Dendritic cells (DCs) are a critical lineage for host defenses, important in bridging innate and adaptive responses. Their continuous replenishment from hematopoietic progenitors in the bone marrow, however, is sensitive to inflammatory stimuli, and during viral infection DC progenitors undergo several adaptations that alter the output and functional potential of the different DC subsets.
To define the mechanisms and potential regulators behind DC progenitors’ adaptations at the single-cell level, we performed scRNA-seq on purified bone marrow DC progenitors (Lin- c-Kit int/lo Flt3+) from mice infected with lymphocytic choriomeningitis virus (LCMV), a natural murine pathogen. Our analysis reveals a profound and selective reduction of lymphoid progenitors and their downstream plasmacytoid (p)DC-primed states, together with an increase in myeloid-derived conventional (c)DC progenitors. Within the cDC trajectory, we observed a substantial increase in pre-DC2 signatures enriched for inflammatory markers such as Tgfbi and Fcgr3. Using gene regulatory network inference, we also identified candidate regulatory transcription factors that may be driving the observed changes in lineage specification, namely Cebpb and Nfix.
Within the pDC lineage, we observed a downregulation of the HP1-family of chromatin regulators, suggestive of a permissive chromatin landscape that may facilitate the transition to alternative transcriptional programs. Additionally, we observed reduced expression of a subunit of cytochrome C oxidase, indicating that the metabolic deficiencies supporting reduced IFN output observed in pDCs shortly after infection may be established early in development.
These findings suggest that inflammatory stimuli not only alter the early developmental trajectories of the DC lineage, driving cDC development at the expense of pDC output, but may also induce an early functional imprint that pre-determines the suppressed states in pDCs prior to their de-novo generation.