Faircloth Tyler U, Temple Sara, Parr Rhett, Soma Alyssa, Massoumi Hamed, Jalilian Elmira, Djalilian Ali R, Hematti Peiman, Rajan Devi, Chinnadurai Raghavan
Department of Biomedical Sciences, Mercer University School of Medicine, Savannah, Georgia, USA.
Department of Ophthalmology and Visual Sciences, University of Illinois at Chicago, Chicago, Illinois, USA.
Cytotherapy. 2025 May;27(5):597-608. doi: 10.1016/j.jcyt.2025.01.009. Epub 2025 Jan 20.
Defining the mechanism of immune modulation by mesenchymal stromal cells (MSCs) from distinct anatomical tissues is of great translational interest. The human cornea is an immunologically privileged organ, and the mechanism of immunoregulation of cornea-derived MSCs (cMSCs) is currently unknown. We investigated cMSCs derived from the corneas of 5 independent human donorS for their fitness and mechanism of action in suppressing T cells. cMSCs display the immunophenotype CD45-CD73+CD105+CD90+CD44+ and robust in vitro growth. 30-plex secretome analysis identified that cMSCs innately secrete specific molecules in a dose-dependent manner. cMSCs do not express or upregulate costimulatory but do upregulate coinhibitory molecules upon stimulation with interferon γ (IFNγ). cMSCs inhibit T-cell proliferation in contact-dependent co-cultures, which can be predicted by a unique secretome signature. In addition, co-culturing in a 2-chamber transwell system has demonstrated that cMSCs also inhibit T-cell proliferation in a non-contact-dependent manner. Mechanistic analysis has demonstrated that activated T cells effectively induce indoleamine 2,3-dioxygenase (IDO) but not other enzymes of the tryptophan metabolic pathway in cMSCs. Silencing of IDO in cMSCs reduces their fitness to suppress T cells. These results provide evidence that in cMSCs, one of the principal mechanisms of immunosuppression on T cells is through IDO. These results suggest that MSCs derived from the human cornea display immunoregulatory properties and, thus, may play a role in maintaining the immune-privileged niche of the cornea.
明确来自不同解剖组织的间充质基质细胞（MSCs）的免疫调节机制具有重大的转化研究意义。人类角膜是一个免疫赦免器官，目前角膜来源的MSCs（cMSCs）的免疫调节机制尚不清楚。我们研究了来自5名独立人类供体角膜的cMSCs在抑制T细胞方面的适应性和作用机制。cMSCs表现出CD45-CD73+CD105+CD90+CD44+免疫表型且在体外生长旺盛。30重分泌组分析表明，cMSCs以剂量依赖的方式天然分泌特定分子。cMSCs不表达或上调共刺激分子，但在用干扰素γ（IFNγ）刺激后会上调共抑制分子。cMSCs在接触依赖性共培养中抑制T细胞增殖，这可以通过独特的分泌组特征预测。此外，在双室Transwell系统中共培养表明，cMSCs也以非接触依赖的方式抑制T细胞增殖。机制分析表明，活化的T细胞可有效诱导cMSCs中的吲哚胺2,3-双加氧酶（IDO），但不能诱导色氨酸代谢途径的其他酶。cMSCs中IDO的沉默降低了它们抑制T细胞的能力。这些结果提供了证据，表明在cMSCs中，对T细胞免疫抑制的主要机制之一是通过IDO。这些结果表明，源自人类角膜的MSCs具有免疫调节特性，因此可能在维持角膜的免疫赦免微环境中发挥作用。
