pDC-like cells are pre-DC2 and require KLF4 to control homeostatic CD4 T cells

Abstract

Plasmacytoid dendritic cells (pDCs) have been shown to play an important role during immune responses, ranging from initial viral control through the production of type I interferons to antigen presentation. However, recent studies uncovered unexpected heterogeneity among pDCs. We identified a previously uncharacterized immune subset, referred to as pDC-like cells, that not only resembles pDCs but also shares conventional DC (cDC) features. We show that this subset is a circulating precursor distinct from common DC progenitors, with prominent cDC2 potential. Our findings from human CD2-iCre and CD300c-iCre lineage tracing mouse models suggest that a substantial fraction of cDC2s originates from pDC-like cells, which can therefore be referred to as pre-DC2. This precursor subset responds to homeostatic cytokines, such as macrophage colony stimulating factor, by expanding and differentiating into cDC2 that efficiently prime T helper 17 (T H 17) cells. Development of pre-DC2 into CX3CR1 + ESAM − cDC2b but not CX3CR1 − ESAM + cDC2a requires the transcription factor KLF4. Last, we show that, under homeostatic conditions, this developmental pathway regulates the immune threshold at barrier sites by controlling the pool of T H 17 cells within skin-draining lymph nodes.

Distinct ontogenetic lineages dictate cDC2 heterogeneity

“…The original cDC2B population included a small proportion of cells marked by RORγt fate mapping 15 , later shown to constitute a distinct lymphoid cell type rather than bona fide cDCs 16 . In a further study, KLF4-dependent cDC2s were suggested to correspond to cDC2Bs 17 . Finally, infection or cancer can drive the appearance of cells termed ‘inflammatory cDC2s’ and ‘mature dendritic cells enriched in regulatory molecules’, respectively 12 , 18 , 19 .…”

Genome-wide screening identifies Trim33 as an essential regulator of dendritic cell differentiation

“…2D). We also examined the Cx3cr1 + DC subset that is developmentally related to pDCs and was recently designated as transitional DCs (tDCs) (48)(49)(50)(51). The fraction of tDCs in the spleens of Carm1 Δ chimeras was significantly reduced (Fig.…”

Cross-species analyses reveal RORγt-expressing dendritic cells are a lineage of antigen presenting cells conserved across tissues

“…Their functional versatility makes them attractive for being targeted in vaccination against pathogens or cancer (2-6). Accordingly, considerable work has been invested in understanding the functional and ontogenetic diversity of cDCs, yet these cells remain ambiguous to define as fate mapping has recently uncovered novel populations with overlapping phenotype but distinct origin (2,(7)(8)(9)(10)(11)(12). cDCs are generally considered to descend from committed myeloid cDC progenitors (13)(14)(15) and exist as functionally specialized subtypes.…”

“…Both subtypes can induce Th17 responses but cDC2A appear more potent inducers of T follicular helper cell (Tfh) responses (19), while cDC2B may better promote Th2 responses (20). Fetal liver lymphoid progenitors in neonatal spleen and lymphoid derived transitional DCs (tDCs) in adult spleen can differentiate into cells resembling cDC2A and cDC2B (9)(10)(11)21). tDCs are cells with features of both cDCs and plasmacytoid DCs (pDCs), the latter of which are potent producers of type I interferons in response to viruses (9,10,21).…”

“…Fetal liver lymphoid progenitors in neonatal spleen and lymphoid derived transitional DCs (tDCs) in adult spleen can differentiate into cells resembling cDC2A and cDC2B (9)(10)(11)21). tDCs are cells with features of both cDCs and plasmacytoid DCs (pDCs), the latter of which are potent producers of type I interferons in response to viruses (9,10,21). Monocytic progenitors also generate cDC2B-like cells, which have been termed DC3 because of their distinct origin and similarity to human DC3 populations and in vitro appear superior in polarizing IL17A producing Th17 cells to cDC2B (12,22,23).…”