Increased CD40L+PD-1+ follicular helper T cells (Tfh) as a biomarker for predicting calcineurin inhibitor sensitivity against Tfh-mediated B-cell activation/antibody production after kidney transplantation
Increased CD40L+PD-1+ follicular helper T cells (Tfh) as a biomarker for predicting calcineurin inhibitor sensitivity against Tfh-mediated B-cell activation/antibody production after kidney transplantation
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DOI：
10.1093/intimm/dxy039
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发表时间：
2018-08-01
影响因子：
4.4
通讯作者：
Kobayashi, Takaaki
中科院分区：
文献类型：
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作者：
Iwasaki, Kenta;Kitahata, Nana;Kobayashi, Takaaki
目前尚不清楚肾移植后免疫抑制剂，特别是钙调神经磷酸酶抑制剂（CM；环孢菌素或他克莫司）对滤泡辅助 T 细胞 (Tfh) 的发育和从头供者特异性人白细胞抗原抗体 (DSA) 的产生有多大程度的影响。在此，研究了免疫抑制剂对 Tfh 介导的 B 细胞活化和抗体产生的影响。体外循环Tfh（cTfh；记忆CD4（+）CXCR5（+））/B细胞（CD19（+））共培养测定表明，CM通过抑制IL-21和IL-2显着抑制cTfh介导的B细胞活化和IgG抗体分泌。 IL-21和CD40L均上调B细胞上的IL-2受体(CD25)，并且抗CD25抗体诱导活化的B细胞凋亡，从而抑制IgG产生。移植后 1 年接受 de novo DSA 的患者中 cTfh 表达的 CD40L 和 PD-1 频率升高。 CNI的抑制程度取决于葡萄球菌肠毒素B诱导的CD40L(+)PD-1(+) cTfh上调水平。我们的数据表明，CD40L(+)PD-1(+)cTfh 可能是一个标志物，表明肾移植中 Tfh 介导的 B 细胞激活的 CNI 敏感性存在个体差异。
It is unclear to what extent the development of follicular helper T cells (Tfh) and de novo donor-specific human leukocyte antigen antibody (DSA) production could be influenced by immunosuppressive agents, particularly calcineurin inhibitor (CM; cyclosporine or tacrolimus), after kidney transplantation. Here, the effects of immunosuppressive agents on Tfh-mediated B-cell activation and antibody production were investigated. In vitro circulating Tfh (cTfh; memory CD4(+)CXCR5(+))/B-cell (CD19(+)) co-culture assays revealed that CM considerably inhibited cTfh-mediated B-cell activation and IgG antibody secretion through the suppression of IL-21 and IL-2. Both IL-21 and CD40L up-regulated IL-2 receptors (CD25) on B cells, and anti-CD25 antibody induced apoptosis of activated B cells, resulting in the inhibition of IgG production. The frequency of cTfh-expressed CD40L and PD-1 was elevated in patients with de novo DSA 1 year after transplantation. The degree of inhibition by CNI was dependent on Staphylococcal enterotoxin B-induced CD40L(+)PD-1(+) cTfh up-regulation level. Our data demonstrate that CD40L(+)PD-1(+)cTfh could be a marker to implicate individual difference in CNI sensitivity for Tfh-mediated B-cell activation in kidney transplantation.