Twin Insights: How Overactive, Energy-Hungry T Cells Spark Multiple Sclerosis Before It Begins
Multiple sclerosis (MS) has long puzzled scientists — why does the immune system suddenly attack the brain and spinal cord, leading to inflammation, demyelination, and neurodegeneration? While we know that genetic and environmental factors both play roles, identifying what goes wrong before clinical symptoms appear has been a major challenge.
That’s where twin studies come in. In this groundbreaking work, Vladyslav Kavaka and colleagues from the University of Munich and University of Tübingen used monozygotic twins — one with MS and one without — to explore how the immune system diverges before disease manifests.
Some of the “healthy” twins even showed subtle MRI or cerebrospinal fluid (CSF) signs of inflammation without symptoms — a stage called subclinical neuroinflammation (SCNI). This provided a rare window into MS’s prodromal phase, the earliest detectable stage of disease.
Dissecting the Immune Landscape: Single-Cell by Single-Cell
The team applied single-cell RNA sequencing (scRNA-seq) and T cell receptor (TCR) analysis to study nearly 200,000 CD8⁺ T cells from blood and CSF. This high-resolution approach allowed them to profile each cell’s gene activity, metabolic state, and clonality — in essence, creating a detailed map of how immune cells evolve during MS onset.
They identified 12 distinct CD8⁺ T cell clusters, ranging from naïve cells (quiet, resting) to effector-like cells (highly active, inflammatory). The most activated and clonally expanded clusters were found both in the blood and CSF, suggesting that certain CD8⁺ T cells migrate into the brain early in disease.
Key Findings: The Rise of Hyperactive, Energy-Hungry T Cells
1. Early Immune Activation
Even in the subclinical phase (SCNI), CD8⁺ T cells displayed signs of heightened activation, expressing molecules like:
IL2RB (IL-2 receptor β) – promoting proliferation,
CD69 and CD27 – classic activation markers,
HLA class II molecules (CD74, HLA-DRA, HLA-DRB1) – indicating enhanced antigen presentation.
This means that before overt inflammation, T cells are already revving up and communicating intensely with other immune cells.
2. Inflammatory and Migratory Signatures
These T cells also produced cytotoxic molecules (GZMK, GZMA, PRF1) and chemokines (CCL5, CXCR3), hinting at their ability to:
kill target cells,
recruit other immune cells, and
migrate into the CNS — where MS damage occurs.
3. Metabolic Overdrive
Immune activation demands energy. The researchers found upregulation of genes controlling glucose uptake (SLC2A3), glycolysis, and oxidative phosphorylation — the metabolic engines that fuel sustained T cell function.
This “metabolic reprogramming” enables T cells to remain active longer and mount stronger inflammatory responses, possibly driving MS pathology from the periphery into the brain.
Validation Across Cohorts and Brain Tissue
To ensure these findings weren’t unique to the twin cohort, the team examined:
An independent group of treatment-naive MS patients and controls.
Existing single-nucleus RNA-seq data from actual MS brain lesions.
In both datasets, the same immunological and metabolic signatures appeared. CD8⁺ T cells in MS brains expressed the same inflammatory, antigen-presenting, and metabolic genes — including CD74, HLA-DRA, GZMA, CCL5, and SLC2A3.
This confirmed that the same T cell phenotypes first seen in blood eventually dominate within the central nervous system.
What This Means for MS Research and Therapy
The implications are profound:
CD8⁺ T cells — long considered secondary to CD4⁺ T cells — may actually be primary drivers of early MS pathology.
Metabolic and immunological dysregulation happens before full-blown disease, offering a chance for early detection or intervention.
Targeting IL-2, MAPK, and metabolic pathways might help calm overactive T cells in prodromal or early MS, potentially preventing progression.
As corresponding author Eduardo Beltrán notes, the study identifies “potential immunological and metabolic therapeutic targets in both prodromal and definitive stages of MS.”
This twin-based approach eliminates genetic noise, isolating the true immune differences linked to MS. It suggests that the seeds of neuroinflammation are sown long before diagnosis, hidden in subtle changes in T cell activity and metabolism.
By uncovering this early immune choreography, Kavaka et al. have not only mapped how MS begins — they’ve also pointed to how it might one day be stopped before it starts.
Disclaimer: This blog post is based on the provided research article and is intended for informational purposes only. It is not intended to provide medical advice. Please consult with a healthcare professional for any health concerns.
References:
Kavaka, V., Mutschler, L., de la Rosa del Val, C., et al. (2024). Twin study identifies early immunological and metabolic dysregulation of CD8⁺ T cells in multiple sclerosis. Science Immunology, 9(94), eadj8094. DOI: 10.1126/sciimmunol.adj8094
