EOMES and TBX21 Expression Reveals Stable, Heritable, and Drug-Sensitive Biomarkers in Multiple Sclerosis

For decades, managing multiple sclerosis (MS) has felt like navigating a maze in the dark—an unpredictable chronic disease with no definitive biomarkers to predict therapeutic response or progression. But a study published in Clinical Immunology by Fiona McKay and colleagues offers a glimmer of light. Their findings suggest that the expression levels of two immune-regulating transcription factors—EOMES and TBX21—may serve as reliable molecular signatures of disease and response to therapy.

Unmasking a Low-Expression Phenotype in MS
The researchers began by reaffirming an earlier discovery: people with MS consistently exhibit lower expression of the EOMES and TBX21 genes in their peripheral blood mononuclear cells. These two genes encode transcription factors central to the development and function of natural killer (NK) and memory CD8+ T cells—immune players known to be dysfunctional in MS.

In a newly recruited independent cohort, expression of EOMES, TBX21, and a third gene, CCL5, was significantly reduced in untreated MS patients compared to healthy controls. Interestingly, this low-expression profile, termed the "ET^low phenotype," was not only reproducible but longitudinally stable and highly heritable (heritability estimates: EOMES h² = 0.48, TBX21 h² = 0.20).

A Distinct Immune Cell Signature: CD56+ Cells in the Spotlight
Diving deeper into cellular mechanics, the team found that this low-expression phenotype reflects dysregulation in CD56+ immune cells, especially NK cells. Flow cytometry revealed that EOMES and TBX21 protein levels were markedly lower in NK subsets—particularly the CD3-CD56^bright and CD3-CD56^dim cells—among MS patients. Moreover, CD8+ memory T cells also showed reduced expression, hinting at a widespread functional deficit in cytotoxic immune surveillance.

Therapy Matters: Not All Drugs Are Equal
Perhaps the most clinically promising finding was how immunomodulatory treatments affected this ET^low phenotype. Natalizumab, a potent monoclonal antibody therapy, significantly increased TBX21 expression—restoring it toward normal levels. Other drugs showed varied effects: glatiramer acetate maintained consistent expression levels, while fingolimod and interferon-beta tended to further suppress EOMES expression. This variation suggests that monitoring these gene expressions could eventually help clinicians fine-tune therapy selection or predict response.

A Molecular Compass for MS Treatment?
So why does this matter? These findings position EOMES and TBX21 as more than just transcription factors—they may serve as a molecular compass for navigating MS therapy. Their expression profiles could guide therapeutic decisions, monitor immune competence, or even flag the need to change course before clinical relapse or irreversible damage occurs.

What makes them even more compelling is their stability over time and the fact that their expression isn’t wildly fluctuating due to transient immune changes. This stability, coupled with therapy sensitivity, makes them promising candidates for integration into routine MS monitoring—pending further longitudinal validation.

Looking Ahead
While much work remains to translate these insights into point-of-care diagnostics, the potential is striking. As we inch closer to personalized medicine in MS, EOMES and TBX21 may provide the immune-centric biomarkers we've been waiting for—turning a once invisible signature of disease into a powerful tool for prediction and prevention.

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:
McKay, F. C., Gatt, P. N., Fewings, N., Parnell, G. P., Schibeci, S. D., Basuki, M. A., ... & Booth, D. R. (2016). The low EOMES/TBX21 molecular phenotype in multiple sclerosis reflects CD56+ cell dysregulation and is affected by immunomodulatory therapies. Clinical Immunology, 163, 96-107.