Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Resource
  • Published:

Comparative transcriptional and functional profiling defines conserved programs of intestinal DC differentiation in humans and mice

Nature Immunology volume 15, pages 98–108 (2014)Cite this article

Subjects

Abstract

Dendritic cells (DCs) that orchestrate mucosal immunity have been studied in mice. Here we characterized human gut DC populations and defined their relationship to previously studied human and mouse DCs. CD103+Sirpα− DCs were related to human blood CD141+ DCs and to mouse intestinal CD103+CD11b− DCs and expressed markers of cross-presenting DCs. CD103+Sirpα+ DCs aligned with human blood CD1c+ DCs and mouse intestinal CD103+CD11b+ DCs and supported the induction of regulatory T cells. Both CD103+ DC subsets induced the TH17 subset of helper T cells, while CD103−Sirpα+ DCs induced the TH1 subset of helper T cells. Comparative analysis of transcriptomes revealed conserved transcriptional programs among CD103+ DC subsets and identified a selective role for the transcriptional repressors Bcl-6 and Blimp-1 in the specification of CD103+CD11b− DCs and intestinal CD103+CD11b+ DCs, respectively. Our results highlight evolutionarily conserved and divergent programming of intestinal DCs.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Human SI LP DC subsets can be distinguished by their expression of CD103 and Sirpα.
Figure 2: Expression of mucosa-associated chemokine receptors and integrins by LP DCs.
Figure 3: Comparison of the transcriptomes and phenotypes of DC subsets in human gut and blood.
Figure 4: Involvement of human intestinal DC subsets in the 'education' of CD4+ T cells.
Figure 5: Transcriptomic relationship between human intestinal DC and mouse DC subsets.
Figure 6: Difference in the expression of Bcl-6 and Blimp-1 in DC subsets.
Figure 7: Bcl-6-deficient mice lack splenic CD8α+ DCs and intestinal mSP DCs.
Figure 8: Blimp-1 deficiency specifically impairs the frequency of intestinal mDP cells.

Similar content being viewed by others

Accession codes

Primary accessions

Gene Expression Omnibus

Referenced accessions

Gene Expression Omnibus

References

  1. Varol, C. et al. Intestinal lamina propria dendritic cell subsets have different origin and functions. Immunity 31, 502–512 (2009).

    Article  CAS  PubMed  Google Scholar 

  2. Bogunovic, M. et al. Origin of the lamina propria dendritic cell network. Immunity 31, 513–525 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Miller, J.C. et al. Deciphering the transcriptional network of the dendritic cell lineage. Nat. Immunol. 13, 888–899 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Helft, J., Ginhoux, F., Bogunovic, M. & Merad, M. Origin and functional heterogeneity of non-lymphoid tissue dendritic cells in mice. Immunol. Rev. 234, 55–75 (2010).

    Article  CAS  PubMed  Google Scholar 

  5. Uematsu, S. et al. Regulation of humoral and cellular gut immunity by lamina propria dendritic cells expressing Toll-like receptor 5. Nat. Immunol. 9, 769–776 (2008).

    Article  CAS  PubMed  Google Scholar 

  6. Kinnebrew, M.A. et al. Interleukin 23 production by intestinal CD103+CD11b+ dendritic cells in response to bacterial flagellin enhances mucosal innate immune defense. Immunity 36, 276–287 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Coombes, J.L. et al. A functionally specialized population of mucosal CD103+ DCs induces Foxp3+ regulatory T cells via a TGF-β and retinoic acid-dependent mechanism. J. Exp. Med. 204, 1757–1764 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Manicassamy, S. & Pulendran, B. Dendritic cell control of tolerogenic responses. Immunol. Rev. 241, 206–227 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Persson, E.K. et al. IRF4 Transcription-factor-dependent CD103CD11b dendritic cells drive mucosal T helper 17 cell differentiation. Immunity 38, 958–969 (2013).

