Biology subjects

Seyedsadr, M.

Publications and source records attributed to Seyedsadr, M..

5 recordsLinked to original sources

bioRxiv2026

Pathologic T cell immunosenescence drives the development of age-associated autoimmune peripheral neuropathy

While certain autoimmune conditions are more common in the young (e.g. Type 1 Diabetes), others are more frequent in the aged. A striking example is chronic inflammatory demyelinating polyneuropathy (CIDP), a CD4+ T cell-mediated autoimmune disease of the peripheral nervous system, which has a peak decade of onset of 70-79 years. How aging predisposes to autoimmunity, however, remains unclear. CD4+ T cells are highly susceptible to age-associated changes, including acquisition of immunosenescent features such as enhanced SA-{beta}-gal activity, increased Cdkn1a (p21) expression, and upregulation of Tnfsf8 (CD153). We show here that CD4+ T cells exhibiting these changes are increased in CIDP patients and mice with CIDP-like disease. These CD4+ T cells exhibit a senescence-associated secretory phenotype (SASP), show functional senescence (i.e., decreased proliferation and resistance to apoptosis), and have enhanced capacity for inciting neuropathy. Notably, a senescent cell-clearing senolytic agent (fisetin) decreased the pathogenic capacity of CD4+ T cells, and a SASP-suppressing senomorphic therapy (ruxolitinib) protected mice against autoimmune demyelination. Together, these findings delineate a key role for age-associated senescent CD4+ T cells in driving age-associated autoimmunity.

immunology↗

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

UTX Epigenetically Imposes a Cytolytic Effector Program in Autoreactive Stem-like CD8+ T cell Progenitors

Type 1 Diabetes Mellitus (T1D) is a chronic disease caused by an unremitting autoimmune attack on pancreatic beta cells. This autoimmune chronicity is mediated by stem-like progenitor CD8+ T cells that continually repopulate the pool of beta cell-specific cytolytic effectors. Factors governing the conversion of progenitors to effectors, however, remain unclear. T1D has been linked to a chromosomal region (Xp13-p11) that contains the epigenetic regulator UTX, which suggests a key role for UTX in T1D pathogenesis. Here, we show that T cell-specific UTX deletion in NOD mice protects against T1D development. In T cells of NOD mice and T1D patients, UTX ablation resulted in the accumulation of CD8+ progenitor cells with concomitant deficiency of effectors, suggesting a key role for UTX in poising progenitors for transition to effectors. Mechanistically, UTXs role in T1D was independent of its inherent histone demethylase activity but instead relied on binding with transcription factors (TCF1 and STAT3) to co-regulate genes important in the maintenance and differentiation of progenitor CD8+ T cells. Together, these findings identify a critical role for UTX in T1D and the UTX:TCF1:STAT3 complex as a therapeutic target for terminating the long-lived autoimmune response.

immunology↗

bioRxiv2024

A pathologically expanded, clonal lineage of IL-21 producing CD4+ T cells drives Inflammatory neuropathy

Inflammatory neuropathies, which include CIDP (chronic inflammatory demyelinating polyneuropathy) and GBS (Guillain Barre Syndrome), result from autoimmune destruction of the peripheral nervous system (PNS) and are characterized by progressive weakness and sensory loss. CD4+ T cells play a key role in the autoimmune destruction of the PNS. Yet, key properties of pathogenic CD4+ T cells remain incompletely understood. Here, we use paired scRNAseq and scTCRseq of peripheral nerves from an inflammatory neuropathy mouse model to identify IL-21 expressing CD4+ T cells that are clonally expanded and multifunctional. These IL-21-expressing CD4+ T cells are comprised of two transcriptionally distinct expanded populations, which express genes associated with Tfh and Tph subsets. Remarkably, TCR clonotypes are shared between these two IL-21-expressing populations, suggesting a common lineage differentiation pathway. Finally, we demonstrate that IL-21 signaling is required for neuropathy development and pathogenic T cell infiltration into peripheral nerves. IL-21 signaling upregulates CXCR6, a chemokine receptor that promotes CD4+ T cell localization in peripheral nerves. Together, these findings point to IL-21 signaling, Tfh/Tph differentiation, and CXCR6-mediated cellular localization as potential therapeutic targets in inflammatory neuropathies.

immunology↗

bioRxiv2020

Targeting CSF-1 ameliorates experimental autoimmune encephalomyelitis by depleting inflammatory monocytes and microglia in the central nervous system without affecting quiescent microglia.

The receptor for colony stimulating factor 1 (CSF-1R) is important for the survival and function of myeloid cells that mediate pathology during experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis (MS). CSF-1 and IL-34, the ligands of CSF-1R, have similar bioactivities but distinct tissue and context-dependent expression patterns, suggesting that they have different roles. This could be the case in EAE, given that CSF-1 expression is upregulated in the CNS, while IL-34 remains constitutively expressed. We found that targeting CSF-1 with neutralizing mAb halted ongoing EAE, with efficacy superior to CSF-1R inhibitor BLZ945, whereas IL-34 neutralization had no effect, suggesting that pathogenic myeloid cells were maintained by CSF-1, not IL-34. Both anti-CSF-1- and BLZ945-treatment greatly reduced numbers of monocyte-derived cells and microglia in the CNS. However, anti-CSF-1 selectively depleted inflammatory microglia and monocytes in inflamed CNS areas, whereas BLZ945 depleted virtually all myeloid cells, including quiescent microglia, throughout the CNS. Anti-CSF-1 treatments reduced the size of demyelinated lesions, and microglial activation in the grey matter. Lastly, we found that bone marrow-derived immune cells were the major mediators of CSF-1R-dependent pathology, while microglia played a lesser role. Our findings suggest that targeting CSF-1 could be effective in ameliorating MS pathology, while preserving the homeostatic functions of myeloid cells, thereby minimizing risks associated with total ablation of CSF-1R-dependent cells. Significance StatementMultiple sclerosis (MS) and its animal model, experimental autoimmune encephalomyelitis (EAE), are autoimmune diseases characterized by accumulation of myeloid immune cells into the central nervous system (CNS). Both harmful and beneficial myeloid cells are present in EAE/MS, and a goal of MS therapy is to preferentially remove harmful myeloid cells. The receptor for CSF-1 (CSF-1R) is found on myeloid cells and it is important for their survival. CSF-1R can bind two ligands, CSF-1 and IL-34, but is unknown whether their functions in EAE/MS differ. We found that blocking CSF-1 depleted only harmful myeloid cells in the CNS and suppressed EAE, whereas blocking IL-34 had no effect. Thus, we propose that blocking CSF-1 could be a novel therapy for MS.

immunology↗