Functional role of skull lymphoid structures in CNS immunosurveillance

Abstract 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 skull and the dura mater facilitate the exchange of cerebrospinal fluid and immune cells between the CNS and skull bone marrow of mice under both homeostatic and disease conditions 1–6 . Skull bone marrow functions as a source of immune cells for the CNS 5 , yet its role in CNS antigen-specific adaptive immune responses remains unclear. Here we identify lymphoid structures within the skull bone marrow, featuring germinal-centre-like formations and containing a distinct population of follicular-helper-like T cells that promote B cell activation and humoral immunity through CD40L, IL-21 and IFNγ signalling. Adaptive immune cells within these skull bone marrow lymphoid structures surveil and respond to CNS-derived antigens and contribute to anti-tumour immune responses in mouse brain cancer models. Together, our findings show that the skull bone marrow is a site of CNS immunosurveillance that may influence immune responses across diverse neurological diseases.