The Hidden GPS of Immune Cells and How Natalizumab Turns Up Its Signal in Multiple Sclerosis

The immune system is a well-choreographed dance of cells constantly moving to where they are needed. In multiple sclerosis (MS), however, immune cells—especially autoreactive T cells—take a wrong turn and enter the brain and spinal cord, sparking inflammation and damaging myelin. Understanding what directs this cellular “traffic” is crucial for designing better therapies.

A study by Clottu et al. (2017) turns the spotlight on EBI2 (Epstein-Barr virus-induced gene 2), a receptor that senses a special type of oxidized cholesterol called 7α,25-dihydroxycholesterol (7α,25-OHC). This receptor acts like a GPS for immune cells, guiding their migration. The authors explored EBI2's role in healthy people, untreated MS patients, and those receiving natalizumab—a powerful therapy that blocks immune cell entry into the brain.

EBI2: Not Just Another Immune Receptor
EBI2 belongs to the family of G protein-coupled receptors. Its preferred ligand, 7α,25-OHC, is produced by enzymes in various immune and support cells. In mice, EBI2 is abundant on mature B cells and CD4+ T cells, influencing their location in lymphoid tissues and their migration during inflammation. Until now, little was known about its presence and function in human lymphocytes—especially in the context of MS.

Key Findings
EBI2 is Strongest on Memory CD4+ T Cells and B Cells
In healthy donors, EBI2 levels were highest in memory CD4+ T cells and CD19+ B cells, far exceeding levels in CD8+ T cells, NK cells, or NKT cells.

Memory cells—unlike naïve cells—are “battle-experienced” and more mobile, making EBI2’s high expression particularly interesting.

EBI2 Drives Migration Toward 7α,25-OHC
Using a lab-based transwell assay, the authors showed that memory CD4+ T cells migrated strongly toward 7α,25-OHC, and this movement was EBI2-dependent.

Blocking EBI2 with a small molecule inhibitor (NIBR189) sharply reduced migration without harming cell viability.

MS Patients Show Similar EBI2 Levels but a Stronger Link to Migration
Untreated MS patients had roughly the same EBI2 expression as healthy individuals, but in these patients, higher EBI2 expression correlated more closely with increased migration—hinting that EBI2 signaling might be more “active” in MS. Natalizumab Supercharges EBI2 in Memory CD4+ T Cells
After 9–12 months of natalizumab therapy, patients’ memory CD4+ T cells showed up to a threefold increase in EBI2 expression.

Migration toward 7α,25-OHC also rose in these cells, suggesting that natalizumab may indirectly amplify this pathway.

This effect was not seen in CD8+ T cells or B cells, nor with another MS drug, dimethyl fumarate.

A See-Saw Between EBI2 and CD11a
Natalizumab-treated patients showed decreased levels of CD11a (part of the LFA-1 integrin important for adhesion) alongside increased EBI2 in memory CD4+ T cells.

This shift could reflect changes in how these cells navigate the body during treatment.

Why Does This Matter?
The boost in EBI2 under natalizumab could be a compensatory mechanism—a way for the immune system to preserve brain surveillance despite the drug’s blockade of other trafficking routes. Alternatively, it might influence the rebound inflammation seen when natalizumab is stopped.

Because a potent EBI2 inhibitor (NIBR189) already exists, targeting this pathway could offer new therapeutic strategies—either to fine-tune immune migration in MS or potentially limit harmful infiltration during rebound phases.

Future Directions
The findings open several intriguing questions:

Does the blood-brain barrier produce 7α,25-OHC, creating a chemical gradient for EBI2-positive T cells?

Could EBI2 changes under natalizumab predict the risk of progressive multifocal leukoencephalopathy (PML), a rare but serious side effect?

Might EBI2 be involved in other neuroinflammatory or autoimmune diseases?

Conclusion
This study reveals that EBI2 is not only a critical migration receptor in human memory lymphocytes but also a surprisingly dynamic one—capable of ramping up under certain therapies like natalizumab. By mapping this lesser-known route in the immune GPS network, researchers may have found a new checkpoint to control immune traffic in MS.

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:
Clottu, A.S., Mathias, A., Sailer, A.W., Schluep, M., Seebach, J.D., Du Pasquier, R., & Pot, C. (2017). EBI2 Expression and Function: Robust in Memory Lymphocytes and Increased by Natalizumab in Multiple Sclerosis. Cell Reports, 18(1), 213–224. https://doi.org/10.1016/j.celrep.2016.12.006