Skull Bone Marrow Hosts Lymphoid Niches That Monitor Brain and Boost Tumor Immunity

In mice, the skull bone marrow harbors organized lymphoid formations that resemble peripheral germinal centers, populated by follicular-helper-like CD4⁺ T cells and activated B cells. These cells receive cerebrospinal fluid-borne antigens through osseous channels and mount antigen-specific adaptive responses, driven by CD40L, IL-21 and IFNγ signals. When glioma cells expressing model antigens were implanted in the brain, the skull niches generated robust T-cell activation and B-cell germinal-center activity, which enhanced anti-tumor immunity.

Pharmacologic blockade of CD40L within the skull reduced immune cell infiltration and shortened survival, whereas localized delivery of a CD40 agonist together with IL-21 and IFNγ amplified the niches and extended survival in tumor-bearing mice. The immune benefits persisted even when peripheral secondary lymphoid organs were removed, indicating the skull marrow can act independently as an immunosurveillance hub. These results reveal a previously unappreciated adaptive immune compartment that may be leveraged for therapies against brain tumors and other neurological diseases.