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Kasimoglu, E.

Publications and source records attributed to Kasimoglu, E..

2 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↗
bioRxiv2025

CD11c+ CD8 T cells cause IFN-g-dependent autoimmune neuroinflammation that is restrained by PD-1 signaling.

In multiple sclerosis (MS) lesions, CD8 T cells outnumber CD4 T cells, suggesting that they contribute to MS pathology. However, little is known on the role of CD8 T cells in MS, partially due to the nearly ubiquitous use of experimental autoimmune encephalomyelitis (EAE) models that are mediated by CD4 T cells, with no CD8 T cell contribution. Importantly, MS and EAE differ in both their distribution of CNS lesions and their symptoms, indicating differences in CNS inflammation. MS lesions are more prevalent in the brain, while EAE lesions are more frequent in the spinal cord. Additionally, neurologic deficits in MS rarely parallel the paralysis typical for CD4 T cell-mediated EAE (CD4-EAE). In contrast, CD8-EAE models suggest that CD8 T cells preferentially cause brain inflammation, but little is known regarding how brain and spinal cord inflammation may differ, and how CD8 T cells may contribute to those differences. We have established an adoptive CD8-EAE mouse model characterized by brain-centered inflammation, severe ataxia, and weight loss. CNS inflammation in the brain and spinal cord differed in immune cell numbers, cellular composition, and inflammatory signatures. CD8-EAE could be suppressed by blocking IFN-{gamma}, and exacerbated by blocking PD-1, with concomitant changes in numbers of CNS-infiltrating monocytes. Most CD8 T cells in the CNS were CD11c+, suggesting that they are the pathogenic subset. We describe a robust CD8-EAE model, identify differences between brain and spinal cord inflammation, and characterize mechanisms that control CD8 T cell-mediated neuroinflammation, thereby furthering understanding of these cells in EAE/MS. Brief SummaryCD8 T cells are understudied in MS due to a lack of suitable animal models. We developed a CD8 T cell dependent model of MS.

immunology↗