Functional specialization of short-lived and long-lived macrophage subsets in human tonsils

Macrophages play a central role in tissue homeostasis and host defense. However, the properties of human macrophages in non-diseased tissues remain poorly understood. Here, we characterized human tonsil macrophages and identified three subsets with distinct phenotype, transcriptome, life cycle, and function. CD36^hi macrophages were related to monocytes, while CD36^lo macrophages showed features of embryonic origin and CD36^int macrophages had a mixed profile. scRNA-seq on non-human primate tonsils showed that monocyte recruitment did not pre-exist an immune challenge. Functionally, CD36^hi macrophages were specialized for stimulating T follicular helper cells, by producing Activin A. Combining reconstruction of ligand–receptor interactions and functional assays, we identified stromal cell–derived TNF-α as an inducer of Activin A secretion. However, only CD36^hi macrophages were primed for Activin A expression, via the activity of IRF1. Our results provide insight into the heterogeneity of human lymphoid organ macrophages and show that tonsil CD36^hi macrophage specialization is the result of both intrinsic features and interaction with stromal cells.