Innate immune cells adjust to microbial and inflammatory stimuli through a process termed environmental plasticity, which links a given individual stimulus to a unique activated state. Here, we report that activation of human plasmacytoid predendritic cells (pDCs) with a single microbial or cytokine stimulus triggers cell diversification into three stable subpopulations (P1–P3). P1-pDCs (PD-L1+CD80) displayed a plasmacytoid morphology and specialization for type I interferon production. P3-pDCs (PD-L1CD80+) adopted a dendritic morphology and adaptive immune functions. P2-pDCs (PD-L1+CD80+) displayed both innate and adaptive functions. Each subpopulation expressed a specific coding- and long-noncoding-RNA signature and was stable after secondary stimulation. P1-pDCs were detected in samples from patients with lupus or psoriasis. pDC diversification was independent of cell divisions or preexisting heterogeneity within steady-state pDCs but was controlled by a TNF autocrine and/or paracrine communication loop. Our findings reveal a novel mechanism for diversity and division of labor in innate immune cells.

Access optionsAccess options

Rent or Buy article

Get time limited or full article access on ReadCube.


All prices are NET prices.

Additional information

Publisher’s note: Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.


  1. 1.

    Huang, Q. The plasticity of dendritic cell responses to pathogens and their components. Science 294, 870–875 (2001).

  2. 2.

    Liu, Y. J., Kanzler, H., Soumelis, V. & Gilliet, M. Dendritic cell lineage, plasticity and cross-regulation. Nat. Immunol. 2, 585–589 (2001).

  3. 3.

    Amit, I. et al. Unbiased reconstruction of a mammalian transcriptional network mediating pathogen responses. Science 326, 257–263 (2009).

  4. 4.

    Reis e Sousa, C. Activation of dendritic cells: translating innate into adaptive immunity. Curr. Opin. Immunol. 16, 21–25 (2004).

  5. 5.

    Mosser, D. M. & Edwards, J. P. Exploring the full spectrum of macrophage activation. Nat. Rev. Immunol. 8, 958–969 (2008).

  6. 6.

    Peritt, D. et al. Differentiation of human NK cells into NK1 and NK2 subsets. J. Immunol. 161, 5821–5824 (1998).

  7. 7.

    Fridlender, Z. G. et al. Polarization of tumor-associated neutrophil phenotype by TGF-β: “N1” versus “N2” TAN. Cancer Cell 16, 183–194 (2009).

  8. 8.

    Lawrence, T. & Natoli, G. Transcriptional regulation of macrophage polarization: enabling diversity with identity. Nat. Rev. Immunol. 11, 750–761 (2011).

  9. 9.

    Torri, A. et al. Gene expression profiles identify inflammatory signatures in dendritic cells. PLoS One 5, e9404 (2010).

  10. 10.

    Ito, T. et al. TSLP-activated dendritic cells induce an inflammatory T helper type 2 cell response through OX40 ligand. J. Exp. Med. 202, 1213–1223 (2005).

  11. 11.

    Xue, J. et al. Transcriptome-based network analysis reveals a spectrum model of human macrophage activation. Immunity 40, 274–288 (2014).

  12. 12.

    Liu, Y.-J. IPC: professional type 1 interferon-producing cells and plasmacytoid dendritic cell precursors. Annu. Rev. Immunol. 23, 275–306 (2005).

  13. 13.

    Cavaleiro, R. et al. Major depletion of plasmacytoid dendritic cells in HIV-2 infection, an attenuated form of HIV disease. PLoS Pathog. 5, e1000667 (2009).

  14. 14.

    Jaehn, P. S., Zaenker, K. S., Schmitz, J. & Dzionek, A. Functional dichotomy of plasmacytoid dendritic cells: antigen-specific activation of T cells versus production of type I interferon. Eur. J. Immunol. 38, 1822–1832 (2008).

  15. 15.

    Villani, A.-C. et al. Single-cell RNA-seq reveals new types of human blood dendritic cells, monocytes, and progenitors. Science 356, eaah4573 (2017).

  16. 16.

    See, P. et al. Mapping the human DC lineage through the integration of high-dimensional techniques. Science 356, eaag3009 (2017).

  17. 17.

    Sadaka, C., Marloie-Provost, M.-A., Soumelis, V. & Benaroch, P. Developmental regulation of MHC II expression and transport in human plasmacytoid-derived dendritic cells. Blood 113, 2127–2135 (2009).

  18. 18.

