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.

  • Technical Report
  • Published:

Humanized mice mount specific adaptive and innate immune responses to EBV and TSST-1

Nature Medicine volume 12, pages 1316–1322 (2006)Cite this article

Abstract

Here we show that transplantation of autologous human hematopoietic fetal liver CD34+ cells into NOD/SCID mice previously implanted with human fetal thymic and liver tissues results in long-term, systemic human T-cell homeostasis. In addition, these mice show systemic repopulation with human B cells, monocytes and macrophages, and dendritic cells (DCs). T cells in these mice generate human major histocompatibility complex class I– and class II–restricted adaptive immune responses to Epstein-Barr virus (EBV) infection and are activated by human DCs to mount a potent T-cell immune response to superantigens. Administration of the superantigen toxic shock syndrome toxin 1 (TSST-1) results in the specific systemic expansion of human Vβ2+ T cells, release of human proinflammatory cytokines and localized, specific activation and maturation of human CD11c+ dendritic cells. This represents the first demonstration of long-term systemic human T-cell reconstitution in vivo allowing for the manifestation of the differential response by human DCs to TSST-1.

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 reconstitution of NOD/SCID-hu thy-liv mice transplanted with autologous human hematopoietic stem cells.
Figure 2: Human hematopoietic cells in BLT mice.
Figure 3: Human thymopoiesis and Vβ T-cell diversity in BLT mice.
Figure 4: Analysis of the human T-cell adaptive immune response to EBV infection in BLT mice.
Figure 5: Innate immune response to TSST-1.

Similar content being viewed by others

References

  1. Greiner, D.L., Hesselton, R.A. & Shultz, L.D. SCID mouse models of human stem cell engraftment. Stem Cells 16, 166–177 (1998).

    Article  CAS  Google Scholar 

  2. Bente, D.A., Melkus, M.W., Garcia, J.V. & Rico-Hesse, R. Dengue fever in humanized NOD/SCID mice. J. Virol. 79, 13797–13799 (2005).

    Article  CAS  Google Scholar 

  3. Cravens, P.D. et al. Development and activation of human dendritic cells in vivo in a xenograft model of human hematopoiesis. Stem Cells 23, 264–278 (2005).

    Article  Google Scholar 

  4. Palucka, A.K. et al. Human dendritic cell subsets in NOD/SCID mice engrafted with CD34+ hematopoietic progenitors. Blood 102, 3302–3310 (2003).

    Article  CAS  Google Scholar 

  5. Islas-Ohlmayer, M. et al. Experimental infection of NOD/SCID mice reconstituted with human CD34+ cells with Epstein-Barr virus. J. Virol. 78, 13891–13900 (2004).

    Article  CAS  Google Scholar 

  6. Aldrovandi, G.M. et al. The SCID-hu mouse as a model for HIV-1 infection. Nature 363, 732–736 (1993).

    Article  CAS  Google Scholar 

  7. McCune, J.M. et al. The SCID-hu mouse: murine model for the analysis of human hematolymphoid differentiation and function. Science 241, 1632–1639 (1988).

    Article  CAS  Google Scholar 

  8. Vandekerckhove, B.A. et al. Clonal analysis of the peripheral T cell compartment of the SCID-hu mouse. J. Immunol. 146, 4173–4179 (1991).

    CAS  PubMed  Google Scholar 

  9. Akkina, R.K., Rosenblatt, J.D., Campbell, A.G., Chen, I.S. & Zack, J.A. Modeling human lymphoid precursor cell gene therapy in the SCID-hu mouse. Blood 84, 1393–1398 (1994).

    CAS  PubMed  Google Scholar 

  10. An, D.S. et al. High-efficiency transduction of human lymphoid progenitor cells and expression in differentiated T cells. J. Virol. 71, 1397–1404 (1997).

    CAS  PubMed  PubMed Central  Google Scholar 

  11. Roos, M.T. et al. Changes in the composition of circulating CD8+ T cell subsets during acute Epstein-Barr and human immunodeficiency virus infections in humans. J. Infect. Dis. 182, 451–458 (2000).

    Article  CAS  Google Scholar 

  12. Dinges, M.M., Orwin, P.M. & Schlievert, P.M. Exotoxins of Staphylococcus aureus. Clin. Microbiol. Rev. 13, 16–34 (2000).

    Article  CAS  Google Scholar 

  13. Makida, R., Hofer, M.F., Takase, K., Cambier, J.C. & Leung, D.Y. Bacterial superantigens induce Vβ-specific T cell receptor internalization. Mol. Immunol. 33, 891–900 (1996).

    Article  CAS  Google Scholar 

  14. Kum, W.W., Cameron, S.B., Hung, R.W., Kalyan, S. & Chow, A.W. Temporal sequence and kinetics of proinflammatory and anti-inflammatory cytokine secretion induced by toxic shock syndrome toxin 1 in human peripheral blood mononuclear cells. Infect. Immun. 69, 7544–7549 (2001).

    Article  CAS  Google Scholar 

  15. Karp, D.R., Teletski, C.L., Scholl, P., Geha, R. & Long, E.O. The α1 domain of the HLA-DR molecule is essential for high-affinity binding of the toxic shock syndrome toxin-1. Nature 346, 474–476 (1990).

    Article  CAS  Google Scholar 

  16. Traggiai, E. et al. Development of a human adaptive immune system in cord blood cell-transplanted mice. Science 304, 104–107 (2004).

    Article  CAS  Google Scholar 

  17. Gimeno, R. et al. Monitoring the effect of gene silencing by RNA interference in human CD34+ cells injected into newborn RAG2−/− γc−/− mice: functional inactivation of p53 in developing T cells. Blood 104, 3886–3893 (2004).

