Impairment of regulatory T cell stability in axial spondyloarthritis: role of EZH2 and pSTAT5

Majda Lyna Mebrek; Tessnime Abaab; Delphine Lemeiter; Magali Breckler; Roxane Hervé; Mylène Petit; Gaëlle Clavel; Johanna Sigaux; Marie-Christophe Boissier; Luca Semerano; Jérôme Biton; Natacha Bessis

doi:10.3389/fimmu.2024.1484321

Impairment of regulatory T cell stability in axial spondyloarthritis: role of EZH2 and pSTAT5

Front Immunol. 2024 Nov 6:15:1484321. doi: 10.3389/fimmu.2024.1484321. eCollection 2024.

Authors

Majda Lyna Mebrek^#^{1

2}, Tessnime Abaab^#^{1

2}, Delphine Lemeiter^{1

2}, Magali Breckler^{1

2}, Roxane Hervé^{1

2}, Mylène Petit^{1

2

3}, Gaëlle Clavel^{1

2

4}, Johanna Sigaux^{1

2

3}, Marie-Christophe Boissier^{1

2

3}, Luca Semerano^{1

2

3}, Jérôme Biton^#^{1

2}, Natacha Bessis^#^{1

2}

Affiliations

¹ UMR 1125 INSERM, Bobigny, France.
² Sorbonne Paris Nord University, Bobigny, France.
³ Assistance-Publique Hôpitaux de Paris (AP-HP), GHUPSSD, Department of Rheumatology, Bobigny, France.
⁴ Department of Internal Medicine, Fondation Rothschild, Paris, France.

^# Contributed equally.

Abstract

Background and objectives: Axial spondyloarthritis (axSpA) is a chronic inflammatory disease involving the spine, peripheral joints, and entheses. Functional impairment of regulatory T cells (Treg) is linked to inflammatory diseases, but limited data is available regarding Treg involvement in axSpA. Treg stability refers to their ability to maintain their functions and characteristics in pro-inflammatory environments. EZH2 and phosphorylated STAT5 (pSTAT5) play a critical role in maintaining Treg stability. We aimed to characterize Treg stability in patients with axSpA.

Methods: Peripheral blood mononuclear cells (PBMCs) from axSpA patients, either naïve from targeted therapy or treated by TNF inhibitors (TNFi), and from healthy donors (HD), were freshly isolated. Expression of stability (EZH2, pSTAT5) and suppressive (TNFR2 and CD39) markers by Treg was analyzed by flow cytometry.

Results: EZH2 expression by Treg was decreased in axSpA patients as compared to HD (p<0.01). Mechanistic study showed that inhibition of EZH2 attenuated Treg differentiation and suppressive phenotype in vitro. EZH2 was predominantly expressed by highly suppressive TNFR2⁺ and CD39⁺ Treg. Additionally, axSpA patients also exhibited a reduced frequency of pSTAT5⁺ Treg compared to HD (p<0.05), and pSTAT5⁺ Treg frequency increased at 3 months of TNFi treatment compared to baseline (p<0.05). This last result suggested a restoration of Treg stability upon TNFi treatment.

Conclusion: By highlighting a deficient expression of EZH2 and pSTAT5 by Treg, we revealed an impaired Treg stability in axSpA. Deciphering the pathways influenced by these molecules is necessary to assess the potential therapeutic benefits of restoring Treg stability in axSpA.

Keywords: EZH2; PSTAT5; TNF inhibitors; regulatory T cells; spondyloarthritis.

MeSH terms

Adult
Axial Spondyloarthritis* / immunology
Enhancer of Zeste Homolog 2 Protein* / metabolism
Female
Humans
Male
Middle Aged
Phosphorylation
STAT5 Transcription Factor* / metabolism
T-Lymphocytes, Regulatory* / immunology
T-Lymphocytes, Regulatory* / metabolism

Substances

Enhancer of Zeste Homolog 2 Protein
STAT5 Transcription Factor
EZH2 protein, human

Grants and funding

The author(s) declare financial support was received for the research, authorship, and/or publication of this article. Supported by unrestricted research grants from Chloé Recherche Foundation (Paris, France). A grant was also obtained from the Institut Fédératif de Recherche Biomédicale of Sorbonne Paris Nord University. This project has received funding from the Sorbonne Paris Nord University. The authors declare that this study received unrestricted research grants from Sandoz Inc. The funder was not involved in the study design, collection, analysis, interpretation of data, the writing of this article, or the decision to submit it for publication.