    Dzionek, A. et al. BDCA-2, a novel plasmacytoid dendritic cell-specific type II C-type lectin, mediates antigen capture and is a potent inhibitor of interferon alpha/beta induction. J. Exp. Med. 194, 1823–1834 (2001).

  19. 19.

    Cao, W. et al. Plasmacytoid dendritic cell-specific receptor ILT7-Fc epsilonRI gamma inhibits Toll-like receptor-induced interferon production. J. Exp. Med. 203, 1399–1405 (2006).

  20. 20.

    Chen, X. et al. Automated flow cytometric analysis across large numbers of samples and cell types. Clin. Immunol. 157, 249–260 (2015).

  21. 21.

    Kohrgruber, N. et al. Survival, maturation, and function of CD11c- and CD11c+ peripheral blood dendritic cells are differentially regulated by cytokines. J. Immunol. 163, 3250–3259 (1999).

  22. 22.

    Swiecki, M. et al. Type I interferon negatively controls plasmacytoid dendritic cell numbers in vivo. J. Exp. Med. 208, 2367–2374 (2011).

  23. 23.

    Siegal, F. P. et al. The nature of the principal type 1 interferon-producing cells in human blood. Science 284, 1835–1837 (1999).

  24. 24.

    Grouard, G. et al. The enigmatic plasmacytoid T cells develop into dendritic cells with interleukin (IL)-3 and CD40-ligand. J. Exp. Med. 185, 1101–1111 (1997).

  25. 25.

    Vu Manh, T. P., Bertho, N., Hosmalin, A., Schwartz-Cornil, I. & Dalod, M. Investigating evolutionary conservation of dendritic cell subset identity and functions. Front. Immunol 6, 260 (2015).

  26. 26.

    Jego, G. et al. Plasmacytoid dendritic cells induce plasma cell differentiation through type I interferon and interleukin 6. Immunity 19, 225–234 (2003).

  27. 27.

    Colonna, M., Trinchieri, G. & Liu, Y.-J. Plasmacytoid dendritic cells in immunity. Nat. Immunol. 5, 1219–1226 (2004).

  28. 28.

    Seth, S. et al. CCR7 essentially contributes to the homing of plasmacytoid dendritic cells to lymph nodes under steady-state as well as inflammatory conditions. J. Immunol. 186, 3364–3372 (2011).

  29. 29.

    Cella, M., Facchetti, F., Lanzavecchia, A. & Colonna, M. Plasmacytoid dendritic cells activated by influenza virus and CD40L drive a potent TH1 polarization. Nat. Immunol. 1, 305–310 (2000).

  30. 30.

    Kadowaki, N., Antonenko, S., Lau, J. Y. & Liu, Y. J. Natural interferon alpha/beta-producing cells link innate and adaptive immunity. J. Exp. Med. 192, 219–226 (2000).

  31. 31.

    Lande, R. et al. Plasmacytoid dendritic cells sense self-DNA coupled with antimicrobial peptide. Nature 449, 564–569 (2007).

  32. 32.

    Sisirak, V. et al. Genetic evidence for the role of plasmacytoid dendritic cells in systemic lupus erythematosus. J. Exp. Med. 211, 1969–1976 (2014).

  33. 33.

    Roubinet, C. & Cabernard, C. Control of asymmetric cell division. Curr. Opin. Cell Biol. 31, 84–91 (2014).

  34. 34.

    Bao, M. & Liu, Y. J. Regulation of TLR7/9 signaling in plasmacytoid dendritic cells. Protein Cell 4, 40–52 (2013).

  35. 35.

    Miller, J. G. The nature of living systems. Behav. Sci. 16, 277–301 (1971).

  36. 36.

    Banchereau, J. et al. Immunobiology of dendritic cells. Annu. Rev. Immunol. 18, 767–811 (2000).

  37. 37.

    Cella, M. et al. Plasmacytoid monocytes migrate to inflamed lymph nodes and produce large amounts of type Iinterferon. Nat. Med 5, 919–923 (1999).

  38. 38.

    Villadangos, J. A. & Young, L. Antigen-presentation properties of plasmacytoid dendritic cells. Immunity 29, 352–361 (2008).

  39. 39.

    Lewis, K. L. & Reizis, B. Dendritic cells: arbiters of immunity and immunological tolerance. Cold Spring Harb. Perspect. Biol. 4, a007401 (2012).

  40. 40.

