Three-dimensional imaging and single-cell transcriptomics of the human kidney implicate perturbation of lymphatics in alloimmunity-猫眼课题宝

DOI：

10.1101/2022.10.28.514222

发表时间：

2022-10

期刊：

bioRxiv

影响因子：

通讯作者：

中科院分区：

其他

文献类型：

作者：

D. Jafree;B. Stewart;M. Kolatsi-Joannou;B. Davis;H. Mitchell;Lauren G. Russell;Lucía Marinas del Rey;W. Mason;Byung Il Lee;L. Heptinstall;Gideon Pomeranz;D. Moulding;Laura Wilson;Tahmina Wickenden;Saif N. Malik;N. Holroyd;C. Walsh;J. Chandler;Kevin X. Cao;P. Winyard;K. Price;A. Woolf;M. A. Busche;S. Walker-Samuel;P. Scambler;R. Motallebzadeh;M. Clatworthy;D. Long

从组织微环境中清除液体、大分子和白细胞的淋巴管系统的结构和分子特征的研究在很大程度上依赖于动物模型，除了传统的免疫组织化学评估之外，人体器官中的信息有限。在这里，我们使用三维成像和单细胞RNA测序来研究人类肾脏的代谢。我们发现人类肾脏内的淋巴管呈分层排列，从肾皮质中沿着专门的肾单位上皮细胞开始，并显示出独特的肾脏特异性转录谱。在慢性移植排斥反应中，我们发现肾移植淋巴管扩张伴随着结构层次的丧失，表达人类白细胞抗原的淋巴管浸润髓质，为同种异体反应性抗体提供了假定的靶点。这与淋巴管在淋巴细胞定植早期侵入和互连三级淋巴结构同时发生。细胞间信号传导的分析揭示了共抑制分子介导的CD 4 + T细胞-淋巴串扰在排斥肾中的上调，可能起到限制局部同种免疫应答的作用。总的来说，我们描绘了新的结构和分子特征的人类肾脏免疫系统，并揭示扰动其表型和转录组的背景下同种免疫。淋巴管调节体液平衡和免疫细胞积累，但在人体器官如肾脏中研究不足。Jafree及其同事使用三维成像和单细胞RNA测序分析了人类肾脏的结构，揭示了排斥肾移植的结构和转录扰动。

Studies of the structural and molecular features of the lymphatic vasculature, which clears fluid, macromolecules and leukocytes from the tissue microenvironment, have largely relied on animal models, with limited information in human organs beyond traditional immunohistochemical assessment. Here, we use three-dimensional imaging and single-cell RNA-sequencing to study lymphatics in the human kidney. We found a hierarchical arrangement of lymphatic vessels within human kidneys, initiating along specialised nephron epithelium in the renal cortex and displaying a distinct, kidney-specific transcriptional profile. In chronic transplant rejection we found kidney allograft lymphatic expansion alongside a loss of structural hierarchy, with human leukocyte antigen-expressing lymphatic vessels infiltrating the medulla, presenting a putative target for alloreactive antibodies. This occurred concurrently with lymphatic vessels invading and interconnecting tertiary lymphoid structures at early stages of lymphocyte colonisation. Analysis of intercellular signalling revealed upregulation of co-inhibitory molecule-mediated CD4+ T cell-lymphatic crosstalk in rejecting kidneys, potentially acting to limit local alloimmune responses. Overall, we delineate novel structural and molecular features of human kidney lymphatics and reveal perturbations to their phenotype and transcriptome in the context of alloimmunity. SUMMARY Lymphatics regulate fluid balance and immune cell accumulation but are under-studied in human organs such as the kidney. Jafree and colleagues profiled human kidney lymphatics using three-dimensional imaging and single-cell RNA-sequencing, revealing structural and transcriptional perturbations in rejecting kidney transplants.

Three-dimensional imaging and single-cell transcriptomics of the human kidney implicate perturbation of lymphatics in alloimmunity

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