Ocrelizumab’s Hidden Side: How MS Therapy Shapes Memory CD8+ T Cells and Infection Risk

Ocrelizumab (OCRE) has transformed the treatment landscape for multiple sclerosis (MS). As a monoclonal antibody that targets CD20, its primary role is depleting B cells — long considered key culprits in MS progression. Clinical trials and long-term follow-up studies confirm that OCRE reduces relapses, dampens MRI activity, and slows disability progression.

But science rarely paints with a single brushstroke. While the focus has been on B cells, growing evidence suggests that OCRE doesn’t act in isolation. What about T cells, particularly memory CD8+ T cells, which play pivotal roles in viral defense and potentially MS pathology?

This is where the recent study by Mathias et al. (2023) comes in, offering new insights into OCRE’s broader immunological impact.

The Study at a Glance
Participants: 38 people with relapsing-remitting, secondary progressive, or primary progressive MS.

Design: A 1-year longitudinal study with blood samples collected before OCRE treatment, and at 6 and 12 months.

Techniques:

Mass cytometry (CyTOF) with a 38-parameter panel to map immune cell diversity.

ELISPOT assays to test viral-specific CD8+ T-cell responses against CMV, EBV, and influenza.

Key Findings
1. Expected: B Cell Depletion
As anticipated, OCRE rapidly and profoundly depleted CD20+ B cells. This validated the study’s approach and reinforced OCRE’s known mechanism of action.

2. Unexpected: Memory CD8+ T Cells Hit Hard
Memory CD8+CD20+ T cells were significantly reduced at both 6 and 12 months.

Central memory (CM) CD8+ T cells declined, while naïve CD8+ T cells expanded.

The surviving memory CD8+ T cells showed altered phenotypes, including reduced CXCR3 and LFA-1 integrin expression — molecules critical for migration into inflamed tissues like the brain.

This suggests OCRE not only reduces numbers but also impairs the functionality of these cells.

3. Functional Deficit: Antiviral Responses Weakened
Antiviral CD8+ T-cell responses against CMV, EBV, and influenza dropped by more than 50% in many patients after 6 months.

By 12 months, some patients had almost no detectable reactivity.

Importantly, this effect was not just due to B-cell absence (tested through coculture experiments) but reflected a direct impairment of CD8+ memory T-cell function.

4. Clinical Impact: Infection Risk
18% of patients developed infections during the study period.

Many of these patients had previously been treated with dimethyl fumarate (DMF), raising the possibility of a “legacy effect” — where past therapies imprint lasting vulnerabilities that OCRE amplifies.

Why Does This Matter?
Double-Edged Sword
On one hand, depleting pathogenic memory CD8+ T cells may contribute to OCRE’s therapeutic success in MS by limiting their ability to enter the central nervous system.

On the other, this comes at a cost: weakened antiviral immunity.

Rethinking Infection Risks
The study highlights that not only B-cell depletion but also T-cell dysfunction could underlie the increased infection risk seen in OCRE-treated patients.

Clinicians may need to pay special attention when switching patients from drugs like DMF to OCRE.

A New Layer of Mechanism
OCRE’s effects extend beyond B cells. This broadens our understanding of how anti-CD20 therapies shape the immune landscape — not just removing the fuel (B cells) but also reshaping the fire (T-cell responses).

Final Thoughts
Mathias et al.’s work reminds us that immunotherapies often have ripple effects across the immune system. Ocrelizumab, while highly effective, is not a laser-focused weapon but a complex immunomodulator.

For patients, this study underscores the importance of careful infection monitoring during treatment. For researchers, it opens new doors: can we harness OCRE’s benefits while safeguarding antiviral defenses? Could biomarkers predict which patients are most vulnerable?

As MS care moves forward, these questions will be crucial. What’s clear is that OCRE’s story isn’t just about B cells — it’s also about the memory CD8+ T cells silently shaping outcomes behind the scenes.

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:
Hauser SL, Strauli N, Raievska A, Harp C, Koendgen H, Kletzl H, Bonati U, Jia X, Herman A, Kappos L, Bar-Or A. B-Cell Subset Depletion Following Ocrelizumab Treatment in Patients With Relapsing Multiple Sclerosis. Neurology. 2021;96(15_suppl):4292. doi:10.1212/WNL.96.15_supplement.4292