Venous plexus-associated lymphoid hubs support meningeal humoral immunity

Abstract There is increasing interest in how immune cells in the meninges, the membranes that surround the brain and spinal cord, contribute to homeostasis and disease in the central nervous system. The outer layer of meninges, the dura mater, contains both innate and adaptive immune cells and functions as a site for B cell development. In this study, we identified previously undescribed lymphoid structures surrounding fenestrated venous plexi in the dura mater. We found the most elaborate immune organization, including lymphatic vessels, surrounding the rostral-rhinal confluence of sinuses. We termed this structure that interfaced with the skull bone marrow and a comparable venous plexus at the skull base, the rostral-rhinal venolymphatic hub. This hub emerged during development in mice at P8/9 before formation of the superior sagittal sinus. Single cell RNA sequencing demonstrated that rostral rhinal hub hosts a diverse array of resident innate and adaptive immune cells during steady state. Immune aggregates were also present in this structure during homeostasis and expanded with age or following challenge with systemic or nasal antigens. Following intranasal VSV infection, the rostral-rhinal hub supported local germinal center (GC) reactions consisting of T follicular helper cells as well as GC B cells that underwent proliferation, somatic hypermutation, class switch, and conversion into plasma cells locally. These data demonstrate lymphoid architecture around vascular plexi in the dura mater that can sample antigens and rapidly elaborate local humoral immune responses to protect the meninges and underlying brain parenchyma from pathogens. This research was supported by the intramural program of the National Institute of Neurological Disorders and Stroke, NIH