    Duramad, O. et al. IL-10 regulates plasmacytoid dendritic cell response to CpG-containing immunostimulatory sequences. Blood 102, 4487–4492 (2003).

  41. 41.

    Bauer, J. et al. Cutting edge: IFN-β expression in the spleen is restricted to a subpopulation of plasmacytoid dendritic cells exhibiting a specific immune modulatory transcriptome signature. J. Immunol. 196, 4447–4451 (2016).

  42. 42.

    Zucchini, N. et al. Individual plasmacytoid dendritic cells are major contributors to the production of multiple innate cytokines in an organ-specific manner during viral infection. Int. Immunol. 20, 45–56 (2008).

  43. 43.

    Djebali, S. et al. Landscape of transcription in human cells. Nature 489, 101–108 (2012).

  44. 44.

    Derrien, T. et al. The GENCODE v7 catalog of human long noncoding RNAs: analysis of their gene structure, evolution, and expression. Genome Res. 22, 1775–1789 (2012).

  45. 45.

    Hu, G. et al. Expression and regulation of intergenic long noncoding RNAs during T cell development and differentiation. Nat. Immunol. 14, 1190–1198 (2013).

  46. 46.

    Matsui, T. et al. CD2 distinguishes two subsets of human plasmacytoid dendritic cells with distinct phenotype and functions. J. Immunol. 182, 6815–6823 (2009).

  47. 47.

    Zhang, H. et al. A distinct subset of plasmacytoid dendritic cells induces activation and differentiation of B and T lymphocytes. Proc. Natl. Acad. Sci. USA 114, 1988–1993 (2017).

  48. 48.

    Morrison, S. J. & Kimble, J. Asymmetric and symmetric stem-cell divisions in development and cancer. Nature 441, 1068–1074 (2006).

  49. 49.

    Kim, S. et al. Self-priming determines high type I IFN production by plasmacytoid dendritic cells. Eur. J. Immunol. 44, 807–818 (2014).

  50. 50.

    Prinz, J. C. Autoimmune-like syndromes during TNF blockade: does infection have a role? Nat. Rev. Rheumatol 7, 429–434 (2011).

  51. 51.

    Alculumbre, S. & Pattarini, L. Purification of human dendritic cell subsets from peripheral blood. in Dendritic Cell Protocols (eds. Segura, E. & Onai, N.) 153–167 (Humana, New York, 2016).

  52. 52.

    Antons, A. K., Wang, R., Kalams, S. A. & Unutmaz, D. Suppression of HIV-specific and allogeneic T cell activation by human regulatory T cells is dependent on the strength of signals. PLoS One 3, e2952 (2008).

  53. 53.

    Schindelin, J. et al. Fiji: an open-source platform for biological-image analysis. Nat. Methods 9, 676–682 (2012).

  54. 54.

    Trapnell, C., Pachter, L. & Salzberg, S. L. TopHat: discovering splice junctions with RNA-Seq. Bioinformatics 25, 1105–1111 (2009).

  55. 55.

    Anders, S., Pyl, P. T. & Huber, W. HTSeq: a Python framework to work with high-throughput sequencing data. Bioinformatics 31, 166–169 (2015).

  56. 56.

    Love, M. I., Huber, W. & Anders, S. Moderated estimation of fold change and dispersion for RNA-seq data with DESeq2. Genome Biol. 15, 550 (2014).

  57. 57.

    Huang, W., Sherman, B. T. & Lempicki, R. A. Bioinformatics enrichment tools: paths toward the comprehensive functional analysis of large gene lists. Nucleic Acids Res 37, 1–13 (2009).

  58. 58.

    Wolf, K. et al. Physical limits of cell migration: control by ECM space and nuclear deformation and tuning by proteolysis and traction force. J. Cell Biol. 201, 1069–1084 (2013).

  59. 59.

    Preibisch, S., Saalfeld, S. & Tomancak, P. Globally optimal stitching of tiled 3D microscopic image acquisitions. Bioinformatics 25, 1463–1465 (2009).

  60. 60.

    Maiuri, P. et al. The first world cell race. Curr. Biol. 22, R673–R675 (2012).

  61. 61.

    Rissoan, M. C. et al. Reciprocal control of T helper cell and dendritic cell differentiation. Science 283, 1183–1186 (1999).

  62. 62.

    Nestle, F. O. et al. Plasmacytoid predendritic cells initiate psoriasis through interferon-alpha production. J. Exp. Med. 202, 135–143 (2005).

