The calcineurin-NFAT axis controls allograft immunity in myeloid-derived suppressor cells through reprogramming T cell differentiation.
The calcineurin-NFAT axis controls allograft immunity in myeloid-derived suppressor cells through reprogramming T cell differentiation.
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钙调神经磷酸酶-NFAT 轴通过重编程 T 细胞分化来控制骨髓源性抑制细胞的同种异体移植免疫。
DOI：
10.1128/mcb.01251-14
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发表时间：
2015
影响因子：
5.3
通讯作者：
Liu Guangwei
中科院分区：
文献类型：
--
作者：
Wang Xiao;Bi Yujing;Xue Lixiang;Liao Jiongbo;Chen Xi;Lu Yun;Zhang Zhengguo;Wang Jian;Liu Huanrong;Yang Hui;Liu Guangwei
虽然环孢素（CsA）抑制钙调神经磷酸酶，并在延长移植患者的排斥反应是非常有效的，免疫学机制仍不清楚。在此，研究了钙调磷酸酶信号传导在小鼠同种异体皮肤移植模型中的作用。钙调神经磷酸酶抑制剂CsA可显著改善同种异体移植排斥反应。在CsA治疗的同种异体移植受体小鼠中，CD 11b（+）Gr 1（+）骨髓源性抑制细胞（MDSC）是功能抑制性免疫调节剂，导致产生γ干扰素（IFN-γ）的CD 8（+）T细胞和CD 4（+）T细胞（T（H）1 T辅助细胞）减少，产生白细胞介素4（IL-4）的CD 4（+）T细胞（T（H2））增加，并延长同种异体皮肤移植物的存活时间。重要的是，在CsA诱导的MDSC中，NFATc 1的表达显著减少。用VIVIT阻断NFAT（活化T细胞的核因子）可表型模拟CsA对MDSC的作用，并增加同种异体移植受体小鼠中CD 11b（+）Gr 1（+）MDSC的抑制活性和募集。机制上，CsA治疗增强了吲哚胺2，3-双加氧酶（IDO）的表达和MDSC在同种异体移植受体中的抑制活性。IDO的抑制几乎完全恢复了增加的MDSC抑制活性和对T细胞分化的影响。本研究的结果表明，MDSC是CsA或VIVIT治疗后控制同种异体移植物存活的重要组分，验证了钙调神经磷酸酶-NFAT-IDO信号传导轴作为移植中的潜在治疗靶点。
While cyclosporine (CsA) inhibits calcineurin and is highly effective in prolonging rejection for transplantation patients, the immunological mechanisms remain unknown. Herein, the role of calcineurin signaling was investigated in a mouse allogeneic skin transplantation model. The calcineurin inhibitor CsA significantly ameliorated allograft rejection. In CsA-treated allograft recipient mice, CD11b(+) Gr1(+) myeloid-derived suppressor cells (MDSCs) were functional suppressive immune modulators that resulted in fewer gamma interferon (IFN-gamma)-producing CD8(+) T cells and CD4(+) T cells (T(H)1 T helper cells) and more interleukin 4 (IL-4)-producing CD4(+) T cells (T(H2)) and prolonged allogeneic skin graft survival. Importantly, the expression of NFATc1 is significantly diminished in the CsA-induced MDSCs. Blocking NFAT (nuclear factor of activated T cells) with VIVIT phenocopied the CsA effects in MDSCs and increased the suppressive activities and recruitment of CD11b(+) Gr1(+) MDSCs in allograft recipient mice. Mechanistically, CsA treatment enhanced the expression of indoleamine 2,3-dioxygenase (IDO) and the suppressive activities of MDSCs in allograft recipients. Inhibition of IDO nearly completely recovered the increased MDSC suppressive activities and the effects on T cell differentiation. The results of this study indicate that MDSCs are an essential component in controlling allograft survival following CsA or VIVIT treatment, validating the calcineurin-NFAT-IDO signaling axis as a potential therapeutic target in transplantation.