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Summary Dendritic cell (DC)-mediated cross-presentation of exogenous antigens acquired in the periphery is critical for the initiation of CD8+ T cell responses. Several DC subsets are described in human tissues but migratory cross-presenting DCs have not been isolated, despite their potential importance in immunity to pathogens, vaccines, and tumors and tolerance to self. Here, we identified a CD141hi DC present in human interstitial dermis, liver, and lung that was distinct from the majority of CD1c+ and CD14+ tissue DCs and superior at cross-presenting soluble antigens. Cutaneous CD141hi DCs were closely related to blood CD141+ DCs, and migratory counterparts were found among skin-draining lymph node DCs. Comparative transcriptomic analysis with mouse showed tissue DC subsets to be conserved between species and permitted close alignment of human and mouse DC subsets. These studies inform the rational design of targeted immunotherapies and facilitate translation of mouse functional DC biology to the human setting., Graphical Abstract Highlights ► Human tissues contain CD1c+ DCs, CD14+ DCs, and a CD141hi cross-presenting DC subset ► CD141hi DCs migrate to draining lymph nodes and probably arise from blood CD141+ DCs ► Human tissue CD141hi DCs are homologous to mouse CD103+ or CD8+ DCs ► Human tissue CD1c+ DCs are homologous to mouse CD4+ DCs

Summary Dendritic cells (DCs), monocytes, and macrophages are leukocytes with critical roles in immunity and tolerance. The DC network is evolutionarily conserved; the homologs of human tissue CD141hiXCR1+CLEC9A+ DCs and CD1c+ DCs are murine CD103+ DCs and CD64−CD11b+ DCs. In addition, human tissues also contain CD14+ cells, currently designated as DCs, with an as-yet unknown murine counterpart. Here we have demonstrated that human dermal CD14+ cells are a tissue-resident population of monocyte-derived macrophages with a short half-life of, Graphical Abstract, Highlights • Human dermal CD14+ cells are a transient population of macrophages • Dermal CD14+ cells are derived from circulating blood monocytes • Human CD14+ cells are homologous to murine CD11b+CD64+ monocyte-derived macrophages • Human and mouse mononuclear phagocyte network organization is conserved, It is unclear whether human dermal CD14+ cells are bona fide dendritic cells. Haniffa and colleagues demonstrate that dermal CD14+ cells are monocyte-derived macrophages and complete the human and mouse tissue dendritic cell network alignment.