de Campos Mata, L.; Yong, S.; Du, L.; Wan, H.; Marani, E.; Nilsen, V.; Sekine, T.; Marchalot, A.; Tibbitt, C.; Kammann, T.; Mouchtaridi, E.; Brownlie, D.; Marquardt, N.; Flodström-Tullberg, M.; Sandberg, J. K.; Lutolf, M. P.; Cabon, L.; Mjösberg, J.; Jorns, C.; Buggert, M.; Hammarström, L.; Ye, X.; Pan-Hammarström, Q.

The immune system is a dynamic network of diverse cell types distributed across tissues. While mouse studies have highlighted the importance of tissue-localized B-cell responses in infection and tissue repair, research on human B cells has remained largely confined to peripheral blood. Here, we specifically investigated the human B-cell compartment and its interactions with the immune microenvironment across 10 tissues, using single-cell RNA sequencing and paired B-cell receptor sequencing. We mapped the full spectrum of B-cell populations and revealed diverse differentiation trajectories spanning naive, memory, and plasma cell types. Germinal center B cells and plasma cells showed tissue-specific adaptations in transcriptional states, isotype usage, and functional profiles. Plasma cell isotypes influenced both effector functions and predicted interactions with T cells. Finally, we defined tissue-specific residency gene modules that outperformed existing memory B-cell signatures. Together, this dataset serves as a foundation for systematically studying tissue-localized B cells and reveals how local microenvironments shape humoral immunity.