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Background <p>Behçet’s uveitis (BU) is a severe inflammatory ocular manifestation of Behçet’s disease, characterized by dysregulated T cell responses. However, the precise mechanisms underlying T cell dysfunction and local immune activation in BU remain poorly understood.</p> Methods <p>We performed single-cell RNA sequencing (scRNA-seq) of peripheral blood mononuclear cells (PBMCs) from BU patients and healthy controls (HCs). These data were integrated with publicly available single-cell transcriptomes of aqueous humor (AH) samples from BU patients. Key findings were validated using qPCR, flow cytometry, and functional assays.</p> Results <p>We observed a significant depletion of naive CD4⁺ T cells in BU, accompanied by their differentiation toward terminal effector states characterized by IL-32 and CXCR4 upregulation. IL-32 was identified as a central regulator promoting Th1 and Th17 polarization. Pseudotime trajectory analysis revealed a progressive differentiation process from circulating CD4⁺ T cells to Th17-like inflammatory cells within the AH, enriched for NF-κB and JAK-STAT signaling pathways. CXCR4 expression was associated with T cell chemotaxis into the ocular microenvironment. Cell-cell interaction analyses further highlighted active crosstalk between macrophages and CD4⁺ T cells via the MIF-(CD74<sup>+</sup>CXCR4/CD44) signaling axis.</p> Conclusion <p>Our study reveals a coordinated mechanism linking systemic T cell dysregulation to localized ocular inflammation in BU. Targeting IL-32 and CXCR4 may represent promising strategies for restoring immune balance and preventing tissue damage in BU.</p>

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Single-cell transcriptomic profiling reveals aberrant CD4⁺ naive T cell differentiation driving immune activation in Behçet’s uveitis

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年12月2日

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  • Lu Zhang,
  • Yimeng Sun,
  • Xinyu Yao,
  • Chun Yan,
  • Yunfei Liu,
  • Dijie Qiao,
  • Ziyu Du,
  • Cong Hu,
  • Fuying Guo,
  • Ziwei Meng,
  • Wei Chi

摘要

Background

Behçet’s uveitis (BU) is a severe inflammatory ocular manifestation of Behçet’s disease, characterized by dysregulated T cell responses. However, the precise mechanisms underlying T cell dysfunction and local immune activation in BU remain poorly understood.

Methods

We performed single-cell RNA sequencing (scRNA-seq) of peripheral blood mononuclear cells (PBMCs) from BU patients and healthy controls (HCs). These data were integrated with publicly available single-cell transcriptomes of aqueous humor (AH) samples from BU patients. Key findings were validated using qPCR, flow cytometry, and functional assays.

Results

We observed a significant depletion of naive CD4⁺ T cells in BU, accompanied by their differentiation toward terminal effector states characterized by IL-32 and CXCR4 upregulation. IL-32 was identified as a central regulator promoting Th1 and Th17 polarization. Pseudotime trajectory analysis revealed a progressive differentiation process from circulating CD4⁺ T cells to Th17-like inflammatory cells within the AH, enriched for NF-κB and JAK-STAT signaling pathways. CXCR4 expression was associated with T cell chemotaxis into the ocular microenvironment. Cell-cell interaction analyses further highlighted active crosstalk between macrophages and CD4⁺ T cells via the MIF-(CD74+CXCR4/CD44) signaling axis.

Conclusion

Our study reveals a coordinated mechanism linking systemic T cell dysregulation to localized ocular inflammation in BU. Targeting IL-32 and CXCR4 may represent promising strategies for restoring immune balance and preventing tissue damage in BU.