LAUSR

Human 6‐sulfo LacNac‐positive (slan+) cells have been subject to a paradigm debate. They have previously been classified as a distinct dendritic cell (DC) subset. However, evidence has emerged that they may be more related to monocytes than to DCs. To gain deeper insight into the functional specialization of slan+ cells, we have compared them with both conventional myeloid DC subsets (CD1c+ and CD141+) in human peripheral blood (PB). With the use of genome‐wide transcriptional profiling, as well as functional tests, we clearly show that slan+ cells form a distinct, non‐DC‐like population. They cluster away from both DC subsets, and their gene‐expression profile evidently suggests involvement in distinct inflammatory processes. An extensive transcriptional meta‐analysis confirmed the relationship of slan+ cells with the monocytic compartment rather than with DCs. From a functional perspective, their ability to prime CD4+ and CD8+ T cells is relatively low. Combined with the finding that “antigen presentation by MHC class II” is at the top of under‐represented pathways in slan+ cells, this points to a minimal role in directing adaptive T cell immunity. Rather, the higher expression levels of complement receptors on their cell surface, together with their high secretion of IL‐1β and IL‐6, imply a specific role in innate inflammatory processes, which is consistent with their recent identification as non‐classical monocytes. This study extends our knowledge on DC/monocyte subset biology under steady‐state conditions and contributes to our understanding of their role in immune‐mediated diseases and their potential use in immunotherapeutic strategies.