On or within: spatial determinants of antigen handling in the nasal turbinates.

The SARS-CoV-2 pandemic has renewed interest in mucosal vaccines, yet these approaches have long struggled to generate durable protection against airway pathogens. A key limitation is the incomplete understanding of how upper airway antigens are handled to shape immune response quality and durability. Antigens located within the airspace or on the mucosal surface can be directly sampled by mucosal-associated lymphoid tissues (MALTs), such as Nasal-associated lymphoid tissue (NALT) in mice, or tonsils in humans. Because MALTs lack afferent lymphatics, antigen entry occurs primarily across a specialized epithelium. In contrast, antigens that arise within the mucosa following barrier breach are captured by immune cells and lymphatics for delivery to draining lymph nodes. This framework suggests that 'on the mucosa' antigens preferentially engage MALTs, whereas 'within the mucosa' antigens are handled by lymph nodes. However, the rules governing antigen handling within the nasal cavity remain poorly defined, limiting rational mucosal vaccine design.