STAT1 deficiency underlies a proinflammatory imprint of naive CD4+ T cells in spondyloarthritis

Bilade Cherqaoui; Frédéric Crémazy; Marc Lauraine; Ghazal Shammas; Roula Said-Nahal; Hendrick Mambu Mambueni; Félicie Costantino; Marine Fourmont; Audrey Hulot; Henri-Jean Garchon; Simon Glatigny; Luiza M Araujo; Maxime Breban

doi:10.3389/fimmu.2023.1227281

STAT1 deficiency underlies a proinflammatory imprint of naive CD4⁺ T cells in spondyloarthritis

Front Immunol. 2023 Oct 18:14:1227281. doi: 10.3389/fimmu.2023.1227281. eCollection 2023.

Authors

Bilade Cherqaoui^{1

2}, Frédéric Crémazy^{1

2}, Marc Lauraine^{1

2}, Ghazal Shammas^{1

2}, Roula Said-Nahal³, Hendrick Mambu Mambueni^{1

2

4}, Félicie Costantino^{1

2

3}, Marine Fourmont^{1

2}, Audrey Hulot^{1

2}, Henri-Jean Garchon^{1

2

4}, Simon Glatigny^{1

2}, Luiza M Araujo^{1

2}, Maxime Breban^{1

2

3}

Affiliations

¹ Infection & Inflammation, UMR 1173, Inserm, UVSQ/Université Paris Saclay, Montigny-le-Bretonneux, France.
² Laboratoire d'Excellence Inflamex, Université Paris-Centre, Paris, France.
³ Rheumatology Division, Ambroise Paré Hospital, AP-HP, Boulogne-Billancourt, France.
⁴ Genomic Platform of Faculty of Health Simone Veil, UVSQ/Université Paris Saclay, Montigny-le-Bretonneux, France.

Abstract

Introduction: In spondyloarthritis (SpA), an increased type 3 immune response, including T helper cells (Th) 17 excess, is observed in both human and SpA animal models, such as the HLA-B27/human β2-microglobulin transgenic rat (B27-rat).

Methods: To investigate this unexplained Th17-biased differentiation, we focused on understanding the immunobiology of B27-rat naive CD4⁺ T cells (Tn).

Results: We observed that neutrally stimulated B27-rat Tn developed heightened Th17 profile even before disease onset, suggesting an intrinsic proinflammatory predisposition. In parallel with this observation, transcriptomic and epigenomic analyses showed that B27-rat Tn exhibited a decreased expression of Interferon/Th1- and increased expression of Th17-related genes. This molecular signature was predicted to be related to an imbalance of STAT1/STAT3 transcription factors activity. Stat1 mRNA and STAT1 protein expression were decreased before disease onset in Tn, even in their thymic precursors, whereas Stat3/STAT3 expression increased upon disease establishment. Confirming the relevance of these results, STAT1 mRNA expression was also decreased in Tn from SpA patients, as compared with healthy controls and rheumatoid arthritis patients. Finally, stimulation of B27-rat Tn with a selective STAT1 activator abolished this preferential IL-17A expression, suggesting that STAT1-altered activity in B27-rats allows Th17 differentiation.

Discussion: Altogether, B27-rat Tn harbor a STAT1 deficiency preceding disease onset, which may occur during their thymic differentiation, secondarily associated with a persistent Th17 bias, which is imprinted at the epigenomic level. This early molecular phenomenon might lead to the persistent proinflammatory skew of CD4⁺ T cells in SpA patients, thus offering new clues to better understand and treat SpA.

Keywords: HLA-B27; STAT1; T helper 17; ankylosing spondylitis; dendritic cells; epigenomic; naive CD4 + T cells; spondyloarthritis.

Publication types

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

MeSH terms

Animals
Arthritis, Rheumatoid* / metabolism
CD4-Positive T-Lymphocytes
Humans
RNA, Messenger / metabolism
Rats
Rats, Transgenic
STAT1 Transcription Factor / metabolism
Spondylarthritis*

Substances

RNA, Messenger
STAT1 protein, human
STAT1 Transcription Factor
Stat1 protein, rat

Grants and funding

This work was supported in part by grants from Inflamex Laboratory of Excellence (INFLAMEX G11003LH), unrestricted grant from Novartis Pharma (19DON039). BC’s work was supported by a grant from the Société Française de Rhumatologie (SFR). The funders were not involved in the study design, collection, analysis, interpretation of data, the writing of this article or the decision to submit it for publication.