Metaphocytes are IL-22BP-producing cells regulated by ETS transcription factor Spic and essential for zebrafish barrier immunity.

Metaphocytes are tissue-resident macrophage (TRM)/dendritic cell (DC)-like cells of non-hematopoietic origin in zebrafish barrier tissues. One remarkable property of metaphocytes is their ability to capture soluble antigens from the external environment via transepithelial protrusions, a unique function manifested by specialized subpopulations of the TRMs/DCs in mammal barrier tissues. Yet, how metaphocytes acquire myeloid-like cell properties from non-hematopoietic precursors and how they regulate barrier immunity remains unknown. Here, we show that metaphocytes are in situ generated from local progenitors guided by the ETS transcription factor Spic, the deficiency of which results in the absence of metaphocytes. We further document that metaphocytes are the major IL-22BP-producing cells, and the depletion of metaphocytes causes dysregulated barrier immunity that resembles the phenotype of IL-22BP-deficient mice. These findings reveal the ontogeny, development, and function of metaphocytes in zebrafish, which facilitates our understanding of the nature and function of the mammalian TRM/DC counterparts.