Biology subjects

Baeten, P.

Publications and source records attributed to Baeten, P..

4 recordsLinked to original sources

bioRxiv2025

Targeting Impaired Type I Interferon IL-27 Signaling Rescues T Regulatory Cell Suppressive Function in Relapsing-Remitting Multiple Sclerosis

T Regulatory T cells (Tregs) from patients with relapsing-remitting multiple sclerosis (RRMS) exhibit impaired suppressive function, yet the underlying molecular mechanisms remain elusive. Single-cell RNA sequencing (scRNAseq) of ex vivo-sorted Tregs from RRMS patients and matched healthy controls (HCs) revealed down-regulation of type I IFN (IFN) and IL-27 signaling pathways in RRMS Tregs. These Tregs showed reduced expression of IFN-stimulated genes (ISGs) (ISG15, MX1, IFITM1, IFI44L, OAS1), as well as key mediators of Treg suppressive function (LGALS3, CD81, FCRL3, CD7, CSTB), all suggesting a key role of decreased IFN signaling in RRMS Treg dysfunction. To therapeutically target IFN signaling pathways and improve Treg suppressive functions, we used cGAMP-loaded microparticles (MPs) to activate the stimulator of IFN genes (STING) in experimental autoimmune encephalomyelitis (EAE). cGAMP-MP treatment ameliorated EAE via induction of Tregs expressing IL-27R, IL-10, TGF-b, and Granzyme B. This effect was abolished in Treg-specific IL-27R (Treg{Delta}Il27ra) knockout mice, confirming that IL-27 signaling is essential for Treg suppression. In vitro IL-27 stimulation of RRMS-derived Tregs restored expression of IFN pathway genes (IRF1, IFNGR, IFI16) and Treg suppressive genes (ICOS, IKZF3, IL7R, TIGIT). Thus, we propose that IL-27 pre-stimulation may restore their suppressive function and migration (via CCR6, CCR7, S100A11 and S1PR4) to the central nervous system (CNS) in future clinical trials. SignificanceSeveral studies have reported a role for type I IFN and IL-27 signaling in the induction of suppressive Tregs in autoimmune diseases. We report that RRMS Tregs have decreased expression of type I IFN and IL-27 signalling-related genes in comparison to HCs. The animal model of MS (EAE) was successfully treated with cGAMP-MPs, which, via induction of type I IFN, IL-27 and IL-10, restored Treg suppressive function. A scRNAseq study of Tregs from MS patients revealed that IL-27 in vitro stimulation normalized the expression of type I IFN genes and Treg suppressive genes. We propose that IL-27 pre-treatment may enhance Treg suppressive function and migration to the CNS in future clinical trials.

immunology↗

bioRxiv2024

IL-34 empowers regulatory T cells with novel non-canonical function to safeguard brain barrier integrity during neuro-inflammation.

In efforts to find reparative strategies for brain damage, brain-associated regulatory T cells (Tregs) have gained increasing attention in recent years. Beyond their textbook immunoregulatory function, Tregs have emerged as key players in the response to brain trauma and the restoration of damaged brain tissue. Here, we are the first to describe a novel, non-canonical function of Tregs in maintaining the sealing capacity of both the blood-brain barrier (BBB) and the blood-cerebrospinal fluid (CSF) barrier. Moreover, we identified the cytokine IL-34 as a critical determinant in this newly unveiled Treg function. Mechanistically, IL-34 exerts its influence by modulating the expression and localization of the tight junction protein ZO-1 in both BBB endothelial cells and choroid plexus epithelial cells, thereby reinforcing the strength of the brain barriers. Given the well-established notion of leaky brain barriers and the involvement of immunological components in neurological diseases such as Alzheimers disease (AD) and multiple sclerosis (MS), we further demonstrate diminished IL-34 expression in Tregs derived from patients with relapsing-remitting MS (RR-MS) and patients with AD and even mild cognitive impairment (MCI). Remarkably, our study reveals the potential of IL-34 treatment in reinstating the integrity of brain barriers within murine models mimicking these neurological disorders. These ground-breaking findings shed light on the intricate relationship between Tregs, IL-34, and the integrity of brain barriers. They offer novel avenues for therapeutic approaches to ameliorate brain barrier dysfunction in the context of neurological disorders.

immunology↗

bioRxiv2022

Rapamycin rescues loss-of-function in blood-brain barrier-interacting regulatory T cells

In many autoimmune diseases, FOXP3+ regulatory T cells (Tregs) skew towards a pro-inflammatory and non-suppressive phenotype and are therefore unable to control the exaggerated autoimmune response. This may largely impact the success of autologous Treg therapy which is currently under investigation for treatment of autoimmune diseases, including multiple sclerosis (MS). Thus, there is a need to ensure in vivo stability of Tregs before successful Treg therapy can be applied. Using a murine genetic fate-mapping model, we demonstrate that inflammatory exFOXP3 T cells accumulate in the central nervous system (CNS) during experimental autoimmune encephalomyelitis (EAE). In a human in vitro BBB model, we discovered that interaction with inflamed blood-brain barrier (BBB)-endothelial cells induces loss of suppressive function in Tregs. Transcriptome analysis further revealed that Tregs which migrated across inflamed BBB-endothelial cells in vitro have a pro-inflammatory Th1/17 signature and upregulate the mTORC1 signaling pathway compared to non-migrated Tregs. These findings suggest that interaction with BBB-endothelial cells is sufficient to affect Treg function, and that transmigration triggers an additive pro-inflammatory phenotype switch, which was also seen in CNS-derived exFOXP3 T cells of EAE mice. In vitro treatment of migrated human Tregs with the clinically-approved mTORC1 inhibitor rapamycin completely restored the loss of suppressive function. Finally, flow cytometric analysis indicated an enrichment of inflammatory, less suppressive CD49d+ Tregs in the cerebrospinal fluid of MS patients, thereby underscoring the relevance of our findings for human disease. In sum, our findings provide firm evidence that the inflamed BBB affects human Treg stability, which can be restored using a mTORC1 inhibitor. These insights can help in significantly improving the efficacy of autologous Treg therapy of MS.

immunology↗

bioRxiv2022

Fatty acid desaturation by stearoyl-CoA desaturase-1 controls regulatory T cell differentiation and autoimmunity

The imbalance between pathogenic and protective T cell subsets is a cardinal feature of autoimmune disorders such as multiple sclerosis (MS). Emerging evidence indicates that endogenous and dietary-induced changes in fatty acid metabolism have a major impact on both T cell fate and autoimmunity. To date, however, the molecular mechanisms that underlie the impact of fatty acid metabolism on T cell physiology and autoimmunity remain poorly understood. Here, we report that stearoyl-CoA desaturase-1 (SCD1), an enzyme essential for the desaturation of fatty acids and highly regulated by dietary factors, acts as an endogenous brake on regulatory T cell (Treg) differentiation and augments autoimmunity in an animal model of MS. Guided by RNA sequencing and lipidomics analysis, we found that absence of Scd1 promotes hydrolysis of triglycerides and phosphatidylcholine through adipose triglyceride lipase (ATGL). ATGL-dependent release of docosahexaenoic acid enhanced Treg differentiation by activating the nuclear receptor peroxisome proliferator-activated receptor gamma. Our findings identify fatty acid desaturation by SCD1 as an essential determinant of Treg differentiation and autoimmunity, with potentially broad implications for the development of novel therapeutic strategies and dietary interventions for autoimmune disorders.

immunology↗