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.