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<p>Lupus nephritis (LN), a serious complication of systemic lupus erythematosus, is characterized by the deposition of IgG immune complexes. The generation of these autoantibodies depends on T follicular helper (Tfh) cells within secondary lymphoid organs. However, the potential contribution of Tfh cells residing within the kidney has remained unexplored. Here, our analysis of a single-cell kidney dataset from LN patients, alongside studies in humanized chimeras and kidney organoids, identifies the accumulation of renal Tfh cells. Mechanistically, self-DNA-stimulated LN-associated mesangial cells (MC) promote Tfh differentiation by inducing CNBP-mediated MPC1 deficiency, leading to increased lactate production. In turn, elevated lactate levels enhance PCAF-catalyzed BCL6 lactylation and subsequent K6- and K29-linked ubiquitination at Lys430, preventing proteasomal degradation of BCL6. Stabilization of BCL6 ultimately reinforces Tfh differentiation, amplifying renal autoimmune responses. Importantly, targeted depletion of Tfh cells mitigates disease progression in humanized chimeras. Thus, our findings reveal a tissue program of Tfh differentiation within the autoimmune kidney microenvironment, identifying a potential therapeutic target for the management of LN.</p>

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Lactate bridges mesangial cells to the differentiation of follicular helper T cells in lupus nephritis

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年12月11日

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  • Mengdi Liu,
  • Huiyan Ji,
  • Jiaxin Lei,
  • Ming Zheng,
  • Lingyi Li,
  • Xingyu Zhai,
  • Hongmin Wang,
  • Ting Liu,
  • Qinghua Cao,
  • Lin Xu,
  • Zhenke Wen

摘要

Lupus nephritis (LN), a serious complication of systemic lupus erythematosus, is characterized by the deposition of IgG immune complexes. The generation of these autoantibodies depends on T follicular helper (Tfh) cells within secondary lymphoid organs. However, the potential contribution of Tfh cells residing within the kidney has remained unexplored. Here, our analysis of a single-cell kidney dataset from LN patients, alongside studies in humanized chimeras and kidney organoids, identifies the accumulation of renal Tfh cells. Mechanistically, self-DNA-stimulated LN-associated mesangial cells (MC) promote Tfh differentiation by inducing CNBP-mediated MPC1 deficiency, leading to increased lactate production. In turn, elevated lactate levels enhance PCAF-catalyzed BCL6 lactylation and subsequent K6- and K29-linked ubiquitination at Lys430, preventing proteasomal degradation of BCL6. Stabilization of BCL6 ultimately reinforces Tfh differentiation, amplifying renal autoimmune responses. Importantly, targeted depletion of Tfh cells mitigates disease progression in humanized chimeras. Thus, our findings reveal a tissue program of Tfh differentiation within the autoimmune kidney microenvironment, identifying a potential therapeutic target for the management of LN.