A comprehensive analysis of the maturation process of the immune system’s dendritic cells reveals an additional cell subtype. This finding could lead to new potential targets for more effective immunotherapy treatments and vaccines, but also raises questions about the accuracy of previous studies.

Pathogens such as bacteria and viruses trigger an immediate, nonspecific immune response. Dendritic cells are immune system cells that decide whether to mount a longer, specific and more complex immune response that will protect against subsequent re-infection with the same pathogen. “Characterizing the immune system’s key decision-making cells is crucial to improve the efficacy of vaccines and develop better therapeutics for devastating autoimmune diseases such as multiple sclerosis or lupus,” explained Florent Ginhoux, from the A*STAR Singapore Immunology Network, who led the international team of researchers.

There are two main types of dendritic cells: plasmacytoid DCs (pDCs), which promote antiviral immune responses through the production of interferons, and conventional DCs (cDCs). The latter come in two flavors or subsets: cDC-1 and cDC-2 and have crucial roles in mounting immune responses to intracellular and extracellular pathogens, respectively.

However, little is known about the origin of dendritic cells and the mechanisms through which they become specialized to carry out these functions.

Until now, dendritic cells have been identified and characterized based on the expression of particular proteins or surface markers. Ginhoux and colleagues took a different approach, which does not rely on prior knowledge, to re-examine the classification and interrelationship of dendritic cells.

They applied two powerful technologies: single-cell RNA sequencing and cytometry by time-of-flight to a fraction of human blood cells containing dendritic cells and dendritic cell precursors (pre-DCs), and analyzed the entire gene expression and protein profile of these cells.

They identified pre-DCs that share surface markers with pDCs, but that are functionally distinct as they are able to mature into cDC1 and cDC2 cell types but not pDCs. “We were amazed to find this cluster of cells with unique properties that lie between those of pre-DCs and pDCs,” said Ginhoux.

These findings bring into question results from many studies that have relied on a small set of markers to isolate pDCs. “It is likely that such studies were contaminated with pre-DCs,” Ginhoux explained.

Further analyses confirmed previous findings in mice that the pre-DC population can be split into pre-cDC1 and pre-cDC2 lineages as the precursors start to commit to a particular lineage.