in autoimmune BXD2 mice.
abstract: OBJECTIVE
  Follicular regulatory T (Tfr) cells act as the regulatory counterpart of follicular helper T (Tfh) cells to suppress germinal center (GC) B cell differentiation. We recently showed that interleukin-21 (IL-21) promoted Tfh cell differentiation in autoimmune BXD2 mice that develop spontaneous GCs. This study was undertaken to determine the modulatory effects of IL-21 on Tfr cells and the Tfr cell to Tfh cell balance in BXD2 mice.
  
  
  METHODS
  The percentage and phenotype of Tfr cells were determined in BXD2 and BXD2-IL21(-/-) mice. The effects of IL-21 on Tfr cells and the Tfr cell:Tfh cell ratio were evaluated. Sorted Tfr cells from BXD2-IL21(-/-) mice were cocultured with Tfh cells and B cells, or transferred into BXD2 mice to determine their function.
  
  
  RESULTS
  The percentages and numbers of GC B cells and Tfh cells were significantly reduced, but the percentage of Tfr cells was 2-fold higher in BXD2-IL21(-/-) mice than in wild-type BXD2 mice. Administration of AdIL-21 to BXD2-IL21(-/-) mice decreased the percentages and numbers of Tfr cells and the Tfr cell:Tfh cell ratio but increased the number of GC B cells in the spleen. Recombinant murine IL-21 suppressed FoxP3 and significantly reduced Tgfb1, Il2, and Gitr but enhanced Il21, Il6, Pd1, Cxcr5, and Icos expression in Tfr cells. IL-21 also counteracted Tfr cell-mediated inhibition of antibody secretion in the Tfh cell-B cell coculture system. Transfer of Tfr cells into young BXD2 mice reduced GC size and decreased the numbers of autoantibody-producing B cells.
  
  
  CONCLUSIONS
  Our findings indicate that high levels of IL-21 selectively enhance Tfh cell differentiation but inhibit Tfr cell commitment and the suppressive function of Tfr cells on Tfh cells and B cells, suggesting that IL-21 skews the balance from Tfr cells to Tfh cells to promote autoreactive GC reactions in BXD2 mice.
authors.affiliation: University of Alabama at, Birmingham.
authors.forename: Yanna
authors.initials: Y
authors.lastname: Ding
authors.forename: Jun
authors.initials: J
authors.lastname: Li
authors.forename: PingAr
authors.initials: P
authors.lastname: Yang
authors.forename: Bao
authors.initials: B
authors.lastname: Luo
authors.forename: Qi
authors.initials: Q
authors.lastname: Wu
authors.forename: Allan J
authors.initials: AJ
authors.lastname: Zajac
authors.forename: Oliver
authors.initials: O
authors.lastname: Wildner
authors.forename: Hui-Chen
authors.initials: HC
authors.lastname: Hsu
authors.forename: John D
authors.initials: JD
authors.lastname: Mountz
mesh_terms: D000818:Animals; D001323:Autoantibodies / Q000276:immunology; D002454:Cell Differentiation / Q000276:immunology*; D018858:Germinal Center / Q000166:cytology / Q000276:immunology / Q000378:metabolism*; D007378:Interleukins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D006377:T-Lymphocytes, Helper-Inducer / Q000166:cytology / Q000276:immunology / Q000378:metabolism*; D050378:T-Lymphocytes, Regulatory / Q000166:cytology / Q000276:immunology / Q000378:metabolism*; D000098546:Interleukin-21
chemical_list: D001323:Autoantibodies; D007378:Interleukins; D000098546:Interleukin-21