Abstract
Type 2 conventional dendritic cells (cDC2s) are functionally and phenotypically heterogenous. Previous work in mice and humans identified two cDC2 subsets (cDC2As and cDC2Bs) and a monocytic DC3 subset. However, the microenvironmental cues governing their distinct differentiation pathways remain unclear. Here, we delineate mouse cDC2 lineage relationships and the sequential signals required for cDC2A maintenance. We show that cDC2s, arising from the CLEC9A+ cDC progenitor, encompass T-BET-expressing cDC2As and two cDC2B subsets distinguished by MGL2 expression, with monocytic DC3s exhibiting transcriptional overlap with Mgl2− cDC2Bs. Among these subsets, T-BET+ cDC2As dominate the spleen where they require cell-intrinsic retinoic acid signaling to sustain their differentiation via Notch signals. Lymphotoxin-β receptor signaling on splenic cDC2s limits F-actin content retaining cDC2s at sites of retinol delivery. In summary, these data establish the developmental and transcriptional relationships between diverse cDC2 subsets and identify signals that regulate their prevalence in specific lymphoid tissues.
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Data availability
The mouse sequencing data are available through the Gene Expression Omnibus under accession number GSE302089. This manuscript makes use of previously published scRNA-seq data from GSE262474, GSE137710 and FigShare (https://doi.org/10.6084/m9.figshare.22232056.v1)52.
Code availability
This study did not report original code.
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Acknowledgements
We thank C. Ware for agonist antibodies to LTβR (rat IgG anti-mouse LTβR clone 4H8), Sanford Burnham Prebys Institute, the veterinary staff at the Division of Comparative Medicine and the staff at the Faculty of Medicine Flow Cytometry Core Facility (University of Toronto) for support and all members of the laboratory of J.L.G. for help. We are grateful for funding support from the Canadian Institutes for Health Research/Instituts de Recherche en Santé du Canada (CIHR/IRSC) to J.L.G. (FDN-159922 and PJT-195705) and FRN-165973 to C.J.G. Flow cytometry was performed at the Centre for Immune Analytics Flow Cytometry Facility, University of Toronto, and the SickKids Flow Cytometry Facility, supported by the SickKids Foundation and a CFI John Evans Fund Leaders grant to C.J.G. This work was supported by a Parker Institute for Cancer Immunotherapy Senior Fellowship (C.C.B.), an NIH NIAID DP2 award (DP2AI171116; C.C.B.), Pew Biomedical Scholar Award (C.C.B.) and Josie Robertson Investigator Award (C.C.B.). A.A.N. was supported by a CIHR Frederick Banting and Charles Best Canada Graduate Scholarship Doctoral (CGS-D) Award (FRN-165746). L.F. is supported by an MSK Houghton-Coit Fellowship. We acknowledge the use of the Integrated Genomics Operation Core, MSKCC, funded by the NCI Cancer Center Support Grant (CCSG, P30 CA08748), Cycle for Survival and the Marie-Josée and Henry R. Kravis Center for Molecular Oncology. J.L.G receives salary support as a Canada Research Chair in tissue specific immunity.
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A.A.N., L.F., J.L.G. and C.C.B. designed, conceptualized and conducted the experiments, analyzed the data and wrote the manuscript. A.A.N. conducted the experiments, with assistance from J.S.Y.A., D.C.D., C.L., L.A.W., A.A.W. and B.M. M.Z. and T.M. performed the imaging analyses. T.P., A.Y. and Z.T. performed scRNA-seq data analyses. K.H. aided in data analysis and presentation. M.S.G., C.J.G. and C.L.M. provided mutant mice and mouse BM. D.T. and J.S.A. provided Myc. B reagent and contributed to the design of the F-actin inhibition experiments in mice. J.L.G. and C.C.B. supervised the project. All authors reviewed and edited the manuscript.