    Article  CAS  PubMed  Google Scholar 

  10. Lewis, K.L. et al. Notch2 receptor signaling controls functional differentiation of dendritic cells in the spleen and intestine. Immunity 35, 780–791 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Poulin, L.F. et al. DNGR-1 is a specific and universal marker of mouse and human Batf3-dependent dendritic cells in lymphoid and nonlymphoid tissues. Blood 119, 6052–6062 (2012).

    Article  CAS  PubMed  Google Scholar 

  12. Haniffa, M. et al. Human tissues contain CD141hi cross-presenting dendritic cells with functional homology to mouse CD103+ nonlymphoid dendritic cells. Immunity 37, 60–73 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Villadangos, J.A. & Shortman, K. Found in translation: the human equivalent of mouse CD8+ dendritic cells. J. Exp. Med. 207, 1131–1134 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Schlitzer, A. et al. IRF4 rranscription factor-dependent CD11b dendritic cells in human and mouse control mucosal IL-17 cytokine responses. Immunity 38, 970–983 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Jaensson, E. et al. Small intestinal CD103+ dendritic cells display unique functional properties that are conserved between mice and humans. J. Exp. Med. 205, 2139–2149 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Mittag, D. et al. Human dendritic cell subsets from spleen and blood are similar in phenotype and function but modified by donor health status. J. Immunol. 186, 6207–6217 (2011).

    Article  CAS  PubMed  Google Scholar 

  17. Tamoutounour, S. et al. CD64 distinguishes macrophages from dendritic cells in the gut and reveals the Th1-inducing role of mesenteric lymph node macrophages during colitis. Eur. J. Immunol. 42, 3150–3166 (2012).

    Article  CAS  PubMed  Google Scholar 

  18. Denning, T.L. et al. Functional specializations of intestinal dendritic cell and macrophage subsets that control Th17 and regulatory T cell responses are dependent on the T cell/APC ratio, source of mouse strain, and regional localization. J. Immunol. 187, 733–747 (2011).

    Article  CAS  PubMed  Google Scholar 

  19. Baumgart, D.C. et al. Patients with active inflammatory bowel disease lack immature peripheral blood plasmacytoid and myeloid dendritic cells. Gut 54, 228–236 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Hadeiba, H. et al. CCR9 expression defines tolerogenic plasmacytoid dendritic cells able to suppress acute graft-versus-host disease. Nat. Immunol. 9, 1253–1260 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Cerovic, V. et al. Intestinal CD103− dendritic cells migrate in lymph and prime effector T cells. Mucosal Immunol. 6, 104–113 (2013).

    Article  CAS  PubMed  Google Scholar 

  22. Ito, T., Carson, W.F.t., Cavassani, K.A., Connett, J.M. & Kunkel, S.L. CCR6 as a mediator of immunity in the lung and gut. Exp. Cell Res. 317, 613–619 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Jang, M.H. et al. CCR7 is critically important for migration of dendritic cells in intestinal lamina propria to mesenteric lymph nodes. J. Immunol. 176, 803–810 (2006).

    Article  CAS  PubMed  Google Scholar 

  24. Takeuchi, A. et al. CRTAM confers late-stage activation of CD8+ T cells to regulate retention within lymph node. J. Immunol. 183, 4220–4228 (2009).

    Article  CAS  PubMed  Google Scholar 

  25. Kobayashi, K.S. & van den Elsen, P.J. NLRC5: a key regulator of MHC class I-dependent immune responses. Nat. Rev. Immunol. 12, 813–820 (2012).

    Article  CAS  PubMed  Google Scholar 

  26. Bouloc, A., Bagot, M., Delaire, S., Bensussan, A. & Boumsell, L. Triggering CD101 molecule on human cutaneous dendritic cells inhibits T cell proliferation via IL-10 production. Eur. J. Immunol. 30, 3132–3139 (2000).

    Article  CAS  PubMed  Google Scholar 

  27. Huber, S. et al. IL-22BP is regulated by the inflammasome and modulates tumorigenesis in the intestine. Nature 491, 259–263 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Sonnenberg, G.F., Fouser, L.A. & Artis, D. Border patrol: regulation of immunity, inflammation and tissue homeostasis at barrier surfaces by IL-22. Nat. Immunol. 12, 383–390 (2011).

