IL-21 and IL-5 coordinately induce surface IgA⁺ cells

Intestinal IgA is induced by microbes and food antigens. Peyer's patches (PPs) are known as one of the inductive sites for intestinal IgA production. However, the precise mechanism of IgA induction is as yet unknown. IgA secretion was induced from IgD⁺ B cells in vitro by stimulus with lipopolysaccharide in the presence of only retinoic acid (RA) and low doses of TGF-β1. Surface IgA⁺ cells were effectively induced from IgD⁺ B cells in vitro by the mixture of RA and the cytokines TGF-β1, APRIL, IL-5 and IL-21. rIL-21 upregulated surface IgA⁺ but impaired the proliferation of stimulated B cells in the presence of rTGF-β1, RA and rAPRIL, in vitro. The addition of rIL-5 restored the impaired proliferation by rIL-21, resulting in the expansion of IgA⁺ cells. rIL-21 induced the expression of Aicda and Prdm1, and impaired Rel in IgD⁺ B cells. Blockade of IL-21R signaling by a neutralizing mAb in vivo led to lower frequencies of IgA⁺ and IgG2b⁺ cells and lower germinal center B cells in PPs in a homeostatic condition. Although amounts of small intestinal IgA and titers of anti-dsDNA, the major target of intestinal IgA, in these mice were not altered, anti-OVA IgA titers induced by OVA drinking in OVA-specific T-cell receptor (TCR) transgenic mice were decreased. PP-deficient TCR transgenic mice showed diminished anti-OVA IgA induction. Blockade of IL-5R signaling in vivo led to similar results with relatively weaker effects than that of IL-21R mAb administration. These results suggest that IL-21 and IL-5 play cooperative roles in surface expression of IgA in PPs.