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<p>Follicular regulatory T (Tfr) cells maintain immune homeostasis by suppressing excessive germinal center (GC) responses. However, the molecular mechanisms governing Tfr differentiation remain incompletely understood. Here, we identify interleukin-6 (IL-6) as a key regulator of Tfr generation. IL-6/IL-6Rα signaling promotes the differentiation of regulatory T cells (Treg) into Tfr cells by inducing CCAAT/enhancer binding protein α (C/EBPα), which binds the <i>Bcl6</i> and <i>Cxcr5</i> promoters in Tfr cells. Treg-specific deletion of C/EBPα in mice impairs Tfr differentiation, resulting in hyperactive GC responses and exacerbated pathology in mouse models of systemic lupus erythematosus (SLE) and HDM-induced allergy. In humans, in silico perturbation of <i>CEBPA</i> in Tregs disrupts the Tfr differentiation trajectory. Furthermore, <i>CEBPA</i> expression in Tregs, but not total CD4<sup>+</sup> T cells, from patients with SLE negatively correlates with disease activity (SLEDAI). Thus, these findings establish the IL-6–C/EBPα axis as a critical mechanism driving Tfr differentiation to restrain pathogenic humoral immunity.</p>

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IL-6-induced C/EBPα drives follicular regulatory T cell differentiation to regulate humoral immunity in mice

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年7月7日

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  • Haena Lee,
  • Chan Johng Kim,
  • Hyunsoo Ahn,
  • Gayeon Cho,
  • Sang-Hyeon Mun,
  • Seung Won Kim,
  • Hyung-Seok Choi,
  • Dahun Um,
  • Hyeongseop Kim,
  • Haeun Ko,
  • Jaegyun Noh,
  • John Chulhoon Park,
  • Hye Eun Park,
  • Amit Sharma,
  • Yoontae Lee,
  • Seung-Woo Lee,
  • Youn Soo Choi,
  • Chang-Hee Suh,
  • Ji-Won Kim,
  • Tae-Kyung Kim,
  • Cheol-Sang Hwang,
  • Jong Kyoung Kim,
  • Sanguk Kim,
  • Sin-Hyeog Im

摘要

Follicular regulatory T (Tfr) cells maintain immune homeostasis by suppressing excessive germinal center (GC) responses. However, the molecular mechanisms governing Tfr differentiation remain incompletely understood. Here, we identify interleukin-6 (IL-6) as a key regulator of Tfr generation. IL-6/IL-6Rα signaling promotes the differentiation of regulatory T cells (Treg) into Tfr cells by inducing CCAAT/enhancer binding protein α (C/EBPα), which binds the Bcl6 and Cxcr5 promoters in Tfr cells. Treg-specific deletion of C/EBPα in mice impairs Tfr differentiation, resulting in hyperactive GC responses and exacerbated pathology in mouse models of systemic lupus erythematosus (SLE) and HDM-induced allergy. In humans, in silico perturbation of CEBPA in Tregs disrupts the Tfr differentiation trajectory. Furthermore, CEBPA expression in Tregs, but not total CD4+ T cells, from patients with SLE negatively correlates with disease activity (SLEDAI). Thus, these findings establish the IL-6–C/EBPα axis as a critical mechanism driving Tfr differentiation to restrain pathogenic humoral immunity.