Multimodal profiling reveals tissue-directed signatures of human immune cells altered with age

The immune system comprises multiple cell lineages and heterogeneous subsets found in blood and tissues throughout the body. While human immune responses differ between sites and over age, the underlying sources of variation remain unclear as most studies are limited to peripheral blood. Here, we took a systems approach to comprehensively profile RNA and surface protein expression of over 1.25 million immune cells isolated from blood, lymphoid organs, and mucosal tissues of 24 organ donors aged 20-75 years. We applied a multimodal classifier to annotate the major immune cell lineages (T cells, B cells, innate lymphoid cells, and myeloid cells) and their corresponding subsets across the body, and integrated differential expression analysis with probabilistic modeling to define bases for immune variations across donors, tissues, and age. We identified dominant tissue-specific effects on immune cell composition and function across lineages for lymph nodes, intestines, and lungs. Age-associated effects were manifested in specific lineages and for certain sites as revealed by macrophages in mucosal sites, B cells in lymphoid organs, and specific T and NK cell subsets across blood and tissues. Our results reveal tissue specific signatures of immune homeostasis throughout the body, providing a molecular basis for immune variation from which to define immune pathologies across the human lifespan.