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  1. Evaluation Summary:

    In this manuscript, the authors map the cellular landscape in the tongue, which is an underrated immunological organ, with a main focus on tissue-resident myeloid cells under homeostatic and inflammatory conditions. They identify two major subsets of macrophages, which occupy distinct anatomical niches and develop from local precursors, while under immune compromised conditions they can also be replenished from circulating hematopoietic precursors. These findings provide an important basis for future investigations of the tongue immune function in the context of infection, inflammation, and neoplastic diseases.

    (This preprint has been reviewed by eLife. We include the public reviews from the reviewers here; the authors also receive private feedback with suggested changes to the manuscript. The reviewers remained anonymous to the authors.)

  2. Reviewer #1 (Public Review):

    Authors propose here a detailed analysis of tongue macrophages and notably identify two populations of murine tongue macrophages. By combining scRNAseq, genetic mouse models and microscopy, they extensively characterize these two populations.

    The study is original and very seriously conducted. Data reported are convincing and fit with author interpretations.

  3. Reviewer #2 (Public Review):

    Despite its anatomical location at the entry point of the gastrointestinal tract and the airways, its constant exposure to microbes and non-microbial compounds and its important role in articulation, mastication and taste perception, the tongue remains an understudied organ. Here, the authors undertook a tour-de-force to map the immune compartment of the murine tongue. By means of single cell RNAseq, in combination with bulk RNAseq, flow cytometry and microscopy, they established an atlas of 20 immune cell populations in the murine tongue during homeostasis and during systemic inflammation. Mononuclear phagocytes represent the majority of all CD45+ tongue cell subsets. Among the terminally differentiated macrophages, the authors identified two new subsets that can be distinguished on the basis of CX3CR1 and FLOR2/LYVE1 expression. When comparing the gene expression profile of these macrophage subsets with tissue resident macrophages in other tissues, it became clear that they are distinct from Langerhans cells in skin and tongue, from alveolar macrophages in the airways, from microglia in the CNS and from red pulp macrophages in the spleen, but rather resemble interstitial macrophages such as those in the heart. They occupy distinct anatomical niches in the tongue, with FLOR2/LYVE1-expressing macrophages, which are more numerous in adults. being found in the lamina propria and throughout the tongue, while CX3CR1-expressing macrophages are restricted to the lamina propria and found enriched in proximity to nerve fibres in taste buds. Moreover, the two macrophage subsets respond differently to systemic LPS challenge. When assessing the development of the two macrophage subsets, the authors detected CX3CR1+ macrophages from E17.5, while the FLOR2/LYVE1 expressing subset only emerged after birth from a CX3CR1+FOLR2+ subset. From modelling the developmental trajectories, the authors concluded that both subsets develop from proliferating myeloid precursors in the tongues that lose proliferative capacity during terminal differentiation. In immunocompromised animals, however, such as lethally irradiated mice, adoptively transferred bone marrow precursors were found to restore both macrophage populations. Together, this is an important study with impact for those interested in the biology of the tongue in healthy and diseased conditions. It provides the basis for exploring the role of macrophages (and other immune cell types) for physiological functions of the tongue and in disease context including infection and cancer. The identification of specific markers in each macrophage subsets also opens the path towards selectively targeting them for further dissecting their relevance.