IL-21 and IL-5 coordinately induce surface IgA+ cells
IL-21 and IL-5 coordinately induce surface IgA+ cells
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DOI：
10.1016/j.imlet.2020.05.004
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发表时间：
2020-08-01
影响因子：
4.4
通讯作者：
Kobata, Tetsuji
中科院分区：
文献类型：
--
作者：
Hashiguchi, Masaaki;Kashiwakura, Yuji;Kobata, Tetsuji
肠道IgA是由微生物和食物抗原诱导的。Peyer’s patches （PPs）被认为是肠道IgA产生的诱导位点之一。然而，IgA诱导的确切机制尚不清楚。体外实验中，仅在维甲酸（RA）和低剂量tgf - β 1存在下，脂多糖刺激IgD(+) B细胞分泌IgA。RA与tgf - β 1、APRIL、IL-5、IL-21等细胞因子混合可有效诱导体外IgD(+) B细胞表面IgA（+）细胞。在体外实验中，在rtgf - β 1、RA和rAPRIL存在的情况下，rIL-21上调表面IgA(+)，但损害受刺激的B细胞的增殖。il -5的加入恢复了被il -21破坏的增殖，导致IgA（+）细胞的扩增。il -21诱导了IgD(+) B细胞中Aicda和Prdm1的表达，并损伤了Rel。在体内通过中和单克隆抗体阻断IL-21R信号通路，导致在稳态条件下PPs中IgA（+）和IgG2b（+）细胞的频率降低，生发中心B细胞的频率降低。虽然这些小鼠的小肠IgA的数量和抗dsdna（肠道IgA的主要靶点）的滴度没有改变，但在OVA特异性t细胞受体（TCR）转基因小鼠中，饮用OVA诱导的抗OVA IgA滴度降低。pp缺陷TCR转基因小鼠抗ova IgA诱导减弱。在体内阻断IL-5R信号通路的效果与阻断IL-21R单抗的效果相似，但相对较弱。提示IL-21和IL-5在PPs表面IgA表达中起协同作用。
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-beta 1. Surface IgA(+) cells were effectively induced from IgD(+) B cells in vitro by the mixture of RA and the cytokines TGF-beta 1, APRIL, IL-5 and IL-21. rIL-21 upregulated surface IgA(+) but impaired the proliferation of stimulated B cells in the presence of rTGF-beta 1, 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.