Lymphoid structures in the skull bone marrow control homeostatic and anti-tumor immune responses in the CNS [skull/sternum]

Accumulating evidence demonstrates that the central nervous system (CNS) is not disconnected from the peripheral immune system; however, precisely how the adaptive immune system surveils the CNS remains a critical question. Recent findings reveal that channels between the dura mater and the skull facilitate the exchange of cerebrospinal fluid and immune cells between the CNS and skull bone marrow (BM) under both homeostatic and disease conditions. Skull BM serves as a source of innate immune cells for the CNS, yet its role in adaptive immune responses remains insufficiently characterized. Here, we identify lymphoid structures within the skull BM, featuring germinal center-like formations and harboring a distinct population of follicular helper-like T cells that promote B cell activation and humoral immunity through CD40L, IL-21, and IFN-γ signaling. Adaptive immune cells within these skull BM lymphoid structures surveil and respond to CNS-derived antigens, which we demonstrate to be critical for optimal antitumor immunity in murine brain cancer models. Our discovery of distinct anatomical sites in the skull BM that enable adaptive immunosurveillance of the CNS highlights promising avenues for immunotherapies targeting neurological diseases, including brain cancers.