Monocyte-lineage dendritic cell (DC) precursors are pre-positioned in normal lymph nodes and rapidly differentiate into Batf3+ cross-presenting APCs during inflammation

Abstract

Abstract We have shown (Immunity 48:91–106, 2018) that a subset of murine monocytic precursor cells are plastic, and can up-regulate a Batf3-driven differentiation program resembling classical cDC1 cells. The resulting inflammatory DCs are important in tumor immunity, but it has been unclear whether they played a role in normal immune responses. We now identify the precursor cells for these inflammatory DCs as a population of Ly6c+ ckit+ c− fms+ CD11b-neg cells. These are constitutively present in all resting LNs (comprising up to half of the Ly6c+ cells). In response to a standard vaccination model of cross-presented antigen (whole OVA protein plus CpG adjuvant in IFA), the precursor cells rapidly up-regulated Batf3 and differentiated into CD103+ IRF8+ DCs. Just as in tumors, maturation was dependent on intracellular p53 signaling in the precursor cells. Targeted disruption of p53 (LysMcre/p53-KO) had no effect on the number of precursors, but abrogated their ability to mature into Batf3+ DCs. In KO mice, the loss of this single monocytic DC population entirely abrogated the ability to create an inflammatory milieu in the vaccine-draining LN, and abolished cross-presentation of protein antigen to T cells. In contrast, direct presentation (soluble siinfekl peptide) remained intact. We hypothesize that the ability of monocyte-lineage cells to differentiate into Batf3+ APCs during inflammation is an important component of the normal cross-presentation process.