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Extended data
Extended Data Fig. 1 cDC2 development and heterogeneity.
a, Gating strategy for identification of cDC2 subsets in skin-draining peripheral lymph nodes (pLN) of Clec9aCre/CreTbx21RFP-CreERT2R26lsl-YFP mice. b, Representative flow cytometry of T-BET− cDC2 from indicated lymph nodes of Clec9aCre/CreTbx21RFP-CreERT2R26lsl-YFP mice showing expression of CD16/32 and summary graph showing frequency of CD16/32+ cells among Clec9a-fate mapped (YFP+) and non-fate mapped CD11b+T-BET− DCs (n = 4 mice). c, Gating strategy for FACS isolation of YFP+ and YFP− Lin−MHCII+ cells from spleen and lymph nodes of Clec9aCre/CreTbx21RFP-CreERT2R26lsl-YFP mice for scRNA-seq analysis. d, Representative flow cytometry of splenic cDC2s showing expression of MGL2 and CLEC10A (n = 3 mice). e, Violin plot depicting the expression of Zbtb46 in YFP+ and YFP− cells across clusters defined in Fig. 1b. f, Uniform manifold approximation and projection (UMAP) visualization of dendritic cells profiled by scRNA-seq in Rodrigues et al., colored by cluster. g, UMAP overlaid by expression of indicated genes. h, Heatmap showing scaled, imputed expression of all DEGs (pairwise comparison, fold change>1.5, adjusted P < 0.01) for indicated cDC2A, cDC2B and DC3 clusters. i, Violin plots depicting the expression of tdTomato in indicated clusters (as in f) derived from Cd300cCre-hCD2R26tdTomato, Il7rCreR26tdTomato, and Ms4a3CreR26tdTomato mice. j, Schematic showing cDC2 development and heterogeneity with transcriptional overlap between subsets indicated by dashed box. Data in in a, b, and d are representative of 2 independent experiments. Data are mean ± s.e.m., each symbol represents an individual mouse. Unpaired two-tailed t test; *P < 0.05, **P < 0.01.
Extended Data Fig. 2 Vitamin A and RAR signaling are required for optimal generation of cDC2 numbers.
a-c, Compiled data showing (a) cDC2/cDC1 ratio (b) %ESAM expression and (c) MFI of ESAM on cDC2 in mice given a VAD or control diet. DCs were distinguished identified based on Live B220−CD11c+MHCIIhi singlets, before being delineated into CD8+ cDC1 or CD11b+ cDC2 (n = 8 per group). d, Representative IMC images of three different 7 μm spleen cross-sections (10X magnification) depicting DCIR2+ cDC2 (red) within marginal zone bridging channels (MZBCs) in control and VAD diet animals. CD169 (blue pseudocolour) was used to outline the marginal zone; B220 (green pseudocolour) and CD3 (red pseudocolour) were used to outline the B cell follicle. Average DCIR2 pixel intensity was measured in MZBCs of control and VAD diet animals (n = 5 per group). e, Representative images of three different 7 μm spleen cross-sections (10X magnification) depicting spleen follicles using CD3 (red pseudocolour), CD169 (blue pseudocolour), and B220 (green pseudocolour). (Bottom) Quantification of average follicle size across control and VAD diet animals. Scale bars indicate 250μm (n = 5 per group). f-h, Compiled data showing (f) cDC2/cDC1 ratio (g) %ESAM expression and (h) MFI of ESAM on cDC2 in mice supplemented with RA or vehicle control for 9 days (n = 7 per group for f and g, n = 4 per group for h). i, Compiled data showing cDC1 frequencies in mice given a Control Diet (n = 6) or VAD diet (n = 5). j, Compiled data showing cDC1 frequencies in mice supplemented DMSO control or RA (n = 5 per group). k, Compiled data showing absolute numbers of CD11b+ cDC2 and CD8+ cDC1 in the PPs of VAD vs control diet animals (n = 5 per group). Data in a-g, i-k are representative of two independent experiments, and h is representative of one experiment. Statistics were measured by Mann-Whitney U test in a, b, c, d, e, f, g, h, i, and j (ns, P > 0.05, *P < 0.05, **P < 0.01, and ***P < 0.001) and multiple Mann-Whitney tests with Holm Sidak’s adjustment in k (ns, P > 0.05 and ***P < 0.001). Error bars represent the mean ± s.d., each symbol represents an individual mouse.
