Neuroimmune T cell dysregulation in multiple sclerosis: epigenetic mechanisms and antigen-specific interventions

Multiple Sclerosis (MS) is, at its core, a disease of failed molecular immune regulation. Autoreactive T cells shaped by aberrant transcriptional programs and epigenetic remodeling escape peripheral tolerance, breach the blood-brain barrier, and sustain the neuroinflammation and demyelination that define the disease. The central challenge in MS research today is not simply to suppress this immune response, but to understand and correct the molecular machinery driving it. That is precisely what this Research Topic sets out to do. MS affects over 2.8 million people worldwide and remains one of the most therapeutically complex immune-mediated disorders of the central nervous system. Most approved treatments achieve their effects through broad immunosuppression, which carries considerable long-term risk and does little to address the underlying neuroimmune dysregulation at the heart of the disease. A growing body of evidence now points to transcriptional networks and epigenetic modifications as central architects of this dysregulation. Key transcription factors direct the differentiation of naïve CD4+ T cells into pro-inflammatory Th1 and Th17 subsets, while simultaneously limiting the development of regulatory T cell (Treg) populations that would otherwise preserve immune homeostasis at the neuroimmune interface. Epigenetic changes, including aberrant DNA methylation, histone modifications, and shifts in chromatin accessibility, have been documented across both CD4+ and CD8+ T cell compartments in MS patients. Importantly, some of these signatures appear early in the disease course and are increasingly understood not as downstream consequences, but as active drivers of pathogenic T cell programming. This positions them as compelling candidates for both biomarker development and therapeutic targeting. The central nervous system (CNS) microenvironment adds another layer of complexity. Far from being a passive backdrop, the inflamed CNS actively shapes T cell identity through local metabolic signals, antigen re-encounter, glial crosstalk, and cytokine gradients. These cues imprint stable transcriptional and epigenetic states on infiltrating T cells, states that can either perpetuate neuroinflammation or, under the right conditions, facilitate resolution and remyelination. Running in parallel to these mechanistic insights, the field of antigen-specific immunotherapy has seen significant renewed momentum. Biomaterial-based platforms, including PLGA micro- and nanoparticles, tolerogenic vaccines, and engineered delivery systems, have shown the ability to restore antigen-specific tolerance in preclinical MS models without the collateral effects of broad immunosuppression. These approaches are effective precisely because they engage the same transcriptional and regulatory machinery that is disrupted at the neuroimmune interface. Connecting the molecular insights of neuroimmunology with the engineering advances of the biomaterials field represents one of the most productive and underexplored intersections in MS research today. This Research Topic brings together researchers working at the intersection of molecular neuroimmunology, T cell biology, and biomaterial-based therapeutic development. We welcome contributions from basic scientists, translational researchers, and clinicians working on MS and related neuroinflammatory conditions. Whether your work examines the epigenetic reprogramming of autoreactive T cells, the transcriptional circuits that govern their fate in the inflamed CNS, or the engineering of platforms that restore antigen-specific tolerance, we invite you to contribute to this collection. We welcome Original Research, Review, Mini-Review, Perspective, and Clinical Trial articles addressing, but not limited to, the following themes:• Epigenetic and transcriptional drivers of autoreactive T cell programming• Th1/Th17 versus Treg balance at the neuroimmune interface• CNS microenvironmental shaping of infiltrating T cells• Biomaterial-based platforms for antigen-specific toleranceSubmissions focusing on environmental or lifestyle-mediated immune modulation are outside the scope of this topic; we specifically welcome mechanistic and interventional work at the molecular and cellular level.Topic Editor Jonathan Cho is a co-inventor on US Patent No. US-12,109,271-B2, related to a biomaterial-based antigen-specific tolerance platform for multiple sclerosis, a technology relevant to this Research Topic’s scope. Topic editors: Dorina Avram, Jonathan Cho Source: https://www.frontiersin.org/research-topics/84524/neuroimmune-t-cell-dysregulation-in-multiple-sclerosis-epigenetic-mechanisms-and-antigen-specific-interventions