Download references


We thank the Cytometry Core facility of IC for cell sorting. We thank INSERM U932, particularly P. Michea, for frequent discussions. We thank S. Amigorena, N. Manel and L. Pattarini for critical reading of the manuscript. This work was supported by funding from INSERM (BIO2014-08), FRM, ANR-13-BSV1-0024-02, ANR-10-IDEX-0001-02 PSL* and ANR-11-LABX-0043, ERC (IT-DC 281987, HEALTH 2011-261366 and 2013/COG/616180 DARK) and CIC IGR-Curie 1428. S.G.A. was supported by an IC fellowship and LabEx DCbiol. V.S-A. is supported as a Fondation pour la Recherche Médicale fellow (ARF20150934193). High-throughput sequencing was performed by the ICGex NGS platform of the Institut Curie, supported by grants ANR-10-EQPX-03 (Equipex) and ANR-10-INBS-09-08 (France Génomique Consortium) from the Agence Nationale de la Recherche (‘Investissements d’Avenir’ program), by the Canceropole Ile-de-France and by the SiRIC-Curie program, SiRIC Grant INCa-DGOS-4654.

Author information


  1. Institut Curie, Centre de Recherche, PSL Research University, Paris, France

    • Solana G. Alculumbre
    • , Violaine Saint-André
    • , Pablo Vargas
    • , Philemon Sirven
    • , Pierre Bost
    • , Mathieu Maurin
    • , Paolo Maiuri
    • , Maxime Wery
    • , Mabel San Roman
    • , Antonin Morillon
    •  & Vassili Soumelis
  2. INSERM U932, Immunity and Cancer, Paris, France

    • Solana G. Alculumbre
    • , Philemon Sirven
    • , Pierre Bost
    • , Mathieu Maurin
    • , Mabel San Roman
    •  & Vassili Soumelis
  3. CNRS UMR 3244, ncRNA, Epigenetic, and Genome Fluidity, Université Pierre et Marie Curie, Paris, France

    • Violaine Saint-André
    • , Maxime Wery
    •  & Antonin Morillon
  4. Department of Dermatology, University Hospital CHUV, Lausanne, Switzerland

    • Jeremy Di Domizio
    • , Curdin Conrad
    •  & Michel Gilliet
  5. CNRS UMR144, Paris, France

    • Pablo Vargas
  6. Department of Biology, Ecole Normale Supérieure, PSL Research University, Paris, France

    • Pierre Bost
  7. IFOM Foundation, Institute FIRC of Molecular Oncology, Milan, Italy

    • Paolo Maiuri
  8. UMR7211 and Inflammation–Immunopathology–Biotherapy Departement (DHU i2B), Sorbonne Universités, UPMC Université de Paris, Paris, France

    • Léa Savey
    •  & David Saadoun
  9. Assistance Publique-Hôpitaux de Paris (AP-HP), Groupe Hospitalier Pitié Salpétrière, Department of Internal Medicine and Clinical Immunology, National Reference Center for Autoimmune and Systemic Diseases, Paris, France

    • Léa Savey
    •  & David Saadoun
  10. AURA Paris Plaisance, Paris, France

    • Maxime Touzot
  11. Department of Internal Medicine, National Referral Center for Rare Autoimmune and Systemic Diseases, Cochin Hospital, AP-HP, Université Paris Descartes, Paris, France

    • Benjamin Terrier
  12. CIC IGR-Curie 1428, Paris, France

    • Vassili Soumelis


  1. Search for Solana G. Alculumbre in:

  2. Search for Violaine Saint-André in:

  3. Search for Jeremy Di Domizio in:

  4. Search for Pablo Vargas in:

  5. Search for Philemon Sirven in:

  6. Search for Pierre Bost in:

  7. Search for Mathieu Maurin in:

  8. Search for Paolo Maiuri in:

  9. Search for Maxime Wery in:

  10. Search for Mabel San Roman in:

  11. Search for Léa Savey in:

  12. Search for Maxime Touzot in:

  13. Search for Benjamin Terrier in:

  14. Search for David Saadoun in:

  15. Search for Curdin Conrad in:

  16. Search for Michel Gilliet in:

  17. Search for Antonin Morillon in:

  18. Search for Vassili Soumelis in:


S.G.A. designed and performed experiments, analyzed results and wrote the manuscript. V.S.-A. analyzed results and wrote the manuscript. P.B., M.M. and P.M. analyzed results. P.V. performed experiments and analyzed results. P.M. analyzed results. M.W. performed experiments. J.D.D., M.S.R. and P.S. performed experiments. L.S., D.S., M.T., B.T., C.C. and M.G. performed clinical management, selected the patients and provided clinical samples. A.M. designed experiments and supervised the research. V.S. designed experiments, supervised the research and wrote the manuscript.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Vassili Soumelis.

