Distinct ontogenetic lineages dictate cDC2 heterogeneity

Abstract

Conventional dendritic cells (cDCs) include functionally and phenotypically diverse populations, such as cDC1s and cDC2s. The latter population has been variously subdivided into Notch-dependent cDC2s, KLF4-dependent cDC2s, T-bet+ cDC2As and T-bet− cDC2Bs, but it is unclear how all these subtypes are interrelated and to what degree they represent cell states or cell subsets. All cDCs are derived from bone marrow progenitors called pre-cDCs, which circulate through the blood to colonize peripheral tissues. Here, we identified distinct mouse pre-cDC2 subsets biased to give rise to cDC2As or cDC2Bs. We showed that a Siglec-H+ pre-cDC2A population in the bone marrow preferentially gave rise to Siglec-H− CD8α+ pre-cDC2As in tissues, which differentiated into T-bet+ cDC2As. In contrast, a Siglec-H− fraction of pre-cDCs in the bone marrow and periphery mostly generated T-bet− cDC2Bs, a lineage marked by the expression of LysM. Our results showed that cDC2A versus cDC2B fate specification starts in the bone marrow and suggest that cDC2 subsets are ontogenetically determined lineages, rather than cell states imposed by the peripheral tissue environment.

GM-CSF-dependent CD301b+ lung dendritic cells confer tolerance to inhaled allergens

“…3c and d). These results suggest that the majority of lung cDC2s are in the same lineage, which is in agreement with a recent report demonstrating that the type B cDC2 (cDC2B) lineage is the dominant cDC2 population in the lung and that these cells descend from a common preDC2 progenitor 21 .…”

“…By contrast, mouse cDC2s are very heterogeneous, have low amounts of CD103 and display high levels of CD11b. The heterogeneity of cDC2s has confounded efforts to assign specific functions to these cells, but the advent of single cell RNA-sequencing (scRNA-seq) has provided some much needed clarity 18 , 19 , 20 , 21 . Our group recently reported that the cell surface marker CD301b (encoded by Mgl2 ) is present on the cell surface of most lung cDC2s at steady state 18 .…”