    Article  CAS  PubMed  Google Scholar 

  29. Bakri, Y. et al. Balance of MafB and PU.1 specifies alternative macrophage or dendritic cell fate. Blood 105, 2707–2716 (2005).

    Article  CAS  PubMed  Google Scholar 

  30. Liu, W. et al. CD127 expression inversely correlates with FoxP3 and suppressive function of human CD4+ T reg cells. J. Exp. Med. 203, 1701–1711 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Mora, J.R. Homing imprinting and immunomodulation in the gut: role of dendritic cells and retinoids. Inflamm. Bowel Dis. 14, 275–289 (2008).

    Article  PubMed  Google Scholar 

  32. Ivanov, I.I. et al. Induction of intestinal Th17 cells by segmented filamentous bacteria. Cell 139, 485–498 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Atarashi, K. et al. ATP drives lamina propria TH17 cell differentiation. Nature 455, 808–812 (2008).

    Article  CAS  PubMed  Google Scholar 

  34. Rivollier, A., He, J., Kole, A., Valatas, V. & Kelsall, B.L. Inflammation switches the differentiation program of Ly6Chi monocytes from antiinflammatory macrophages to inflammatory dendritic cells in the colon. J. Exp. Med. 209, 139–155 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Dent, A.L., Shaffer, A.L., Yu, X., Allman, D. & Staudt, L.M. Control of inflammation, cytokine expression, and germinal center formation by BCL-6. Science 276, 589–592 (1997).

    Article  CAS  PubMed  Google Scholar 

  36. Johnston, R.J. et al. Bcl6 and Blimp-1 are reciprocal and antagonistic regulators of T follicular helper cell differentiation. Science 325, 1006–1010 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Crotty, S., Johnston, R.J. & Schoenberger, S.P. Effectors and memories: Bcl-6 and Blimp-1 in T and B lymphocyte differentiation. Nat. Immunol. 11, 114–120 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Miller, J.C. et al. Deciphering the transcriptional network of the dendritic cell lineage. Nat. Immunol. 13, 888–899 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Kim, S.J., Zou, Y.R., Goldstein, J., Reizis, B. & Diamond, B. Tolerogenic function of Blimp-1 in dendritic cells. J. Exp. Med. 208, 2193–2199 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Sancho, D. et al. Identification of a dendritic cell receptor that couples sensing of necrosis to immunity. Nature 458, 899–903 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Dorner, B.G. et al. Selective expression of the chemokine receptor XCR1 on cross-presenting dendritic cells determines cooperation with CD8+ T cells. Immunity 31, 823–833 (2009).

    Article  CAS  PubMed  Google Scholar 

  42. Galibert, L. et al. Nectin-like protein 2 defines a subset of T-cell zone dendritic cells and is a ligand for class-I-restricted T-cell-associated molecule. J. Biol. Chem. 280, 21955–21964 (2005).

    Article  CAS  PubMed  Google Scholar 

  43. Yeh, J.H., Sidhu, S.S. & Chan, A.C. Regulation of a late phase of T cell polarity and effector functions by Crtam. Cell 132, 846–859 (2008).

    Article  CAS  PubMed  Google Scholar 

  44. Sigmundsdottir, H. & Butcher, E.C. Environmental cues, dendritic cells and the programming of tissue-selective lymphocyte trafficking. Nat. Immunol. 9, 981–987 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Fujikado, N. et al. Dcir deficiency causes development of autoimmune diseases in mice due to excess expansion of dendritic cells. Nat. Med. 14, 176–180 (2008).

    Article  CAS  PubMed  Google Scholar 

  46. Smythies, L.E. et al. Human intestinal macrophages display profound inflammatory anergy despite avid phagocytic and bacteriocidal activity. J. Clin. Invest. 115, 66–75 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Ohtsuka, H. et al. Bcl6 is required for the development of mouse CD4+ and CD8α+ dendritic cells. J. Immunol. 186, 255–263 (2011).