Integrated Supplementary Information

  1. Supplementary Figure 1 Sorting strategy for the isolation of CD2CD5AXL pDCs.

    a PBMC from human healthy donors were enriched for panDC and pDC were isolated as Linage (Lin)(CD14, CD16, CD19, CD20, CD3, CD56), CD4+, CD11c, CD2, CD5 and AXL. b The population (LinCD4+CD11c) CD2+and/or CD5+and/or AXL+ was isolated and cultured with Flu for 24h. PD-L1 and CD80 expression (left panel) and quantification of populations (right panel). Results shown as median of 3 independent donors.

  2. Supplementary Figure 2 Activated pDC populations show similar viability.

    PDCs were activated with Flu for 24h and the apoptotic marker annexin V was analyzed among each pDC subpopulation (a) and quantified the annexin+ cells (b) Median. n=3 independent donors. ns=non-significant (Friedman test + Dunn’s post-hoc).

  3. Supplementary Figure 3 P3 pDCs showed increased polarization and decreased endoplasmic reticulum.

    After 24h Flu activation, pDCs were sorted as P1-, P2- and P3-pDCs. a and b Immunofluorescence, phalloidin: red and DAPI: blue. Similar results were obtained for 3 independent donors b cells Aspect ratio. Median. P1 n= 230; P2 n=530; P3 n=338 cells. Unpaired t test. *p < 0.05; **p < 0.001; ***p < 0.0001. c EM images of the three pDC populations. Arrows denote the endoplasmic reticulum. Scale bars 2μm. Similar results were obtained for 2 independent donors.

  4. Supplementary Figure 4 IFN production by CD2CD5AXL pDC–derived subpopulations.

    PDC were sorted as CD2CD5AXL and culture 24h with Flu. PDC subpopulations were sorted and kept in culture for extra 24h in medium. IFN-α was measured in the culture supernatants. Results shown as the median of 6 independent donors. (Friedman test + Dunn's post-hoc). *p < 0.01.

  5. Supplementary Figure 5 T helper polarization by P1-, P2- and P3-pDCs.

    a ICOS, CD127, L-Selectin and CCR7 surface expression by CD4 T cells after coculture with pDC activated populations b PDC were sorted as CD2 CD5 AXL and culture 24h with Flu. PDC subpopulations were sorted and coculture with heterologous CD4 naive T cells. T cell expansion was measured after 6 days with P1-, P2- or P3-pDC (P1-T, P2-T and P3-T respectively). Results shown as the median of 3 independent donors. (ANOVA + Tukey’s post-hoc) c T helper cytokines induced by the activated pDC sub populations. Cytokines were measured after 24h polyclonal restimulation of the pDC polarized TH cells. Results include the median for 6 independent donors. (Friedman test + Dunn's post-hoc) d PDC-polarized TH cells were restimulated with PMA and Ionomicine. Intracellular TNF (left) and quantification of TNF producing cells (right). Results shown as the median for 5 donors. ns=non-significant; (ANOVA+ Tukey’s post-hoc). *p < 0.05; **p < 0.01.

  6. Supplementary Figure 6 PDC-derived type I IFN does not affect pDC diversification.

    PDCs were cultured with flu during 24h in the presence of antibodies blocking IFNAR2, IFN-α, and IFN-β or their corresponding isotype controls. a PD-L1 and CD80 expression and b quantification of pDC populations. Results shown as median of 3 independent donors. (paired t test). ns= non-significant.

Supplementary information

  1. Supplementary Text and Figures

    Supplementary Figures 1–6 and Supplementary Tables 1 and 2.

  2. Life Sciences Reporting Summary


  1. Supplementary Video 1: P1-pDC migration

    P1-pDC subpopulation migration in collagen gels towards a CCL21 gradient.

  2. Supplementary Video 2: P2-pDC migration

    P2-pDC subpopulation migration in collagen gels towards a CCL21 gradient.

  3. Supplementary Video 3: P3-pDC migration

    P3-pDC subpopulation migration in collagen gels towards a CCL21 gradient.

About this article

Publication history




Issue Date