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2014 ; 66
(9
): 2601-12
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Interleukin-21 promotes germinal center reaction by skewing the follicular
regulatory T cell to follicular helper T cell balance in autoimmune BXD2 mice
#MMPMID24909430
Ding Y
; Li J
; Yang P
; Luo B
; Wu Q
; Zajac AJ
; Wildner O
; Hsu HC
; Mountz JD
Arthritis Rheumatol
2014[Sep]; 66
(9
): 2601-12
PMID24909430
show ga
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. CONCLUSION: 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.