Title Viral infection engenders bona fide and bystander subsets of lung-resident memory B cells through a permissive mechanismAuthorsClaude Gregoire,1 Lionel Spinelli,1 Sergio Villazala-Merino,1 Laurine Gil,1 María Pía Holgado,1 Myriam Moussa,1 Chuang Dong,1 Ana Zarubica,2 Mathieu Fallet,1 Jean-Marc Navarro,1 Bernard Malissen,1,2 Pierre Milpied,1,* and Mauro Gaya1,*Affiliations1 Centre d'Immunologie de Marseille-Luminy (CIML), Aix Marseille Université, INSERM, CNRS, Marseille, France2 Centre d'Immunophénomique (CIPHE), Aix Marseille Université, INSERM, CNRS, Marseille, France* Correspondence: milpied@ciml.univ-mrs.fr (P.M.), gaya@ciml.univ-mrs.fr (M.G.)SummaryLung-resident memory B cells (MBCs) provide localized protection against reinfection in the respiratory airways. Currently, the biology of these cells remains largely unexplored. Here, we combined influenza and SARS-CoV-2 infection with fluorescent-reporter mice to identify MBCs regardless of antigen specificity. We found that two main transcriptionally distinct subsets of MBCs colonized the lung peribronchial niche after infection. These subsets arose from different progenitors and were both class-switched, somatically mutated and intrinsically biased in their differentiation fate towards plasma cells. Combined analysis of antigen-specificity and B cell receptor repertoire segregated these subsets into “bona fide” virus-specific MBCs and “bystander” MBCs with no apparent specificity for eliciting viruses and generated through an alternative permissive mechanism. Thus, diverse transcriptional programs in MBCs are not linked to specific effector fates but rather to divergent strategies of the immune system to simultaneously provide rapid protection from reinfection while diversifying the initial B cell repertoire. Data custom_201216_m_moFluMemB_processedData.tar.gz : pre-processed data of FB5P-seq protocol (Attaf et al., 2020) on memory B cells sorted from single-cell suspensions of lungs with enzymatic digestion of lung tissue at 37°C, with index sorting information for a panel of antibodies identifying subsets of memory B cells. moFluMemB_DockerImages.tar.gz: Docker images used by the analysis moFluMemB_SingularityImages.tar.gz: Singularity images used by the analysis (conversion of the docker images) See the three other Zenodo deposit for the rest of the data: 10.5281/zenodo.5565863 10.5281/zenodo.5564624 10.5281/zenodo.10559312