The B Cells That Fan the Flames: How T-bet⁺ CXCR3⁺ B Cells Drive Inflammation in Multiple Sclerosis
Multiple sclerosis (MS) is one of those diseases that remind us how astonishing — and sometimes destructive — the immune system can be. In MS, the very cells that are supposed to defend us turn their sights inward, targeting the brain and spinal cord. Scientists have long suspected that autoreactive T cells are the main culprits. But in recent years, B cells have entered the spotlight, not just as antibody factories, but as key instigators of inflammation in MS.
A new study by Jelcic and colleagues, published in Cell Reports Medicine in March 2025, dives deep into this idea and identifies a specialized subset of B cells — T-bet⁺ CXCR3⁺ B cells — as major drivers of hyperactive B–T cell interactions in MS.
B and T Cells: A Risky Partnership
Normally, B and T cells work as a team: B cells present antigens, and T cells help coordinate an immune response. But in MS, this partnership spirals out of control. The researchers studied autoproliferation (AP) — a process where B and T cells start multiplying without any foreign invader, triggered instead by self-peptides presented by B cells. Think of it as the immune system holding up a mirror — and attacking its own reflection.
During AP, the team observed the formation of B–T cell-enriched clusters (BTECs) that looked eerily similar to germinal centers, where immune responses usually mature. Instead of fine-tuning defense against pathogens, these clusters promoted inflammation against the body’s own tissues.
Enter the T-bet⁺ CXCR3⁺ B Cells
Among the proliferating B cells, one group stood out: T-bet⁺ CXCR3⁺ B cells. These cells were not just passengers — they actively amplified the cycle of inflammation:
They boosted Th1 responses, a type of T cell activity linked to high interferon-gamma (IFN-γ) production.
They matured into plasmablasts, capable of producing antibodies with potentially autoreactive properties.
They were found not just in the blood, but also embedded in the inflamed meninges of MS patients, linking them directly to brain pathology.
Importantly, these cells carried an interferon-driven genetic and epigenetic signature, suggesting their identity is hard-wired by inflammatory signaling.
Why This Matters
This work helps answer a lingering question: why are B cell–depleting therapies (like anti-CD20 antibodies) so effective in MS? The answer may lie in eliminating these T-bet⁺ CXCR3⁺ B cells, which otherwise sustain a feedback loop of B–T cell activation and chronic inflammation.
It also provides a new framework for thinking about disease progression. While relapsing MS is marked by bursts of inflammatory activity, progressive MS often smolders more quietly. The presence of these B cells in meningeal structures suggests they may help maintain the slow-burning inflammation that drives neurodegeneration in later stages.
Looking Ahead
The identification of this B cell subset opens several exciting avenues:
Biomarkers: Molecules like CXCL9, secreted by these B cells, could serve as indicators of ongoing inflammatory circuits in the CNS.
Therapies: Beyond broad B cell depletion, strategies targeting the IFN-γ–T-bet–CXCR3 axis might provide more precise control over the inflammatory feedback loop.
Understanding autoimmunity: Similar B cells have been implicated in lupus, rheumatoid arthritis, and other autoimmune diseases, hinting at a shared pathogenic mechanism.
Bottom Line
This study strengthens the case that MS is not just a T cell disease — it’s a disease of dysfunctional B–T cell crosstalk. T-bet⁺ CXCR3⁺ B cells act as dangerous amplifiers, pushing T cells into overdrive and fueling long-lasting inflammation. By dissecting this partnership, researchers are not only solving a central mystery of MS but also carving new paths toward therapies that can better calm the storm inside the nervous system.
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:
Jelcic, I., Naghavian, R., Fanaswala, I., Macnair, W., Esposito, C., Calini, D., ... & Martin, R. (2025). T-bet+ CXCR3+ B cells drive hyperreactive BT cell interactions in multiple sclerosis. Cell Reports Medicine, 6(3).
