2. Academic Validation
  3. The phenotypic and functional characteristics of intrahepatic CD69+CD103+ tissue-resident MAIT cells in primary biliary cholangitis

The phenotypic and functional characteristics of intrahepatic CD69+CD103+ tissue-resident MAIT cells in primary biliary cholangitis

  • J Autoimmun. 2025 Jun:154:103442. doi: 10.1016/j.jaut.2025.103442.
Qiyun Xia 1,  Zhuwan Lyu 1,  Yudong Zhao 1,  Xiting Pu 1,  Jian Wang 2,  Yuyang Liu 1,  Yujie Zhou 1,  Jun Qian 1,  M E Gershwin 3,  Min Lian 4,  Xiong Ma 5
Affiliations

Affiliations

  • 1 Division of Gastroenterology and Hepatology, Shanghai Institute of Digestive Disease, NHC Key Laboratory of Digestive Diseases, State Key Laboratory for Oncogenes and Related Genes, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.
  • 2 Department of Cardiology, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, China.
  • 3 Division of Rheumatology, Allergy and Clinical Immunology, The University of California School of Medicine, Davis, 95616, Calif, USA. Electronic address: megershwin@ucdavis.edu.
  • 4 Division of Gastroenterology and Hepatology, Shanghai Institute of Digestive Disease, NHC Key Laboratory of Digestive Diseases, State Key Laboratory for Oncogenes and Related Genes, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China. Electronic address: sophialian24@163.com.
  • 5 Division of Gastroenterology and Hepatology, Shanghai Institute of Digestive Disease, NHC Key Laboratory of Digestive Diseases, State Key Laboratory for Oncogenes and Related Genes, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China; Institute of Aging & Tissue Regeneration, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China. Electronic address: maxiongmd@hotmail.com.
PMID: 40460780 DOI: 10.1016/j.jaut.2025.103442
Abstract

Background & aims: Mucosal-associated invariant T (MAIT) cells are an innate-like T cell subset that plays a significant role in the immunopathology of primary biliary cholangitis (PBC). However, our understanding of the subpopulations involved in hepatic residency have not been elucidated. Herein, our goal was to delineate the phenotypic and functional properties of intrahepatic tissue-resident MAIT cells in PBC.

Methods: Liver tissue and intrahepatic mononuclear cells were collected and analyzed by immunohistochemistry, immunofluorescence and flow cytometry. The transcriptome was determined using in vitro generated tissue-resident MAIT cells. FOXM1's immunoregulatory role was evaluated with inhibitor treatment and regulatory features of BHLHE40 were confirmed by CUT&Tag-seq and luciferase assays.

Results: In PBC, the frequency of intrahepatic MAIT cell decreased, but tissue-resident (CD69+CD103+) MAIT cells significantly expanded and expressed a notably pro-inflammatory phenotype, with substantial elevated expression of CXCR3, CXCR6; IL-17A, IFN-γ and T-bet. FOXM1, a transcriptional factor governing cell proliferation cycle, exhibited notably higher expression in tissue-resident MAIT cells than in non-resident MAIT cells. Inhibition of FOXM1 compromised the in vitro expansion of MAIT cells, and impaired the expression of CXCR3, IL-17A, IFN-γ and GM-SCF by tissue-resident MAIT cells. CUT&Tag-seq and luciferase assay revealed a direct regulation of FOXM1 of BHLHE40 expression.

Conclusion: Our data reveals a pro-inflammatory role of expanded tissue-resident MAIT cells in PBC mediated via higher expression of effector cytokines, chemokine receptors and a related transcriptional factor. FOXM1 critically regulates MAIT cell proliferation and tissue-resident pro-inflammatory function, via interaction with BHLHE40, and establishes a transcriptional axis linking proliferation to effector responses.

Keywords

Inflammation; Liver microenvironment; Mucosal-associated invariant T cells (MAIT cells); Primary biliary cholangitis (PBC); Tissue-residency.

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