Roch Toralf, Paniskaki Krystallenia, Wehler Patrizia, Thieme Constantin J, Moradian Hanieh, Blazquez-Navarro Arturo, Anft Moritz, Reinke Petra, Westhoff Timm H, Stervbo Ulrik, Babel Nina
Center for Translational Medicine, Medical Department I, Marien Hospital Herne, University Hospital of the Ruhr-University Bochum, Hölkeskampring 40, Herne, Germany.
Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Berlin-Brandenburg Center for Regenerative Therapies, Humboldt-Universität Zu Berlin, and Berlin Institute of Health, Augustenburger Platz 1, 13353, Berlin, Germany.
J Nephrol. 2025 Jun 4. doi: 10.1007/s40620-025-02298-2.
Reactivation of the BK virus (BKV) is a critical adverse event after kidney transplantation and can lead to graft loss. BKV-reactive T cell-mediated viral control can be facilitated by reducing immunosuppression. However, the exact mechanism underlying the T cell-mediated BKV clearance in the kidney transplant is not clear.
Here, we used urine-derived renal tubular epithelial cells as a model system to investigate the immunomodulatory capacity of urine-derived renal tubular epithelial cells and their potential to induce T cell responses against BKV. Urine-derived renal tubular epithelial cells were generated by culturing urine-derived cell pellets. To assess the inflammatory potential of urine-derived renal tubular epithelial cells, the cells were treated with Poly I:C or TNFα/IFNγ. To investigate urine-derived renal tubular epithelial cell-induced T cell responses, autologous T cells, isolated from blood were co-cultured with urine-derived renal tubular epithelial cells, in the presence of BKV protein-derived peptides and PolyI:C or TNFα/IFNγ. BKV-reactive T cells, cytokine/chemokine secretion and expression of co-stimulatory molecules were evaluated using multiplex assays and multi-parameter flow cytometry.
Urine-derived renal tubular epithelial cells phenotypically resemble renal tubular epithelial cells, as they express CD13, EPCAM, cytokeratin and the myo-inositol oxygenase. After stimulation with PolyI:C, urine-derived renal tubular epithelial cells showed increased levels of CD40 and HLA-ABC, whereas TNFα/IFNγ only induced HLA-DR/ABC expression. Poly I:C and TNFα/IFNγ stimulation of urine-derived renal tubular epithelial cells induced a district pattern of inflammatory cytokines and chemokines that facilitate the migration of certain immune cell subsets. Interestingly, urine-derived renal tubular epithelial cells can present BKV peptides, thereby inducing a functional BKV-reactive CD4 and CD8 T cell response.
Urine-derived renal tubular epithelial cells express immunomodulatory molecules, and induce BKV-directed T cell reactivity, indicating that renal epithelial cells may serve as non-conventional antigen-presenting cells in the kidney and thereby help BKV clearance.
BK病毒（BKV）再激活是肾移植后的一个关键不良事件，可导致移植肾丢失。减少免疫抑制可促进BKV反应性T细胞介导的病毒控制。然而，肾移植中T细胞介导的BKV清除的确切机制尚不清楚。
在此，我们使用尿源性肾小管上皮细胞作为模型系统，研究尿源性肾小管上皮细胞的免疫调节能力及其诱导针对BKV的T细胞反应的潜力。尿源性肾小管上皮细胞通过培养尿源性细胞沉淀生成。为评估尿源性肾小管上皮细胞的炎症潜力，用聚肌胞苷酸（Poly I:C）或肿瘤坏死因子α/干扰素γ（TNFα/IFNγ）处理细胞。为研究尿源性肾小管上皮细胞诱导的T细胞反应，将从血液中分离的自体T细胞与尿源性肾小管上皮细胞在BKV蛋白衍生肽以及聚肌胞苷酸或TNFα/IFNγ存在的情况下共培养。使用多重检测和多参数流式细胞术评估BKV反应性T细胞、细胞因子/趋化因子分泌以及共刺激分子的表达。
尿源性肾小管上皮细胞在表型上类似于肾小管上皮细胞，因为它们表达CD13、上皮细胞黏附分子（EPCAM）、细胞角蛋白和肌醇加氧酶。用聚肌胞苷酸刺激后，尿源性肾小管上皮细胞显示CD40和人类白细胞抗原ABC（HLA-ABC）水平升高，而TNFα/IFNγ仅诱导人类白细胞抗原DR/ABC（HLA-DR/ABC）表达。聚肌胞苷酸和TNFα/IFNγ对尿源性肾小管上皮细胞的刺激诱导了一种特定模式的炎性细胞因子和趋化因子，促进某些免疫细胞亚群的迁移。有趣的是，尿源性肾小管上皮细胞可呈递BKV肽，从而诱导功能性BKV反应性CD4和CD8 T细胞反应。
尿源性肾小管上皮细胞表达免疫调节分子，并诱导针对BKV的T细胞反应性，表明肾上皮细胞可能作为肾脏中非传统的抗原呈递细胞，从而有助于BKV清除。
