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As a barrier organ, which is constantly exposed to environmental pathogens, the tongue is expected to host an immune cell network ensuring local immune defence. However, the composition and the transcriptional landscape of the tongue immune system are currently not completely defined. Here, we characterised the tissue-resident immune compartment of the murine tongue during development, health and disease, combining single-cell RNA-sequencing with in situ immunophenotyping. We identified distinct local immune cell populations and described two specific subsets of tongue-resident macrophages occupying discrete anatomical niches.\n                    <jats:italic>Cx3cr1<\/jats:italic>\n                    <jats:sup>+<\/jats:sup>\n                    macrophages were located specifically in the highly innervated lamina propria beneath the tongue epidermis and at times in close proximity to fungiform papillae.\n                    <jats:italic>Folr2<\/jats:italic>\n                    <jats:sup>+<\/jats:sup>\n                    macrophages were detected in deeper muscular tissue. In silico analysis indicated that the two macrophage subsets originate from a common proliferative precursor during early postnatal development and responded differently to systemic LPS in vivo. Our description of the under-investigated tongue immune system sets a starting point to facilitate research on tongue immune-physiology and pathology including cancer and taste disorders.\n                  <\/jats:p>","DOI":"10.7554\/elife.77490","type":"journal-article","created":{"date-parts":[[2022,5,31]],"date-time":"2022-05-31T09:15:24Z","timestamp":1653988524000},"update-policy":"https:\/\/doi.org\/10.7554\/elife.77490","source":"Crossref","is-referenced-by-count":23,"title":["Tongue immune compartment analysis reveals spatial macrophage heterogeneity"],"prefix":"10.7554","volume":"11","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-3269-0854","authenticated-orcid":true,"given":"Ekaterini Maria","family":"Lyras","sequence":"first","affiliation":[{"id":[{"id":"https:\/\/ror.org\/04p5ggc03","id-type":"ROR","asserted-by":"publisher"}],"name":"Max-Delbr\u00fcck-Center for Molecular Medicine Berlin","place":["Berlin, 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