2. Academic Validation
  3. Alcaligenes faecalis induces intestinal T helper-17 cells by enhancing Rorc transcription through E3 ligase Trim21-mediated Fbxw7 degradation

Alcaligenes faecalis induces intestinal T helper-17 cells by enhancing Rorc transcription through E3 ligase Trim21-mediated Fbxw7 degradation

  • Immunity. 2025 Jun 10;58(6):1469-1483.e8. doi: 10.1016/j.immuni.2025.03.008.
Yingying Shen 1,  Zeyu Ma 2,  Hanliang Wang 3,  Yinghu Chen 4,  Yue Fang 5,  Lionel Apetoh 6,  Gensheng Zhang 7,  Fenglian He 8,  Shaofang Xie 9,  Jufeng Guo 10,  Shuaikang Cao 11,  Hai Li 11,  Qingqing Wang 12,  Jianli Wang 13,  Junjie Xu 14,  Zhijian Cai 15
Affiliations

Affiliations

  • 1 Department of Medical Oncology, Cancer Center of Zhejiang University, Sir Run Run Shaw Hospital, Medical School of Zhejiang University, Hangzhou 310020, Zhejiang, China.
  • 2 Department of Dermatology and Venerology, Sir Run Run Shaw Hospital, Medical School of Zhejiang University, Hangzhou 310020, Zhejiang, China.
  • 3 Liangzhu Laboratory, Zhejiang University School of Medicine, Hangzhou 311121, Zhejiang, China.
  • 4 Department of Infectious Disease, Children's Hospital, Zhejiang University School of Medicine, National Clinical Research Center for Child Health, Hangzhou 310052, Zhejiang, China.
  • 5 Liangzhu Laboratory, Zhejiang University School of Medicine, Hangzhou 311121, Zhejiang, China; Institute of Immunology and Department of Orthopaedics of the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310058, Zhejiang, China.
  • 6 Brown Center for Immunotherapy, Indiana University Melvin and Bren Simon Comprehensive Cancer Center, Indiana University School of Medicine, Indianapolis, IN 46202, USA.
  • 7 Department of Critical Care Medicine of the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310009, Zhejiang, China.
  • 8 School of Pharmacy, Fudan University, Shanghai 201203, China.
  • 9 Westlake Laboratory of Life Sciences and Biomedicine, School of Life Sciences, Westlake University, Hangzhou 310024, Zhejiang, China.
  • 10 Department of Breast Surgery, Affiliated Hangzhou First People's Hospital, School of Medicine, Westlake University, Hangzhou 310006, Zhejiang, China.
  • 11 Department of Pediatrics, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei 230001, China.
  • 12 Institute of Immunology, Zhejiang University School of Medicine, Hangzhou 310058, Zhejiang, China.
  • 13 Institute of Immunology and Bone Marrow Transplantation Center of the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310058, Zhejiang, China; Institute of Hematology, Zhejiang University & Zhejiang Engineering Laboratory for Stem Cell and Immunotherapy, Hangzhou 310006, Zhejiang, China.
  • 14 Key Laboratory of Laparoscopic Technology of Zhejiang Province, Department of General Surgery, Sir Run Shaw Hospital, Medical School of Zhejiang University, Hangzhou 310020, Zhejiang, China.
  • 15 Liangzhu Laboratory, Zhejiang University School of Medicine, Hangzhou 311121, Zhejiang, China; Institute of Immunology and Department of Orthopaedics of the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310058, Zhejiang, China. Electronic address: caizj@zju.edu.cn.
PMID: 40215968 DOI: 10.1016/j.immuni.2025.03.008
Abstract

Segmented filamentous bacteria are essential for intestinal T helper 17 (Th17) cell induction, but their colonization in the adult intestine is controversial. Therefore, whether there are gut microbiota (GMs) that mediate Th17 cell generation in humans of different ages is elusive. Here, we reported that colonization of ubiquitous Alcaligenes faecalis was sufficient to induce intestinal Th17 cells. Alcaligenes faecalis proteins were endocytosed by CD4+ T cells in a manner dependent on the small GTPase CDC42, inhibiting the interaction between E2 ubiquitin-conjugating enzyme Ube2w and E3 ubiquitin Ligase Trim21, thereby reducing TRIM21 self-ubiquitination and degradation, which increased Trim21-induced E3 ubiquitin Ligase Fbxw7 degradation and JunB accumulation, subsequently promoting Ahr and Rorc transcription, thus enhancing intestinal Th17 cell differentiation. Furthermore, outer membrane vesicles from Alcaligenes faecalis also induced intestinal Th17 cells in a Trim21-Fbxw7-axis-dependent manner. Altogether, these results reveal a vital role for the Trim21-Fbxw7 axis in intestinal Th17 cell enrichments among most humans.

Keywords

Alcaligenes faecalis; Fbxw7; Gut microbiota; Th17 cells; Trim21.

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