    Article  CAS  Google Scholar 

  18. Ishikawa, F. et al. Development of functional human blood and immune systems in NOD/SCID/IL2 receptor γ chainnull mice. Blood 106, 1565–1573 (2005).

    Article  CAS  Google Scholar 

  19. Shultz, L.D. et al. Human lymphoid and myeloid cell development in NOD/LtSz-scid IL2Rγnull mice engrafted with mobilized human hemopoietic stem cells. J. Immunol. 174, 6477–6489 (2005).

    Article  CAS  Google Scholar 

  20. Ito, M. et al. NOD/SCID/γcnull mouse: an excellent recipient mouse model for engraftment of human cells. Blood 100, 3175–3182 (2002).

    Article  CAS  Google Scholar 

  21. Yahata, T. et al. Functional human T lymphocyte development from cord blood CD34+ cells in nonobese diabetic/Shi-scid, IL-2 receptor γ null mice. J. Immunol. 169, 204–209 (2002).

    Article  CAS  Google Scholar 

  22. Gatlin, J., Padgett, A., Melkus, M.W., Kelly, P.F. & Garcia, J.V. Long-term engraftment of nonobese diabetic/severe combined immunodeficient mice with human CD34+ cells transduced by a self-inactivating human immunodeficiency virus type 1 vector. Hum. Gene Ther. 12, 1079–1089 (2001).

    Article  CAS  Google Scholar 

  23. Gatlin, J., Melkus, M.W., Padgett, A., Kelly, P.F. & Garcia, J.V. Engraftment of NOD/SCID mice with human CD34+ cells transduced by concentrated oncoretroviral vector particles pseudotyped with the feline endogenous retrovirus (RD114) envelope protein. J. Virol. 75, 9995–9999 (2001).

    Article  CAS  Google Scholar 

  24. Estes, J.D. et al. Premature induction of an immunosuppressive regulatory T cell response during acute simian immunodeficiency virus infection. J. Infect. Dis. 193, 703–712 (2006).

    Article  CAS  Google Scholar 

  25. Heslop, H.E. et al. Long-term restoration of immunity against Epstein-Barr virus infection by adoptive transfer of gene-modified virus-specific T lymphocytes. Nat. Med. 2, 551–555 (1996).

    Article  CAS  Google Scholar 

Download references

Acknowledgements

The authors thank M. Islas-Ohlmayer, P. Cravens, M.P. Martin, Z. Sun, A. Curry, S. O'Reilly and R. Getachew for their participation in this study, for the cytokine assay and for assistance with animal care. We thank J. Sixbey for the stock of Akata virus, A. Leen and C. Rooney for their assistance with the establishment of the LCLs and the ELISPOT analysis, K. Hamra and D. Garbers for use of their dissecting microscope and assistance collecting the ELISPOT images, M. Bennett, D. Douek, L. Picker, L. Schultz and J. McCune for their support and contribution to the early stages of this project, J. Tew and M. Kosco-Vilbois for advice and expert discussion regarding the organization of secondary lymphoid tissues, and D. Autry for graphic art assistance. Cord blood samples were provided by the Department of Obstetrics and Gynecology's Tissue Procurement Facility of the University of Texas Southwestern Medical Center at Dallas (US National Institutes of Health (NIH) grant HD011149). This work was supported in part by NIH grants R37 AI028246 (A.T.H.), CA82055 and AI39416 (J.V.G.) and training grants 5T32 AI005284 (P.W.D.) and T32 AI07421 (J.D.E.).

Author information

Authors and Affiliations

  1. Department of Internal Medicine, Division of Infectious Diseases, University of Texas Southwestern Medical Center at Dallas, Dallas, 75390, Texas, USA

    Michael W Melkus, Angela Padgett-Thomas, Paul W Denton, Florence A Othieno, Anja K Wege & J Victor Garcia

  2. Department of Microbiology, Medical School, University of Minnesota, MMC 196, 420 Delaware Street S.E., Minneapolis, 55455, Minnesota, USA

    Jacob D Estes & Ashley T Haase

  3. Arena Pharmaceuticals Inc., 6161 Nancy Ridge Drive, San Diego, 92121, California, USA

    Joel Gatlin

Authors
  1. Michael W Melkus
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Jacob D Estes
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Angela Padgett-Thomas
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Joel Gatlin
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Paul W Denton
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Florence A Othieno
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Anja K Wege
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Ashley T Haase
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. J Victor Garcia
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to J Victor Garcia.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Supplementary information

Supplementary Fig. 1

Immunohistological staining for human CD45+ cells and lineage-specific hematopoietic markers in BLT liver compared to human liver. (PDF 145 kb)

Supplementary Fig. 2

Analysis of EGFP expression in different hematopoietic cell subsets after transplantation with CD34+ cells transduced with a lentivirus-based vector. (PDF 100 kb)

Supplementary Fig. 3

Immunohistological analysis of secondary lymhoid tissues of BLT mice. (PDF 214 kb)

Supplementary Fig. 4

Spleen CD123+ human DCs do not respond to TSST-1. (PDF 65 kb)

Supplementary Table 1

Analysis of human CD4+ and CD8+ T cells in different tissues from BLT mice. (PDF 38 kb)

Supplementary Table 2

Naive versus memory phenotype of human peripheral blood T cells in BLT mice. (PDF 31 kb)

Supplementary Methods (PDF 95 kb)

Rights and permissions

Reprints and permissions

About this article

Cite this article

Melkus, M., Estes, J., Padgett-Thomas, A. et al. Humanized mice mount specific adaptive and innate immune responses to EBV and TSST-1. Nat Med 12, 1316–1322 (2006). https://doi.org/10.1038/nm1431

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nm1431

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