Th1 bias of liver mucosal-associated invariant T cells promotes hepatic gluconeogenesis in type 2 diabetes mellitus

Wenjuan Tang; Kang Ge; Lei Shen; Hongdong Wang; Wenhuan Feng; Xitai Sun; Xuehui Chu; Dalong Zhu; Hongli Yin; Yan Bi

doi:10.1002/dmrr.3620

Th1 bias of liver mucosal-associated invariant T cells promotes hepatic gluconeogenesis in type 2 diabetes mellitus

Diabetes Metab Res Rev. 2023 May;39(4):e3620. doi: 10.1002/dmrr.3620. Epub 2023 Feb 17.

Authors

Wenjuan Tang^{1

2}, Kang Ge^{1

2}, Lei Shen³, Hongdong Wang^{1

2}, Wenhuan Feng^{1

2}, Xitai Sun⁴, Xuehui Chu⁴, Dalong Zhu^{1

2}, Hongli Yin^{1

2}, Yan Bi^{1

2}

Affiliations

¹ Department of Endocrinology, Endocrine and Metabolic Disease Medical Center, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, China.
² Branch of National Clinical Research Center for Metabolic Diseases, Nanjing, China.
³ Shanghai Institute of Immunology, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
⁴ Department of General Surgery, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, China.

PMID: 36738300
DOI: 10.1002/dmrr.3620

Abstract

Aims: It is acknowledged that aberrant liver immunity contributes to the development of type 2 diabetes mellitus (T2DM). Mucosal-associated invariant T (MAIT) cells, an innate-like T-cell subset, are enriched in the human liver. Nevertheless, the characterisation and potential role of hepatic MAIT cells in T2DM remain unclear.

Materials and methods: Fourteen newly diagnosed T2DM subjects and 15 controls received liver biopsy. The frequency and cytokine production of MAIT cells were analysed by flow cytometry. The expression of genes involved in glucose metabolism was determined in HepG2 cells co-cultured with hepatic MAIT cells.

Results: Compared with controls, hepatic MAIT cell frequency was significantly increased in T2DM patients (24.66% vs. 14.61%, p = 0.001). There were more MAIT cells producing interferon-γ (IFN-γ, 60.49% vs. 33.33%, p = 0.021) and tumour necrosis factor-α (TNF-α, 46.84% vs. 5.91%, p = 0.021) in T2DM than in controls, whereas their production of interleukin 17 (IL-17) was comparable (15.25% vs. 4.55%, p = 0.054). Notably, an IFN-γ⁺ TNF-α⁺ IL-17^+/- producing MAIT cell subset was focussed, which showed an elevated proportion in T2DM (42.66% vs. 5.85%, p = 0.021) and positively correlated with plasma glucose levels. A co-culture experiment further indicated that hepatic MAIT cells from T2DM upregulated the gene expression of pyruvate carboxylase, a key molecule involved in gluconeogenesis, in HepG2 cells, and this response was blocked with neutralising antibodies against IFN-γ and TNF-α.

Conclusions: Our data implicate an increased Th1-like MAIT cell subset in the liver of newly diagnosed T2DM subjects, which induces hyperglycaemia by promoting hepatic gluconeogenesis. It provides novel insights into the immune regulation of metabolic homoeostasis.

Clinical trial registration number: NCT03296605 (registered at www.

Clinicaltrials: gov on 12 October 2018).

Keywords: hepatic gluconeogenesis; interferon-γ; mucosal-associated invariant T cells; tumour necrosis factor-α; type 2 diabetes mellitus.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Diabetes Mellitus, Type 2*
Gluconeogenesis
Humans
Interleukin-17
Liver
Mucosal-Associated Invariant T Cells* / physiology
Tumor Necrosis Factor-alpha

Substances

Interleukin-17
Tumor Necrosis Factor-alpha

Associated data

ClinicalTrials.gov/NCT03296605