*Purpose: BK virus nephropathy (BKVN) may cause renal allograft dysfunction and failure. However, a specific antiviral agent for BK virus does not exist. Increasing evidence indicates that targeting the microenvironment (ME) represents a promising therapeutic approach in BKVN, highlighting an urgent need to deepen the understanding of the complex BKVN ME.

*Methods: Single-cell RNA sequencing was performed on 3 BKVN and 2 stable grafts (STA) biopsies (Fig 1A). Consensus non-negative matrix factorization (cNMF) was used to identify the subsets of proximal tubule cells (PTCs). To evaluate the relative abundance of each cell type identified in the present study, MUlti-Subject SIngle Cell deconvolution (MuSiC) was performed. Subsequently, the relative cell abundance was divided into high 50% and low 50%. Kaplan-Meier analysis was performed to evaluate the prognostic value of cell clusters and determine the role of these cell clusters in BKVN progression. Furthermore, we explored potential interactions between different cell types in the ME by CellPhoneDB. Finally, the findings were validated by immunofluorescence (IF) and flow cytometer.

*Results: Eight distinct cell populations (Fig 1B) were identified. Notably, a cluster of epithelial-immune dual-feature of PTCs (IGHM⁺/LRP2⁺ PTCs) were discovered by cNMF and IF (Fig 2A and 2B). The number of IGHM⁺/LRP2⁺ PTCs was significantly increased in BKVN as compared with STA (p < 0.05, Fig 2C and 2D). Additionally, IGHM⁺/LRP2⁺ PTCs were found to be related to poor prognosis of BKVN (p < 0.05). Further characterization of cellular components of the ME and their interactions revealed that IGHM⁺/LRP2⁺ PTCs were positively correlated with the expression of co-inhibitory receptors (e.g. FAM3C-PD1) on T cells, demonstrating their capacity for immune suppression.

*Conclusions: This study provided a high-resolution atlas of BKVN and found IGHM⁺/LRP2⁺ PTCs might lead to T cell exhaustion and then contributed to BKVN progression through co-inhibitory receptors. The results provide new insights into the multicellular ecosystem of BKVN and offer important clinical implications in the future.

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