    Article  CAS  PubMed  Google Scholar 

  48. Milling, S., Yrlid, U., Cerovic, V. & MacPherson, G. Subsets of migrating intestinal dendritic cells. Immunol. Rev. 234, 259–267 (2010).

    Article  CAS  PubMed  Google Scholar 

  49. Bull, D.M. & Bookman, M.A. Isolation and functional characterization of human intestinal mucosal lymphoid cells. J. Clin. Invest. 59, 966–974 (1977).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Zeng, R. et al. Retinoic acid regulates the development of a gut-homing precursor for intestinal dendritic cells. Mucosal Immunol. 6, 847–856 (2013).

    Article  CAS  PubMed  Google Scholar 

  51. Kitano, M. et al. Bcl6 protein expression shapes pre-germinal center B cell dynamics and follicular helper T cell heterogeneity. Immunity 34, 961–972 (2011).

    Article  CAS  PubMed  Google Scholar 

  52. Rutishauser, R.L. et al. Transcriptional repressor Blimp-1 promotes CD8+ T cell terminal differentiation and represses the acquisition of central memory T cell properties. Immunity 31, 296–308 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Suzuki, R. & Shimodaira, H. Pvclust: an R package for assessing the uncertainty in hierarchical clustering. Bioinformatics 22, 1540–1542 (2006).

    CAS  PubMed  Google Scholar 

Download references

Acknowledgements

We thank T. Okada (RIKEN, Japan) for YFP–Bcl-6 mice52; E. Meffre (Yale University) for Blimp-1–YFP mice53; J. Sweere and H. Kiefel for critical reading of the manuscript; L. Rott for assistance with flow cytometry and cell sorting; E. Resurreccion for assistance with immunohistochemistry; K. Bhat for writing Python scripts; all members of the Butcher laboratory for discussions; and the Immunological Genome Project and the Merad laboratory (Mount Sinai School of Medicine) for generating the publicly available microarray data of sorted mouse intestinal DC. Supported by the US National Institutes of Health (R01 AI093981, R01 DK084647 and R37 AI047822 to E.C.B.; 5T32AI007290-25 to M.L.; K01 AR59378 to S.J.K.; and AI07290 to H.H.), the US Department of Veterans Affairs (E.C.B.), the Digestive Disease Center of Stanford University (under P30 DK056339), the German Research Foundation (K.L.), the Crohn's and Colitis Foundation of America (K.L. and M.L.), The Stanford Institute for Immunity, Transplantation and Infection (K.L.), the Agency for Science, Technology And Research of Singapore (R.Z.), the Swiss National Science Foundation (PBBEP3-133516 to D.B.), the Swiss Foundation for Grants in Biology and Medicine (PASMP3-142725 to D.B.), the Leukemia & Lymphoma Society (K.M.A.), the California Institute for Regenerative Medicine (H.H.) and the Arthritis Foundation (H.H.).

Author information

Author notes

  1. Payal B Watchmaker and Katharina Lahl: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Pathology, Laboratory of Immunology and Vascular Biology, Stanford University School of Medicine, Stanford, California, USA

    Payal B Watchmaker, Katharina Lahl, Mike Lee, Ruizhu Zeng & Eugene C Butcher

  2. The Center for Molecular Biology and Medicine, Veterans Affairs Palo Alto Health Care System, Palo Alto, California, USA

    Payal B Watchmaker, Katharina Lahl, Mike Lee, Ruizhu Zeng, Husein Hadeiba & Eugene C Butcher

  3. Department of Microbiology and Immunology, Sandler Asthma Basic Research Center, University of California San Francisco, San Francisco, California, USA

    Dirk Baumjohann & K Mark Ansel

  4. Department of Surgery, Stanford University School of Medicine, Stanford, California, USA

    John Morton

  5. Center for Autoimmune and Musculoskeletal Diseases, the Feinstein Institute for Medical Research, Manhasset, New York, USA

