The skull may be an active part of the brain’s immune defense

The skull may be more than a hard case around the brain. In mice, it appears to contain immune outposts that can sense brain cancer early and help rally a local defense.

A study from Washington University School of Medicine in St. Louis found lymph node-like structures in mouse skull bone marrow for the first time. The research also found evidence of similar immune cells in human skull bone marrow.

The study suggests the brain has nearby immune “security stations” positioned closer than those serving many other organs.

For decades, scientists often treated the brain and immune system as mostly separate. That view has changed as researchers have found lymphatic vessels in the dura mater, the outer tissue layer beneath the skull, and small channels linking the skull, dura and brain tissue.

Jonathan Kipnis, senior author of the study, has helped lead that shift. Kipnis is the Alan A. and Edith L. Wolff Distinguished Professor of Pathology & Immunology and a BJC Investigator at WashU Medicine.

“This study reveals that the skull bone marrow is far more than just a structural framework — it harbors previously unrecognized hubs for brain-specific immune responses,” Kipnis said. “Uncovering this localized immune niche changes how we view neuroimmune interactions and opens exciting new avenues for treating brain tumors and other neurological diseases.”

In the new work, the team tracked proteins moving from the brain through tiny channels directly into the skull bone marrow. There, they found immune structures usually associated with lymph nodes.

Lymph nodes act as training sites for immune responses. In these hubs, T follicular helper cells help B cells make large amounts of antibodies, proteins that help fight disease and infection.

“We have never seen such structures in healthy bone marrow before,” said Jang Hyun Park, the study’s first author and a postdoctoral research fellow in the Kipnis lab. “It is an exciting discovery that points out that a complex brain requires its own specialized immune structures to defend it.”

The researchers then asked whether these nearby immune hubs actually matter during disease. They used a mouse model of glioblastoma, an aggressive brain cancer.

When they disrupted the skull immune hubs with a drug, tumors grew faster than in mice whose hubs remained intact. Survival also dropped. That result showed that the brain depends on these local centers for defense against cancer.

The immune response did not begin in distant lymph nodes. It started in the skull bone marrow, then appeared later in nearby lymph nodes outside the skull.

That timing matters. It suggests the skull marrow can act as a rapid first responder, receiving danger signals from the brain before the broader immune system gets fully involved.

The finding also reframes bone marrow in the skull. It is not only a place where immune cells develop. In this study, it behaved like a local immune command post for the brain.

The team next tested whether they could strengthen the skull immune response. They developed a targeted therapy designed to increase antibody production inside skull marrow.

The method used a gel applied directly under the scalp. The gel delivered a mixture of three immune-boosting proteins. This prompted tumor-fighting immune responses that attacked the cancer.

Mice given the gel rejected tumors more effectively and lived longer than control mice.

The response again began in the skull bone marrow before showing up in lymph nodes outside the skull. That pattern supports the idea that skull marrow sits close enough to the brain to react early, but still links to wider immune activity.

“The finding fundamentally changes our current understanding of neuroimmunology,” said Kipnis. “Knowing that the brain relies on first responders in the surrounding skull for defense has the potential to change how we think about developing therapies for many neurological conditions, including Alzheimer’s disease.”

The work builds on earlier discoveries from Kipnis’ lab. His team previously challenged the idea that the brain is shielded from the immune system by finding lymphatic vessels in the dura mater.

More recently, the group identified tiny physical channels that connect the skull, dura and brain tissue. These channels give immune cells and cellular waste a route between the brain and nearby skull bone marrow.

The new study adds a functional piece to that anatomy. Proteins from the brain can travel through those channels. Once they arrive in skull marrow, they encounter organized immune structures capable of antibody-related responses.

That makes the skull a more active part of neuroimmunology than scientists once recognized. It may help explain how the immune system monitors a delicate organ without relying only on distant lymph nodes.

The evidence in humans remains early. The researchers found evidence of similar immune cells in human skull bone marrow, but the main experiments were done in mice. More studies will be needed to learn whether human skull marrow contains the same kind of functional immune hubs.

Kipnis said the discovery could affect how researchers think about many neurological conditions with immune components.

“Knowing that the brain relies on first responders in the surrounding skull for defense has the potential to change how we think about developing therapies for many neurological conditions, including Alzheimer’s disease, Parkinson’s disease, schizophrenia, long COVID, and many others that have an immune component to them. Such therapies could access these immune hubs directly through the skull, without major peripheral side effects.”

That possibility remains future-looking. The study tested brain cancer in mice, not treatments for those other diseases.

Still, the idea is powerful because skull-directed treatment could, in principle, act near the brain while avoiding broader effects throughout the body. The under-scalp gel experiment offers an early example of that localized approach.

The researchers did not show that this therapy is ready for patients. They showed that skull marrow immune hubs can be manipulated in mice and that doing so changed tumor outcomes.

These studies trace the rapidly developing evidence that skull marrow communicates with the brain and can influence cancer, injury and immune surveillance.

Childhood brain tumors instruct cranial hematopoiesis and immunotolerance: Aggressive childhood brain tumors were shown to reprogram skull bone marrow and promote immune tolerance, highlighting how cancers can exploit the same local immune network. (Nature Genetics, 2026)

Brain tumors induce widespread disruption of calvarial bone and alteration of skull marrow immune landscape: Glioblastoma altered skull structure, marrow immune populations and skull channels in mice and showed related bone abnormalities in patients. (Nature Neuroscience, 2025)

Cranioencephalic functional lymphoid units in glioblastoma: Human skull marrow adjacent to glioblastoma contained tumor-reactive T cells, providing direct evidence that cranial bone participates in local anti-tumor immunity. (Nature Medicine, 2024)

Cerebrospinal fluid regulates skull bone marrow niches via direct access through dural channels: This study showed that cerebrospinal fluid can enter skull marrow through dural channels and directly influence local blood-cell production. (Nature Neuroscience, 2022)

Skull and vertebral bone marrow are myeloid cell reservoirs for the meninges and CNS parenchyma: Researchers demonstrated that skull and vertebral marrow provide local immune cells to the meninges and central nervous system during health and disease. (Science, 2021)

Research findings are available online in the journal Nature.

The original story "The skull may be an active part of the brain’s immune defense" is published in The Brighter Side of News.

Like these kind of feel good stories? Get The Brighter Side of News' newsletter.