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

Abstract 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.