The Detrimental Role of Regulatory T Cells in Nonalcoholic Steatohepatitis
Open accessAbstract
Nonalcoholic steatohepatitis (NASH) is induced by steatosis and metabolic inflammation. While involvement of the innate immune response has been shown, the role of the adaptive immune response in NASH remains controversial. Likewise, the role of regulatory T cells (Treg) in NASH remains unclear although initial clinical trials aim to target these regulatory responses. High‐fat high‐carbohydrate (HF‐HC) diet feeding of NASH‐resistant BALB/c mice as well as the corresponding recombination activating 1 ( Rag )‐deficient strain was used to induce NASH and to study the role of the adaptive immune response. HF‐HC diet feeding induced strong activation of intrahepatic T cells in BALB/c mice, suggesting an antigen‐driven effect. In contrast, the effects of the absence of the adaptive immune response was notable. NASH in BALB/c Rag1−/− mice was substantially worsened and accompanied by a sharp increase of M1‐like macrophage numbers. Furthermore, we found an increase in intrahepatic Treg numbers in NASH, but either adoptive Treg transfer or anti‐cluster of differentiation (CD)3 therapy unexpectedly increased steatosis and the alanine aminotransferase level without otherwise affecting NASH. Conclusion: Although intrahepatic T cells were activated and marginally clonally expanded in NASH, these effects were counterbalanced by increased Treg numbers. The ablation of adaptive immunity in murine NASH led to marked aggravation of NASH, suggesting that Tregs are not regulators of metabolic inflammation but rather enhance it.
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Adoptive Treg transfer and anti-CD3 antibody treatment are associated with increased hepatic steatosis and alanine aminotransferase levels under metabolic stress.
“Similarly, adoptive Treg transfer and anti-CD3 antibody treatment are associated with increased hepatic steatosis and alanine aminotransferase levels under metabolic stress (Dywicki et al. 2022).”
From The double-edged sword of regulatory T cells in MASLD: from inflammation control to fibrosis promotion (2026) · cites this paper as Dywicki et al. 2022
The Results section, “Adoptive Transfer of Tregs Increases Steatosis” (page unavailable), reports increased hepatic triglycerides after Treg transfer but does not report an increase in ALT from that transfer. The Results section on anti-CD3 F(ab)2’ treatment reports both increased hepatic triglycerides and increased ALT in high-fat, high-cholesterol diet–fed mice. Thus, the claim is supported for both outcomes after anti-CD3 treatment, but only for steatosis after Treg transfer. (LLM, conf=0.86)
Experimental — accuracy not yet measuredConflicting evidence exists regarding the safety and efficacy of Treg-based therapies, as adoptive Treg transfer has been reported to exacerbate MASH progression in certain dietary models.
“However, despite these encouraging results, conflicting evidence exists regarding the safety and efficacy of Treg-based therapies, as adoptive Treg transfer has been reported to exacerbate MASH progression in certain dietary models.”
From The double-edged sword of regulatory T cells in MASLD: from inflammation control to fibrosis promotion (2026) · cites this paper as Dywicki et al. 2022
In Results (‘Adoptive Transfer of Tregs Increases Steatosis’; page unavailable), the paper reports that Treg transfer in high-fat, high-carbohydrate-fed mice increased hepatic triglycerides. It also says the transfer had no influence on the aggravated NASH phenotype, so the claim that adoptive transfer exacerbated MASH progression overstates the finding. The more severe NASH phenotype reported elsewhere in Results followed anti-CD3 treatment, not adoptive Treg transfer. (LLM, conf=0.88)
Experimental — accuracy not yet measuredHuman studies have yielded conflicting results, with some reporting increased intrahepatic Treg numbers and others reduced frequencies in patients with MASLD.
“Human studies have similarly yielded conflicting results, with some studies reporting increased intrahepatic Treg numbers, whereas others have observed reduced frequencies in patients with MASLD (Bertola et al. 2010; Dywicki et al. 2022; Wang et al. 2021c).”
From The double-edged sword of regulatory T cells in MASLD: from inflammation control to fibrosis promotion (2026) · cites this paper as Dywicki et al. 2022
The Results and Discussion report increased intrahepatic Treg numbers in diet-fed mice, while the decrease they describe concerns visceral adipose tissue or other mouse models. Our copy does not report conflicting human studies showing increased versus reduced intrahepatic Tregs in patients with MASLD (searched for human patients, liver Treg frequencies, and conflicting results). (LLM, conf=0.76)
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- Authors
- Dywicki, J., Buitrago‐Molina, L. E., Noyan, F., Davalos‐Misslitz, A. C., Hupa‐Breier, K. L., Lieber, M., Hapke, M., Schlue, J., Falk, C. S., Raha, S., Prinz, I., Koenecke, C., Manns, M. P., Wedemeyer, H., Hardtke‐Wolenski, M., & Jaeckel, E.
- Affiliations
- Medizinische Hochschule Hannover (DE)
- Institute of Pathology,Hannover Medical School,Hannover,Germany
- Essen University Hospital (DE)
- Corresponding author
- Hardtke‐Wolenski, Matthias
- ORCID
- Venue
- Hepatology Communications
- Published
- 2021-08-25
- Volume
- 6
- Issue
- 2
- Pages
- 320-333
- ISSN
- 2471-254X (ISSN-L)
- PMC
- PMC8793993
- OpenAlex
- W3195261594
- Cited by
- 57
- References
- 41
- Citations by year
- 2026: 7 · 2025: 14 · 2024: 15 · 2023: 10 · 2022: 10 · 2021: 1
- FWCI
- 6.48
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- Hepatology Communications (publishedVersion, cc-by-nc-nd)
- PubMed Central (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- Universitätsbibliographie, Universität Duisburg-Essen (submittedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- DuEPublico (University of Duisburg-Essen) (submittedVersion, cc-by-nc-nd)
- Funders
- Deutsche Forschungsgemeinschaft (BU 2722/2‐3, HA 6880/2-3, HA6880/2-1)
- Topics
- Health Sciences › Medicine › Epidemiology › Liver Disease Diagnosis and Treatment
- Health Sciences › Medicine › Hepatology › Liver physiology and pathology
- Health Sciences › Medicine › Hepatology › Liver Diseases and Immunity
- Keywords
- nonalcoholic steatohepatitis, regulatory T cells, adaptive immune response, metabolic inflammation, steatosis, intrahepatic T cells, M1-like macrophages, Rag1-deficient mice, high-fat high-carbohydrate diet, adoptive Treg transfer, anti-CD3 therapy, alanine aminotransferase
- MeSH terms
- Diet, Carbohydrate Loading, Alanine Transaminase, Animals, Aspartate Aminotransferases, Disease Models, Animal, Immunologic Factors, Inflammation, Mice, Inbred BALB C, CD3 Complex, Disease Progression, Adoptive Transfer, T-Lymphocytes, Regulatory, Mice, Adaptive Immunity, Diet, High-Fat, Non-alcoholic Fatty Liver Disease
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