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Nat. Commun., 07 July 2026 | https://doi.org/10.1038/s41467-026-75308-x IL-6-induced C/EBPα drives follicular regulatory T cell differentiation to regulate humoral immunity in mice

Haena Lee^1†, Chan Johng Kim^2,3†, Hyunsoo Ahn⁴, Gayeon Cho¹, Sang-Hyeon Mun⁵, Seung Won Kim¹, Hyung-Seok Choi¹, Dahun Um¹, Hyeongseop Kim⁶, Haeun Ko¹, Jaegyun Noh¹, John Chulhoon Park¹, Hye Eun Park¹, Amit Sharma^1,7, Yoontae Lee¹, Seung-Woo Lee¹, Youn Soo Choi^8,9,10, Chang-Hee Suh^11,12, Ji-Won Kim¹¹, Tae-Kyung Kim¹, Cheol-Sang Hwang⁵, Jong Kyoung Kim¹, Sanguk Kim^1,6, and Sin-Hyeog Im^1,6,13*

¹Department of Life Sciences, Pohang University of Science and Technology, Pohang, Republic of Korea.
²Institute for Protein Design, University of Washington, Seattle, WA, USA.
³Department of Biochemistry, University of Washington, Seattle, WA, USA.
⁴Graduate School of Artificial Intelligence, Pohang University of Science and Technology, Pohang, Republic of Korea.
⁵Department of Life Sciences, Korea University, Seoul, Republic of Korea
⁶Division of Interdisciplinary Bioscience & Bioengineering, Pohang University of Science and Technology, Pohang, Republic of Korea.
⁷Innovation Research Center for Bio-future Technology (B-IRC), Pohang University of Science and Technology, Pohang, Republic of Korea.
⁸Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul, Republic of Korea
⁹Department of Medicine, Seoul National University College of Medicine, Seoul, Republic of Korea
¹⁰Transplantation Research Institute, Seoul National University Hospital, Seoul, Republic of Korea
¹¹Department of Rheumatology, Ajou University School of Medicine, Suwon, Republic of Korea.
¹²Department of Molecular Science and Technology, Ajou University, Suwon, Republic of Korea.
¹³ImmunoBiome, Bio Open Innovation Center, Pohang, Republic of Korea.

^†These authors contributed equally
^*Correspondence to: Sin-Hyeog Im

Abstract

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.

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