CXCR4 marks homeostatically activated dendritic cells in the steady state and in cancer.

Conventional dendritic cells (cDCs) can be activated by pathogen signals and inflammation to drive T cell immunity to infection, but they can also undergo "homeostatic activation" at steady state. However, homeostatically activated cDCs closely resemble those activated by microbial or viral stimuli, hindering their study. Here, we identify the chemokine receptor CXCR4 as a specific marker of homeostatically activated cDCs across mouse tissues. CXCR4 is induced in cDCs in the steady state but not following stimulation with Toll-like receptor agonists or type I interferons. In tumors, CXCR4 expression or a gene signature derived from mouse spleen CXCR4hi cDCs marks the so-called "mregDCs" that have acquired tumor-derived material. Notably, the gene signature derived from mouse spleen CXCR4hi cDCs further identifies mregDCs in human cancers. Thus, CXCR4 distinguishes homeostatic from inflammatory cDC activation programs, providing a means to identify and study this cDC state in both physiological and pathological contexts.