Extended Data Fig. 3 Characterization of Tbx21 expression in cDC subsets.
a, Representative plot showing ESAM and RFP (T-BET) expression in Sirpa+ cDC2 in the spleen (left) and Peyer’s Patches (right) of Tbx21RFP-Cre mice. b, Histogram showing ESAM expression is enriched in splenic cDC2A compared to cDC2B. c, Flow cytometry gating strategy to identify cDC2A. In brief, cDC were distinguished from other immune cell populations in the spleen, B220+, Ly6Cint/hi, and Tbx21hi cells (top-left to top-right) were gated out to remove B cells, plasmacytoid DCs, monocytes, neutrophils, and contaminating NK cells and T cell populations (in contrast, cDCs are express moderate levels of Tbx21). Next, the cDC population was gated on by their high surface expression of CD11c and MHCII. Expression of Sirpa and XCR1 was used to distinguish cDC2 vs cDC1 populations respectively (bottom-left and bottom-center). Note that Tbx21 expression is only observed in the cDC2 and not in cDC1. B6 mice lacking the RFP reporter for Tbx21 expression were used as a negative control (bottom-right).
Extended Data Fig. 4 Cellularity and immune cell composition in VAD spleens.
a-g, absolute numbers of (a) total live CD45+ cells and (b) B cell, (c) T cell, (d) macrophage, (e) neutrophil, (f) monocyte, and (g) NK cell populations in the spleen were compared between 10-12-week-old mice fed a Vitamin A-sufficient control or VAD diet since embryonic day 14 (n = 6 per group). Data in a-g are representative of two independent experiments. Mann-Whitney U test was conducted for comparison between two groups in a, b, d, and e (ns, P > 0.05 and **, P < 0.01). 2-Way ANOVA with Tukey’s multiple comparisons test was used for comparison between multiple groups across two categorical variables in c, f, and g (ns, P > 0.05, *P < 0.05, and ***P < 0.001). Error bars represent the mean ± s.d., each symbol represents an individual mouse.
Extended Data Fig. 5 Impact of cDC-intrinsic dnRAR expression on pre-cDC2A and cDC2A in different tissues.
a, Representative flow cytometry plots showing gating strategy for the identification of pre-cDC1, pre-cDC2A, and pre-cDC2B subsets in the BM. b, Compiled data of pre-cDC subsets in the BM of littermate controls (n = 8) vs Zbtb46CrednRaralsl/lsl (n = 9). c, Representative flow cytometry plots comparing cDC2A populations between the spleen and pLN of Tbx21RFP-CrednRaralsl/lsl and Tbx21RFP-Cre littermate controls. d, Compiled data showing frequency of T-BET expression in pLN cDC2s from Tbx21RFP-Cre littermate controls and Tbx21RFP-CrednRaralsl/lsl (n = 6 per group). e, Schematic of mixed competitive BM chimera approach to study cDC2A-intrinsic loss of RAR signaling in vivo. f, Representative flow cytometry plots showing ESAM and T-BET RFP expression from CD45.1+ B6 and CD45.2+ Tbx21RFP-Cre or Tbx21RFP-CrednRaralsl/lsl donors in chimeras from (e). g-i, Compiled data of f showing ESAM expression in CD45.2+ cDC2 containing Tbx21RFP-Cre or Tbx21RFP-CrednRaralsl/lsl donor-derived cells (g), and CD45.2/CD45.1 chimerism of ESAM+ cDC2A (h) and ESAM− cDC2B (i) (n = 5 per group). Data in b, d, and g-i are representative of two independent experiments. in a and b. Statistics were measured by Mann-Whitney U test in b, d, g, h, and i (ns, P > 0.05, **P < 0.01). Error bars represent the mean ± s.d., each symbol represents an individual mouse.
