Ly6D+Siglec-H+ precursors contribute to conventional dendritic cells via a Zbtb46+Ly6D+ intermediary stage

Lutz, Konstantin; Musumeci, Andrea; Sie, Christopher; Dursun, Ezgi; Winheim, Elena; Bagnoli, Johannes W.; Ziegenhain, Christoph; Rausch, Lisa; Bergen, Volker; Luecken, Malte D.; Oostendorp, Robert A.J.; Schraml, Barbara U.; Theis, Fabian J.; Enard, Wolfgang; Korn, Thomas; Krug, Anne

doi:10.1038/s41467-022-31054-4

Cited by 14 publications

(7 citation statements)

References 70 publications

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“…S2E). C-C motif chemokine receptor 9 (CCR9) that, among other receptors, was used to identify CCR9 − immature pDCs from CCR9 + mature pDCs ( 42 , 52 , 53 ) is not expressed on pDC-like cells and remains heterogeneous on conventional pDCs (fig. S1, E and F).…”

Section: Resultsmentioning

confidence: 99%

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

et al. 2023

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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.

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Section: Resultsmentioning

confidence: 99%

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

et al. 2023

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“…It is possible that IFN signaling is inhibitory on pre-DC, or that pre-DC are antagonistic to the pDC that produces IFN-α. The type I IFN stimulation is reported to limit cDC differentiation and promotes pDC differentiation (40) (41). Although type I IFN signaling has been reported to be a factor that predicts development of RA (42), type I IFN signaling predicts a good therapeutic response to TCZ and TNF inhibitors (5,9,10).…”

Section: Discussionmentioning

confidence: 99%

Immunomics analysis of rheumatoid arthritis identified precursor dendritic cells as a key cell subset of treatment resistance

Yamada

Nagafuchi

Wang

et al. 2022

Preprint

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Objectives Little is known about the immunology underlying variable treatment response in rheumatoid arthritis (RA). We performed large scale transcriptome analyses of peripheral blood immune cell subsets to identify immune cells that predict treatment resistance. Methods We isolated 18 peripheral blood immune cell subsets of 55 pre-treatment RA patients and 39 healthy controls, and performed RNA sequencing. Transcriptome changes in RA and treatment effects were systematically characterized. Association between immune cell gene modules and treatment resistance was evaluated. We validated predictive value of identified parameters for treatment resistance using quantitative polymerase chain reaction (qPCR) and mass cytometric analysis cohorts. We also characterized the identified population by synovial single cell RNA-seq analysis. Results Immune cells of RA patients were characterized by enhanced interferon and IL6-JAK-STAT3 signaling that demonstrate partial normalization after treatment. A gene expression module of plasmacytoid dendritic cells (pDC) reflecting the expansion of pre-dendritic cells (pre-DC) exhibited strongest association with treatment resistance. Type I interferon signaling was negatively correlated to pre-DC gene expression. qPCR and mass cytometric analysis in independent cohorts validated that the pre-DC associated gene expression and the proportion of pre-DC were significantly higher before treatment in treatment-resistant patients. A cluster of synovial DCs showed both features of pre-DC and proinflammatory conventional DC2s. Conclusions An increase in pre-DC in peripheral blood predicted RA treatment resistance. Pre-DC could have pathophysiological relevance to RA treatment response.

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“…RNA velocity vectors were visualized on top of the same UMAP embedding to delineate directionality of the transition through the topology. Ly6d + cDCs were excluded from the trajectory due to their high transcriptional similarity to pDCs, suggesting a distinct origin 63 . MonoDC2s were excluded from the cDC2 trajectory because previous studies indicate they migrate to the thymus from the periphery and do not differentiate intrathymically 12,13 .…”

Section: Methodsmentioning

confidence: 99%

Single-cell transcriptomics reveals heterogenous thymic dendritic cell subsets with distinct functions and requirements for thymocyte-regulated crosstalk

Srinivasan,

Helm,

Yang

et al. 2023

Preprint

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SUMMARYDendritic cells (DCs) are essential for establishing central tolerance in the thymus; however, mechanisms supporting their homeostasis and activation remain unresolved. Through single-cell transcriptomics and functional assays, we identify seven thymic conventional DC (cDC) subsets and discriminate their abilities to present self-antigens and induce regulatory T cells (Tregs). Mice blocked at different stages of T-cell development reveal that CD4+single-positive (SP) and CD8SP thymocytes differentially support homeostasis and activation of cDC1s versus cDC2s/ plasmacytoid DCs (pDCs), respectively. CD8SP regulate cDCs via interferon signaling, while CD4SP promote NF-kB activation. CD40, which activates non-canonical NF-kB signaling, is required for both activation and homeostasis of cDC1s, although only activation is driven by cognate interactions with CD4SPs. Surprisingly, some DCs display an activated signature in the absence of mature thymocytes. Altogether, this study comprehensively identifies functionally distinct thymic DC subsets and elucidates requirements for crosstalk with thymocyte subsets that support their homeostasis and activation.

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Ly6D+Siglec-H+ precursors contribute to conventional dendritic cells via a Zbtb46+Ly6D+ intermediary stage

Cited by 14 publications

References 70 publications

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

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

Immunomics analysis of rheumatoid arthritis identified precursor dendritic cells as a key cell subset of treatment resistance

Single-cell transcriptomics reveals heterogenous thymic dendritic cell subsets with distinct functions and requirements for thymocyte-regulated crosstalk

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