Ocrelizumab Rewrites the T-Cell Script in Early Multiple Sclerosis
Multiple sclerosis (MS) is often described as a “T-cell–driven” autoimmune disease, but in the past decade, treatments targeting B cells have transformed the way we think about its biology. One such treatment is ocrelizumab (OCR), a humanized anti-CD20 antibody that depletes B cells and has shown remarkable success in reducing relapses in relapsing-remitting MS (RRMS).
Yet, OCR’s mechanism of action has been something of a mystery. Is it simply about removing autoantibody-producing B cells? Or does B-cell depletion ripple through the immune system in ways that also affect T cells?
A study led by Alexandra Garcia and colleagues (2023) provides fresh insight into this question by deeply profiling immune cells in patients with early, untreated RRMS who began OCR therapy. The work uncovers a surprising story: OCR indirectly alters specific subsets of effector memory T cells, especially those with the capacity to home to the brain.
Study at a Glance
Participants:
42 treatment-naïve patients with early RRMS (diagnosed ≤3 years, active disease).
Additional comparison groups included untreated RRMS patients and individuals with other inflammatory neurological diseases.
Methods:
Blood samples at baseline, 24 weeks, and 48 weeks post-treatment.
High-dimensional spectral flow cytometry to profile T and B cell subsets.
Single-cell gene expression analysis in blood and cerebrospinal fluid (CSF).
Key Question:
How does OCR-induced B-cell depletion reshape T-cell populations that may drive MS inflammation?
What the Researchers Found
1. B Cells Disappear – but T Cells Tell the Real Story
As expected, OCR nearly wiped out circulating B cells. But the overall numbers of CD4+ and CD8+ T cells remained unchanged. Instead, the subtle effects emerged at the level of T-cell subsets.
2. Naïve CD4+ T Cells Rise, Effector Memory T Cells Fall
After one year of OCR therapy:
Naïve CD4+ T cells (the “rookies” of the immune system) increased.
Several clusters of effector memory (EM) CD4+ T cells, especially those expressing CCR5 and migration markers (CD49d, CD11a), decreased.
This suggests OCR shifts the balance from “experienced, aggressive” T cells back toward a less inflammatory, naïve state.
3. A Particular CD8+ Subset Stands Out
The most striking change was in a subset of CD8+ effector memory T cells that express CCR5. These cells:
Were reduced in blood after OCR treatment.
Showed strong expression of brain-homing markers (CD49d, CD11a).
Were enriched in the CSF of MS patients, where they also displayed a cytotoxic, activated profile.
Importantly, the lower the number of these CCR5+ CD8+ T cells in blood, the more recent the patient’s relapse, suggesting these cells may actively migrate into the brain during flare-ups.
4. CD20+ T Cells Are Not the Main Story
Some T cells express low levels of CD20, and OCR can deplete them directly. However, the study found that changes in EM T-cell subsets persisted even after excluding CD20+ T cells from the analysis. This points toward an indirect effect—OCR depletes B cells, which in turn alters the activation and survival of certain T-cell populations.
Why This Matters
This study reshapes our understanding of OCR’s benefits:
It is not only about B-cell depletion but also about rebalancing the T-cell compartment.
The CCR5+ effector memory CD8+ T cells emerge as a critical population that may drive relapses by migrating into the CNS and fueling inflammation.
By reducing these cells in the periphery, OCR may blunt the waves of immune attack that characterize RRMS.
Moreover, CCR5 itself—a chemokine receptor also known in HIV biology—appears to be a key marker of pathogenic T cells in MS. This raises the intriguing possibility that CCR5 blockade (e.g., with the drug maraviroc, already used in HIV) might be another therapeutic strategy.
The Bigger Picture
Ocrelizumab’s success has already shifted the MS treatment paradigm, but studies like this highlight a deeper lesson: immune therapies work not just by removing one type of immune cell, but by resetting the complex crosstalk among B cells, T cells, and the brain’s immune environment.
For patients with early RRMS, OCR may not only prevent relapses by silencing B cells, but also by taming aggressive T cells that would otherwise storm into the central nervous system.
Final Thoughts
The work by Garcia et al. underscores the importance of systems-level immune profiling in understanding how MS therapies achieve their effects. By mapping not just what disappears, but also what rebalances, researchers can identify new therapeutic targets and refine existing strategies.
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:
Gelfand, J.M., Cree, B.A.C. & Hauser, S.L. Ocrelizumab and Other CD20+ B-Cell-Depleting Therapies in Multiple Sclerosis. Neurotherapeutics 14, 835–841 (2017). https://doi.org/10.1007/s13311-017-0557-4