Extended Data Fig. 6 Optimal generation of splenic cDC2A requires cDC-intrinsic LTbR signaling prior to expression of Tbx21.
a, Relative expression of Ltbr mRNA transcripts measured by qPCR in spleen cDC subsets in (a) control diet mice (n = 12) vs VAD diet-fed mice (n = 9). b, Relative expression of Ltbr mRNA transcripts measured by qPCR in spleen cDC2 of mice given a single dose of DMSO, RA after 2- or 24-hours (n = 5 per group). c, d, Surface expression of LTβR measured using anti-LTβR (3C8) antibody in (c) cDC1 or (d) cDC2 of mice given a single dose of DMSO (n = 8), RA after 2 (n = 9) or 24 h (n = 10). e, Representative histograms showing LTβR surface expression (clone 3C8) in splenic cDC2A, cDC2B, and cDC1 populations (as indicated in figure legend (far-right)) in C57Bl/6 (left), Tbx21RFP-Cre (center), and Tbx21RFP-CreLtbrfl/fl (right) mice. f, Compiled data of e showing LTβR surface expression between Tbx21RFP-CreLtbrfl/fl compared to littermate controls (n = 4 per group). g, Representative histograms depicting ESAM expression in cDC2s of Zbtb46CreLtbrfl/fl vs. littermate controls. h, Compiled data of g showing % ESAM expression on splenic cDC2 in littermate controls (n = 4) vs Zbtb46CreLtbrfl/fl mice (n = 7). Data in a, c, d, and h are representative of two independent experiments; b and f are representative of one experiment. Statistics were measured by multiple Mann-Whitney tests with Holm Sidak’s adjustment in a (ns, P > 0.05), Kruskal-Wallis test with Dunn’s multiple-comparisons test in b, c, and d (ns, P > 0.05 and *P < 0.05), and Mann-Whitney U tests in f and h (*P < −0.05). Error bars represent the mean ± s.d., each symbol represents an individual mouse.
Extended Data Fig. 7 RBPR2 (Stra6l) gene/protein expression is enriched in cDC2A.
a, UMAP plot depicting Stra6l gene expression in cDC populations from Fig. 1 scRNA-seq dataset of skin-draining pLN, mLN, and medLN dataset, with accompanying legend of DC clusters.
Extended Data Fig. 8 Phalloidin staining index of splenic cDC2A ex vivo and during Myc. B treatment conditions.
a, Representative flow plots and histograms showing Phalloidin staining in pLN stromal cell subsets (top-left and top-right: CD31+ ECs (blue) vs, CD31+Pdpn+ LECs (red) vs. CD31−Pdpn+ FRCs (orange)) and splenic cDC2 subsets (bottom-left and bottom-right: –FMO staining control (blue) compared to T-BET+ cDC2A (red) and T-BET− cDC2B (orange)). b, Representative plots showing Phalloidin staining of ex-vivo sorted splenic cDC2 after culture in Myc. B at labeled concentrations (or DMSO vehicle control) at 37 °C for 2 h and compiled MFI data on gated T-BET+ cDC2A (right). c, Compiled data of b. Each point on plot is representative of three technical replicates from two pooled Tbx21RFP-Cre spleens.
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Nguyen, A.A., Fisher, L., Ahn, J.S.Y. et al. Sequential lymphotoxin-β receptor and retinoic acid receptor signals regulate cDC2 fate. Nat Immunol 26, 2159–2169 (2025). https://doi.org/10.1038/s41590-025-02329-x
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DOI: https://doi.org/10.1038/s41590-025-02329-x
