迁移性 CD103+ 树突状细胞的后天免疫刺激表型会促进角膜移植后的异体免疫。

IF 6.3 1区 医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL JCI insight Pub Date : 2024-10-22 DOI:10.1172/jci.insight.182469
Tomás Blanco, Hayate Nakagawa, Aytan Musayeva, Mark Krauthammer, Rohan Bir Singh, Akitomo Narimatsu, Hongyan Ge, Sara I Shoushtari, Reza Dana
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引用次数: 0

摘要

移植后,T辅助细胞1(Th1)介导的免疫排斥是移植失败的主要原因。Th1细胞的致敏作用是通过抗原递呈细胞亚群,特别是CD11b+树突状细胞(DC2)和CD103+树突状细胞(DC1)之间复杂且依赖环境的相互作用而发生的。这种相互作用需要在移植免疫的背景下进一步研究。我们利用成熟的角膜移植临床前模型,确定了迁移性 CD103+ DC1 在影响移植组织结果方面的不同作用。在未发炎角膜床的受者中,迁移性 CD103+DC1 表现出耐受表型,主要通过 IL-10 调节 CD11b+DC2 的免疫原性,通过 PD-L1/PD-1 途径抑制异性反应的 CD4+Th1 细胞,通过 αvβ8 整合素激活的 TGFβ1 增强 Treg 介导的耐受性,从而促进移植物存活。相反,在角膜床有炎症和血管的受体中,CD4+Th1 细胞产生的 IFN-γ 会诱导 CD103+DC1 迁移,使其采用免疫刺激表型,其特点是下调包括 αvβ8 整合素和 IL-10 在内的调节标记物,上调 IL-12 和成本刺激分子 CD80/86,从而导致移植物失败。体内外诱导的耐受性 CD103+DC1(iDC1)的收养性转移能有效抑制 Th1 极化,并保留其生理对应物的耐受性表型。总之,我们的研究结果强调了 CD103+DC1 在调节宿主同种免疫反应中的重要作用。
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Acquired immunostimulatory phenotype of migratory CD103+ DCs promotes alloimmunity following corneal transplantation.

After transplantation, Th1-mediated immune rejection is the predominant cause of graft failure. Th1 cell sensitization occurs through complex and context-dependent interaction among antigen-presenting cell subsets, particularly CD11b+ DCs (DC2) and CD103+ DCs (DC1). This interaction necessitates further investigation in the context of transplant immunity. We used well-established preclinical models of corneal transplantation and identified distinct roles of migratory CD103+ DC1 in influencing the outcomes of the grafted tissue. In recipients with uninflamed corneal beds, migratory CD103+ DC1 demonstrate a tolerogenic phenotype that modulates the immunogenic capacity of CD11b+ DC2 primarily mediated by IL-10, suppressing alloreactive CD4+ Th1 cells via the PD-L1/PD-1 pathway and enhancing Treg-mediated tolerance via αvβ8 integrin-activated TGF-β1, thus facilitating graft survival. Conversely, in recipients with inflamed and vascularized corneal beds, IFN-γ produced by CD4+ Th1 cells induced migratory CD103+ DC1 to adopt an immunostimulatory phenotype, characterized by the downregulation of regulatory markers, including αvβ8 integrin and IL-10, and the upregulation of IL-12 and costimulatory molecules CD80/86, resulting in graft failure. The adoptive transfer of ex vivo induced tolerogenic CD103+ DC1 (iDC1) effectively inhibited Th1 polarization and preserved the tolerogenic phenotype of their physiological counterparts. Collectively, our findings underscore the essential role played by CD103+ DC1 in modulating host alloimmune responses.

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来源期刊
JCI insight
JCI insight Medicine-General Medicine
CiteScore
13.70
自引率
1.20%
发文量
543
审稿时长
6 weeks
期刊介绍: JCI Insight is a Gold Open Access journal with a 2022 Impact Factor of 8.0. It publishes high-quality studies in various biomedical specialties, such as autoimmunity, gastroenterology, immunology, metabolism, nephrology, neuroscience, oncology, pulmonology, and vascular biology. The journal focuses on clinically relevant basic and translational research that contributes to the understanding of disease biology and treatment. JCI Insight is self-published by the American Society for Clinical Investigation (ASCI), a nonprofit honor organization of physician-scientists founded in 1908, and it helps fulfill the ASCI's mission to advance medical science through the publication of clinically relevant research reports.
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