    Sun Jung Kim & Betty Diamond

  6. Department of Microbiology and Immunology, Indiana University School of Medicine, Indianapolis, Indiana, USA

    Alexander Dent

  7. Palo Alto Institute for Research & Education, Palo Alto, California, USA

    Husein Hadeiba & Eugene C Butcher

Authors
  1. Payal B Watchmaker
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Katharina Lahl
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Mike Lee
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Dirk Baumjohann
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. John Morton
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Sun Jung Kim
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Ruizhu Zeng
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Alexander Dent
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. K Mark Ansel
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Betty Diamond
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Husein Hadeiba
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Eugene C Butcher
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

P.B.W. designed and did human DC experiments, including microarrays, analyzed gene expression and wrote the manuscript; K.L. designed and did all mouse experiments, analyzed gene expression and wrote the manuscript; M.L. prepared RNA and did quality control for microarray studies; D.B. provided YFP–Bcl-6 and Blimp-1–YFP mice and helped to design and to do the experiments; J.M. provided human tissue; S.J.K. designed and did experiments with mice with DC-specific Blimp-1 deficiency; R.Z. helped with YFP–Bcl-6 experiments; A.D. provided Bcl6−/− mice and feedback; K.M.A. provided feedback and YFP–Bcl-6 and Blimp-1–YFP mice; B.D. provided mice with DC-specific Blimp-1 deficiency; H.H. drove the initial interest and provided advice; and E.C.B. analyzed gene expression, guided the study and wrote the manuscript.

Corresponding author

Correspondence to Katharina Lahl.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Integrated supplementary information

Supplementary Figure 1 Gating strategy for human intestinal DC subsets.

Lamina propria mononuclear cells obtained from jejunal tissue sections were stained for live/dead viability marker, CD45, lineage markers (CD3, CD14, CD16, CD56, CD19), HLADR, CD11c, CD123. Phenotypic Analysis of CD11c+ DC was done by successive gating on live CD45+ population and then the HLADR+ lineage− population.

Supplementary Figure 2 Absence of canonical macrophage marker expression on CD103−Sirpα+ DCs.

a) Expression of CD64 and on CD14+ lamina propria macrophages (open black histograms) and CD103−Sirpα+ DCs (black dashed lines). b) Expression of CX3CR1 (same as in a)).

Supplementary Figure 3 Frequency of total cDCs of gut CD103+Sirpα+ (hDP), CD103+Sirpα− (hSP), and CD103−Sirpα+ DC subets in human small intestine and colon.

Supplementary Figure 4 Pairwise comparison of gene expression profiles of gut DC subsets with blood and skin CD1c+ and CD141+ DCs, skin CD14+ DCs and blood CD14+ monocytes.

Pearson correlation of expression profiles using the same genes as in Fig. 3a. In the comparison of CD103+Sirpα+ (hDP) DCs with blood and skin CD1c+, the individual samples with solid and open symbols correlate significantly (p≤0.001, ANOVA) with blood CD1c+ or with skin CD1c+ DCs, respectively

Supplementary Figure 5 Classification of DCs vs macrophages.

a) CD4 T cell proliferation in allogeneic cultures of responder T cells stimulated by the indicated subsets. b) Gene Expression values of MafB and Spi1 and their ratio in gut and blood DC subsets and tissue macrophages. Dataset for tissue macrophages was obtained from GSE40484.

Supplementary Figure 6 Model of mixed bone marrow chimera setup.

Supplementary information

Supplementary Text and Figures

Supplementary Figures 1–6 and Supplementary Table 3 (PDF 492 kb)

Supplementary Table 1

Gene list to accompany Figure 3. (XLSX 235 kb)

Supplementary Table 2

Gene list to accompany Figure 5. (XLSX 127 kb)

Rights and permissions

Reprints and permissions

About this article

Cite this article

Watchmaker, P., Lahl, K., Lee, M. et al. Comparative transcriptional and functional profiling defines conserved programs of intestinal DC differentiation in humans and mice. Nat Immunol 15, 98–108 (2014). https://doi.org/10.1038/ni.2768

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/ni.2768

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing