Lymph Node Fibroblastic Reticular Cells Attenuate Immune Responses Through Induction of Tolerogenic Macrophages at Early Stage of Transplantation
Lymph Node Fibroblastic Reticular Cells Attenuate Immune Responses Through Induction of Tolerogenic Macrophages at Early Stage of Transplantation
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淋巴结成纤维细胞网状细胞通过在移植早期诱导耐受性巨噬细胞来减弱免疫反应
DOI：
10.1097/tp.0000000000004245
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发表时间：
2022
期刊：
影响因子：
6.2
通讯作者：
H. Ren
中科院分区：
文献类型：
--
作者：
Beichen Liu;Huihui Liu;Siwei Liu;Chenchen Qin;Xiaoya He;Zhengyang Song;Yujun Dong;H. Ren
背景成纤维细胞网状细胞（FRC）是位于次级淋巴器官T区的一类基质细胞。以往的研究表明，FRC具有促进髓系分化的潜力。我们的目的是研究淋巴结（LN）中的FRC是否可以诱导耐受性巨噬细胞的产生，并进一步影响异基因造血干细胞移植（allo-HSCT）早期阶段的T细胞免疫。方法.测定LN以确认allo-HSCT后增殖的巨噬细胞的存在。将体外扩增的FRC和骨髓细胞共培养以验证巨噬细胞的产生。采用实时荧光定量PCR和ELISA方法检测FRC细胞表达的细胞因子。进行转录组测序以比较FRC诱导的巨噬细胞（FM）和常规巨噬细胞之间的差异。采用混合淋巴细胞反应和急性移植物抗宿主病（aGVHD）小鼠对FMs的利用，检测FMs在体内外对T细胞免疫的抑制作用。结果我们发现在allo-HSCT条件下，在具有耐受性表型的LN中，在FRC附近有大量增殖的巨噬细胞。中和抗巨噬细胞集落刺激因子受体抗体在体外消除FM的产生。表型分析和转录组测序结果表明，FMs具有免疫抑制功能。混合淋巴细胞反应证明，FMs能抑制T细胞活化和向Th 1/Tc 1细胞分化。在aGVHD小鼠中注射FM有效地减弱aGVHD严重性和死亡率。结论.这项研究揭示了一种新的免疫调节机制，通过在allo-HSCT的早期阶段在LN中产生FRC诱导的致耐受性巨噬细胞。
Background. Fibroblastic reticular cells (FRCs) are a type of stromal cells located in the T zone in secondary lymphoid organs. Previous studies showed that FRCs possess the potential to promote myeloid differentiation. We aim to investigate whether FRCs in lymph nodes (LNs) could induce tolerogenic macrophage generation and further influence T-cell immunity at an early stage of allogeneic hematopoietic stem cell transplantation (allo-HSCT). Methods. LNs were assayed to confirm the existence of proliferating macrophages after allo-HSCT. Ex vivo—expanded FRCs and bone marrow cells were cocultured to verify the generation of macrophages. Real-time quantitative PCR and ELISA assays were performed to observe the cytokines expressed by FRC. Transcriptome sequencing was performed to compare the difference between FRC-induced macrophages (FMs) and conventional macrophages. Mixed lymphocyte reaction and the utilization of FMs in acute graft-versus-host disease (aGVHD) mice were used to test the inhibitory function of FMs in T-cell immunity in vitro and in vivo. Results. We found a large number of proliferating macrophages near FRCs in LNs with tolerogenic phenotype under allo-HSCT conditions. Neutralizing anti–macrophage colony-stimulating factor receptor antibody abolished FMs generation in vitro. Phenotypic analysis and transcriptome sequencing suggested FMs possessed immunoinhibitory function. Mixed lymphocyte reaction proved that FMs could inhibit T-cell activation and differentiation toward Th1/Tc1 cells. Injection of FMs in aGVHD mice effectively attenuated aGVHD severity and mortality. Conclusions. This study has revealed a novel mechanism of immune regulation through the generation of FRC-induced tolerogenic macrophages in LNs at an early stage of allo-HSCT.
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影响因子：
15.9
作者：
Ito, Toshihiro;Schaller, Matthew;Kunkel, Steven L.
通讯作者：
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影响因子：
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