Constitutive immune surveillance of nasal mucosa by three neutrophil subsets with distinct origin, phenotype, and function

Abstract

The nasal mucosa (NM) has several critical functions, including as a chemosensory organ, as a filter and conditioning surface of inhaled air for the lower airways, and as a first line of defense against airborne infections. Owing to its constant exposure to ever-changing environments, the NM is arguably the most frequently infected tissue in mammals. Consequently, vertebrates harbor an intricate network of subepithelial immune cells that are dispersed throughout the NM. However, the origin, composition, and function of nasal immune cells and their pathophysiological role are poorly understood. Here, we show that murine steady-state NM harbors a prominent population of extravascular neutrophils (EVN) that are abundant in both conventional and germ-free mice, suggesting that their presence is not driven by microbial stimuli. Nasal EVN can be subdivided into three phenotypically distinct subsets: one population that we have termed nN1 is CD11bint Ly6Gint, while the other two subsets are both CD11bhi Ly6Ghi and distinguishable by the absence (nN2) or presence (nN3) of CD11c and SiglecF. nN1 EVN originate in bone marrow (BM) within osseous structures in the skull. These locally produced neutrophils appear to access the adjacent NM via conduits that connect BM cavities to the submucosal lamina propria. nN2 cells reach the NM via the blood and readily engulf infectious microbes. In the absence of infection, nN2 cells differentiate into the nN3 subset, which does not capture microbes but assumes phenotypic and functional features of antigen-presenting cells, including the capacity to cross-present exogenous antigens to CD8 T cells. These findings indicate that steady-state mammalian NM harbors a unique innate cellular immune environment that is unlike any other barrier tissue.