Roser Tachó‐Piñot, Habib Bashour, Martyna Filipska, Celia Corral-Vázquez, Mauricio Guzmán, Xavi Marcos-Fa, Donata Martinuzzi, Hannah Honner, Pablo Canales Herrerias, Sonia Tejedor Vaquero, Alba Sáez Gordón, Júlia Perera‐Bel, Jorge Barragán, Berta Arcós-Ribas, Leire de Campos‐Mata, Andrei Slabodkin, Maria Chernigovskaya, Maria Luisa Rodrı́guez de la Concepción, Jose Gutierrez‐Marcos, Ana García-García, A. Nascimento, M Pascal, Jordi Yagüe, Manel Juan, Juan Ignacio Aróstegui, Rafael Hijano Esqué, Albert Sanchez Font, Stephan Ehl, Bodo Grimbacher, Marta Rizzi, Laura Dotta, Kang Chen, Raffaele Badolato, Laia Alsina, Saurabh Mehandru, Charlotte Cunningham‐Rundles, Jorge Carrillo, Giuliana Magri, Victor Greiff, A Cerutti
Human tonsils from the nasopharyngeal mucosa mount frontline antibody responses, including IgD secretion by IgD+IgM- plasma cells (IgD-PCs). The developmental origins and functional significance of these IgD responses remain poorly understood. Here, we show that most IgD-PCs clonally emerge from a heterogeneous population of IgD class-switched IgD+IgM- memory (IgD-ME) B cells that reside within the epithelial, subepithelial, and interfollicular areas of the nasopharyngeal mucosa and share transcriptional and phenotypic properties with atypical B cells. These IgD-ME B cells arise from a mutation-intensive pathway that involves integrated innate and adaptive signals and engenders reactivities to respiratory commensal bacteria, common environmental antigens, and allergens. Such reactivities weaken in germline IgD revertants. Thus, the secreted IgD response heavily relies on nasopharyngeal mucosal IgD-ME B cells via a germinal center-imprinted mutational program that presumably enhances mucosal homeostasis and environmental tolerance.