How Interferon-β Reprograms Immune Cell Metabolism to Tame Multiple Sclerosis

For over two decades, interferon-β (IFN-β) has been a cornerstone in treating relapsing–remitting multiple sclerosis (RRMS). It is often one of the first therapies patients receive after diagnosis, valued for its effectiveness in reducing relapses and its long-standing safety record. But despite its widespread use, the precise ways in which IFN-β helps tame the immune system remain something of a puzzle.

A study by Aiden Haghikia and colleagues takes us one step closer to solving this puzzle by looking at something that has been largely overlooked in MS research: the energy metabolism of immune cells.

Why Energy Matters in Immunity
Immune cells are like high-performance engines — they need fuel to work. When CD4+ T cells, the main drivers of MS-related inflammation, shift from a resting state to an active, aggressive mode, they ramp up their energy needs. This energy largely comes from mitochondria, the powerhouses of the cell, through a process called oxidative phosphorylation (OXPHOS).

So, what happens if a drug like IFN-β alters how mitochondria function in these cells? Could this help explain why IFN-β calms inflammation in MS?

The Study at a Glance
Haghikia et al. examined the effects of IFN-β on mitochondrial activity in CD4+ T cells from MS patients. Their multi-layered approach included:

Measuring intracellular ATP (iATP): the key energy currency of the cell.

Assessing mitochondrial membrane potential (ΔΨm): a marker of mitochondrial health and activity.

Looking at gene expression: particularly those involved in oxidative phosphorylation.

Considering genetics: specifically variations in the gene PGC-1α, a master regulator of mitochondrial function.

Key Findings
IFN-β lowers energy production in CD4+ T cells.

Patients treated with IFN-β had significantly reduced ATP levels in their CD4+ T cells compared to untreated patients or those on other therapies. The effect was dose-dependent: higher doses and more frequent injections of IFN-β led to greater ATP reductions.

Mitochondria become less active under IFN-β.

Flow cytometry showed that IFN-β caused a depolarization of the mitochondrial membrane potential, another sign of dampened mitochondrial activity.

Gene expression shifts in energy pathways.

Transcriptome analysis revealed altered expression of several OXPHOS-related genes, confirming that IFN-β directly influences mitochondrial programming.

Genetics may predict response.

A particular genetic variant (rs7665116) in PGC-1α correlated with differences in ATP levels and treatment outcomes. Patients with the “wild-type” T allele tended to have lower ATP levels and responded better to IFN-β therapy.

What Does This Mean for MS Treatment?
These findings suggest that IFN-β’s benefits may go beyond simply “modulating” the immune system’s signals. Instead, IFN-β seems to reprogram the metabolic engine of T cells, making them less capable of sustaining the high energy demands of autoimmunity. In other words, IFN-β may weaken the fuel supply that drives MS inflammation.

This metabolic angle opens up several exciting possibilities:

Biomarkers for treatment response: Measuring iATP levels in CD4+ cells, or genotyping patients for PGC-1α variants, might one day help doctors predict who will respond best to IFN-β.

Targeting metabolism directly: Other therapies could be developed to modulate immune cell metabolism in a more precise way.

Personalized medicine: Genetic insights could guide therapy choices, sparing patients from ineffective treatments and unnecessary side effects.

A Word of Caution
While this study is compelling, it was relatively small and exploratory. Larger, prospective trials will be needed to confirm whether ATP levels or PGC-1α variants can serve as reliable clinical tools. Also, the broader effects of altering mitochondrial function in immune cells — both beneficial and potentially harmful — need careful exploration.

Final Thoughts
This research reframes IFN-β not just as an immune modulator, but as a metabolic reprogrammer of T cells. By cutting off the energy supply that fuels autoimmune attacks, IFN-β may be exerting its effects in ways we are only beginning to appreciate.

In the bigger picture, the study highlights an emerging theme in immunology: metabolism and immunity are deeply intertwined. Understanding this relationship could unlock new strategies to treat MS and other autoimmune diseases more effectively.

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:
Haghikia, A., Faissner, S., Pappas, D., Pula, B., Akkad, D. A., Arning, L., ... & Chan, A. (2015). Interferon-beta affects mitochondrial activity in CD4+ lymphocytes: Implications for mechanism of action in multiple sclerosis. Multiple Sclerosis Journal, 21(10), 1262-1270.