A spatial multi-omics atlas of the human lung reveals a novel gland-associated immune niche

Meyer K, Madissoon E, Oliver A, Kleshchevnikov V, Wilbrey-Clark A, Polański K, Richoz N, Orsi AER, Mamanova L, Bolt L, Elmentaite R, Pett J, Huang N, Xu C, He P, Dabrowska M, Pritchard S, Tuck E, Prigmore E, Perera S, Knights A, Oszlanczi A, Hunter A, Vieira SF, Patel M, Yoshida M, Worlock K, Lindeboom R, Nikolic M, Georgakopoulos N, Mahbubani K, Saeb-Parsy K, Bayraktar OA, Clatworthy M, Stegle O, Kumasaka N, Teichmann S.
Preprint from
Research Square
20 May 2022
To (re)define tissue architecture of the lung and airways at the cellular and molecular level, we profiled five proximal-to-distal locations of healthy human lungs in depth using multi-omic single cell/nuclei and Visium Spatial Transcriptomics. Using computational data integration and analysis, we extend beyond the suspension cell paradigm of lung atlases to date, to define and discover macro and micro-anatomical tissue compartments. We describe novel cell types and states in vascular, stromal and nerve bundle microenvironments. From our spatial transcriptomics, we discover and validate a novel survival niche for IgA plasma cells in the airway submucosal glands (SMG). In this niche we define a supporting role for SMG epithelial cells in mucosal immunity through recruitment and maintenance of IgA plasma, B and CD4 T cells locally at the airway SMG. We identify an immune-supporting role for SMG duct and serous cells with distinct signalling circuits to recruit B cells and IgA plasma cells, promoting longevity and antibody secretion through expression of CCL28, APRIL and IL6. We find high expression of MHC-II in SMG duct and serous cells, which are localised closely with memory CD4 T cells, suggesting local modulation of antigen specific immune responses locally at the glands. This new tissue microenvironment, which we term the “gland-associated immune niche” (GAIN) has major implications for respiratory immunity and infection response. Our single cell and spatial data is available for download and query at lungcellatlas.org.